bluuebunny/crossref_metadata_2025 huggingface dataset:
CaMKIIα signaling is required for the neuroprotective effects of Dl‐3‐n‐butylphthalide in Alzheimer’s disease
Authors: Li Bingqiu , Xu LingZhi , Jia Jianping
Published: June 2023

Background

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and most anti‐AD drugs have failed in clinical trials, hence it is urgent to find effective potential drugs against AD. DL‐3‐n‐Butylphthalide (NBP) is a compound extracted from celery seed and is a multiple‐target drug, and we have demonstrated NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety. Even though there are several studies that have demonstrated the neuroprotective effects of NBP on cognitive impairment, and the mechanisms of NBP remains relatively unexplored.

Method

Cell viabilities was observed by MTT. Apoptosis and the level of intracellular Ca2+ were examined by flow cytometry. The activation of CaMKIIα signaling was detected by western blotting and immunofluorescence.

Result

In this study, we found that NBP could alleviated the increase of intracellular Ca2+ and reverse down‐regulation of Ca2+/calmodulin‐dependent protein kinase alpha (CaMKIIα) signaling, and rescue neuronal apoptosis in SH‐SY5Y cells treated by Aβ oligomers. Further, we found that these neuroprotection of NBP on neuronal damage and CaMKIIα signaling were abolished when CaMKIIα expression was knock‐downed or its activity was inhibited.

Conclusion

Thus, our findings suggested that CaMKIIα signaling was required for the neuroprotective effects of NBP in AD, and provide an improved basis for elucidation of the mechanism and treatment of NBP in AD.
Comparison of manual dexterity of people with Alzheimer’s disease and cognitively healthy older adults: The impact of cognition
Authors: Menengiç Kübra Nur , Ovacık Uğur , Güngör Feray , Çınar Nilgün , Yeldan İpek
Published: June 2023

Background

Alzheimer’s disease (AD) not only effects the cognitive level, but also leads to significant decline in motor skill. Manual dexterity emerges with the interaction of cognitive and motor processes and is seen as an important predictor of functional independence. The aim of this study was to compare manual dexterity in people with AD with healthy older adults and to investigate the effect of cognitive level on manual dexterity.

Method

The Nine Hole Peg Test (NHPT) was used for manual dexterity assessment. Cognitive function were assessed with Montreal Cognitive Assessment (MoCA). Statistical analysis was performed by Mann Whitney U Test and regression analysis in SPSS 22.0 package program.

Result

Twenty nine people with AD (78.04±6.49, 48.27% female) and ten cognitively healthy older adult (74.8±7.22, 30% female) included study. NHPT results of the dominant hand were 31.87±7.33 sec. and 21.66±2.85 sec.; MoCA scores were 13.79±5.76 and 24.5±2.32, respectively, in the people with AD and cognitively healthy older adults. There was significant difference in NHPT results between groups (p<.001). Significant correlation was found between NHPT and MoCA (p<.001, r = .648). It was found that cognitive level significantly predicted manual dexterity (β = .648, R2 = .42, F [1,27] = 19.58, p<.001).

Conclusion

Manual dexterity in AD shows a significant decrease compared to the cognitively healthy older adults. In our study, it was shown that the decrease in manual dexterity occurs with the effect of cognition at a rate of 42%. Deteriorating manual dexterity with decreased cognition is likely to accelerate patients' withdrawal from activities of daily living. Also, rehabilitation programs that include activities for manual dexterity may slow down the process of participation restriction in AD.
Analysis of Interaction Characteristics Between Amyloid β and Lecanemab by HDX‐MS
Authors: Yamauchi Emiko , Kimura Ayano , Hagiwara Koji
Published: June 2023

Background

Soluble amyloid‐β (Aβ) aggregates including protofibrils (PFs) have been reported to be more toxic than insoluble fibrils. Recently, pharmaceutical antibodies targeting these soluble Aβ aggregates have been developed. The structural dynamics and heterogeneity of soluble Aβ aggregates have made it difficult to analyze the structural characteristics and tertiary structure. To investigate conformational recognition of lecanemab to Aβ aggregates, the structural characteristics of Aβ PFs and their change upon binding to lecanemab, an antibody with preferential binding to Aβ protofibrils, were studied using hydrogen‐deuterium exchange mass spectrometry (HDX‐MS).

Method

Aβ (1‐42) PFs were prepared in vitro. The hydrogen/deuterium (H/D) exchange status for Aβ (1‐42) PFs and monomeric Aβ (1‐40) were studied by HDX‐MS in phosphate buffered saline (PBS) to explore characteristics of their regional structural dynamics. The effects of the anti–Aβ PF antibody lecanemab on H/D status of Aβ (1‐42) PFs and monomeric Aβ (1‐40) were studied to explore the structural basis for the characteristics of antibody‐ Aβ interaction and specificity against Aβ PFs.

Result

Aβ (1‐42) PFs were more protected from H/D exchange throughout the molecule than monomeric Aβ (1‐40), though the N‐terminal and the mid region of Aβ still showed relatively higher H/D exchange in Aβ (1‐42) PFs. Upon interaction with lecanemab, the mid region of Aβ (1‐42) PFs was also protected further in addition to the N‐terminal region, and its protection level of Aβ (1‐42) PFs was higher than monomeric Aβ (1‐40). The higher protection from H/D exchange both on N‐terminal and mid regions of Aβ PFs is considered to be characteristics of interaction between Aβ (1‐42) PFs and lecanemab.

Conclusion

The results indicate that the mid region of Aβ has relatively high flexibility in PFs in addition to N‐terminal region. The mid region is suggested to be involved in the interaction with lecanemab as well as its N‐terminal region, and the conformational epitope formation was expected, though there are still possibility of structural change in the mid region upon lecanemab binding. The results indicated that the combinational action on the N‐terminal and mid regions of Aβ are involved in the modulation of Aβ PFs by lecanemab.
A transcriptome association study of AD risk genes in the pathogenesis of Alzheimer’s disease
Authors: McCorkindale Andrew N , Guennewig Boris , Eteleeb Abdallah M , Harari Oscar , Sutherland Greg T
Published: June 2023

Background

Alzheimer’s disease (AD) affects millions of people with no effective treatments making it vital to identify potential therapeutic targets. Genome‐wide association studies (GWAS) have consistently identified AD susceptibility loci or ‘hits’. Few of these are differentially expressed in brain transcriptomic studies, meaning that their effects may be manifest via interacting or downstream transcripts. We have recently used machine learning on human brain transcriptomic data to identify and validate an association between lactoferrin and amyloid (1). Here we apply the same method to identify the transcripts associated with AD susceptibility ‘loci’.

Method

Analyses were performed on the disease‐linked genes from our machine learning analyses (LTF, ADAMTS2, PPDPF, PRTN3) and the combined 58 GWAS risk loci from two recent studies (2, 3). Boruta was used to find transcripts associated with each GWAS ‘hit’ and our genes of interest in two pathologically confirmed AD cohorts (Religious Orders Study and Memory and Aging project, Mount Sinai Brain Bank). The GWAS hits and associated transcripts were correlated with disease markers (cognition, plaque number, Braak score, CERAD score) to find direct and indirect effects.

Results

TREM2 was the GWAS ‘hit’ most correlated with disease markers in both cohorts but most GWAS ‘hits’ were either not correlated or negatively correlated with disease markers. Among the GWAS ‘hit’‐associated transcripts, SWAP70, EMP3, and WWTR1 were positively and VGF negatively correlated with disease markers in both cohorts. For our genes of interest, ADAMTS2 and PPDPF shared overlaps between their associated transcripts and that of GWAS ‘hit’ ABCA7. LTF was linked with TREM2 and associated with plaques in both cohorts.

Conclusion

This study has teased apart nascent associations between known susceptibility genes and gene expression data from the AD brain, but it also hints that consideration of pathological sub‐phenotypes are required to make greater progress in understanding AD pathogenesis.

1. Tsatsanis et al. The acute phase protein lactoferrin is a key feature of AD …. Mol Psychiatry. 2021;26(10):5516‐31.

2. Yang et al. A human brain vascular atlas reveals diverse cell mediators of AD risk. BioRxiv [Preprint]. 2021.

3. Wightman et al. A GWAS with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276‐82.
Deletions/duplications in GRN and MAPT genes is not common in frontotemporal dementia
Authors: Shpilyukova Yuliya , Abramycheva Natalya , Grishina Dinara , Fedotova Ekaterina , Illarioshkin Sergey
Published: June 2023

Background

Frontotemporal dementia (FTD) is an umbrella term for several syndromes with behavioural and/or language symptoms. Mutations in GRN and MAPT genes are the most frequent genetic cause of FTD in different populations. Our previous data indicate that the frequency of mutations in GRN gene is up to 12.5% in familial FTD cases in Russian cohort of patients. Mutations in MAPT gene were absent in the same cohort. According to the literature, not only point mutation in these genes, but also deletions/duplications can be the genetic cause of FTD.

Method

We analyzed DNA from 50 patients with clinical diagnosis of behavioural variant of FTD, bvFTD (N = 33) and primary progressive aphasia, PPA (N = 17), picture 1. There were 26 familial and 24 sporadic FTD cases. Exon rearrangements were analyzed by MLPA method (SALSA MLPA P275‐C3, MRC‐Holland, Netherlands) using standard protocol. PCR products were separated by size with capillary electrophoresis using genetic analyzer Nanofor 5 (Syntol, Russia). The analysis of result was performed with GeneMarker V3.0.1.

Result

We did not find any deletion or duplication of exons in the GRN and MAPT genes. The results may indicate that this type of mutation is not common in Russian patients with FTD.

Conclusion

In 2017‐2021, we identified several point mutations in GRN in Russian patients with FTD; here we show that exon rearrangements in GRN and MAPT genes are not frequent in Russia. According to the literature, only 1.5% of individuals with GRN‐associated forms have deletion or duplication in GRN gene. The data about exon rearrangements in MAPT gene are absent. However, in the case of typical clinical phenotype of GRN‐ or MAPT‐associated form of FTD, MLPA analysis can be recommended.
Chronic brain changes caused by severe systemic inflammatory episode
Authors: da Silva Eduarda J.F. , Bellaver Bruna , da Rocha Andreia Silva , Ferreira Pamela C.L. , Da Ros Lucas Uglione , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Souza Diogo O. , Zimmer Eduardo R.
Published: June 2023

Background

Sepsis‐associated encephalopathy (SAS) is a neurological complication of a severe systemic inflammatory episode that compromises brain function. This neurological impairment can lead to cognitive dysfunction that appears to precede neurodegenerative disorders such as Alzheimer’s disease. However, the events by which systemic inflammation causes such significant damage to the brain are not yet fully established. With that in mind, this study sought to investigate persistent brain changes after a severe systemic inflammatory episode.

Method

Male Wistar rats (90 days old) were divided into two experimental groups: sham (n = 33) and sepsis (n = 37). For the induction of severe systemic inflammation, the animals underwent cecal ligation and perforation (CLP). Animals were followed for 30, 60 and 120 days. In all time‐points, we performed the object recognition task to evaluate declarative memory and Western Blotting to assess astrocyte‐related proteins (GFAP, GLT‐1 and Mao‐B). At 30 and 120 days, we evaluated the ΒBB integrity [cerebrospinal fluid (CSF) albumin levels and cellularity by HCLP] and brain glucose metabolism (FDG‐PET imaging).

Result

Our results show that CLP model compromised long‐term memory at 60 and 120 days. Furthermore, we found higher levels of albumin in the CSF in CLP animals compared to sham at 30 (p = 0.023) and 120 days post‐sepsis (p = 0.002). In addition, we also observed an increase in CSF cellularity in CLP animals after 30 days after sepsis induction. We also found persistent glucose whole brain hypometabolism at 30 (local maxima, t(12) = ‐3.7) and 120 days (local maxima, t(9) = ‐8.45), suggesting persistent metabolic abnormalities. Finally, we observed changes in astrocyte‐related proteins. At 30 days, hippocampal GLT‐1 (p<0.001) and cortical GFAP (p < 0.0001) immunocontents were reduced in CLP rats compared to sham. At 60 days, we observed decreased hippocampal GFAP (p < 0,05) and MAO‐B (p < 0.01) immunocontents. At 120 days, we found decreased MAO‐B in the hippocampus (p<0.05).

Conclusion

We found that a severe systemic inflammation episode causes persistent changes in brain glucose metabolism and BBB integrity, which seems associated with long‐term memory impairment. In addition, astrocytes seem to be reacting by changing their protein expression, a typical feature of reactive astrocytes.
Relevance of plasma biomarkers to imaging biomarkers
Authors: Nakamura Akinori , Tokuda Takahiko , Kaneko Naoki , Kato Takashi , Tatebe Harutsugu , Nihashi Takashi , Sakurai Keita , Takeda Akinori , Arahata Yutaka , Ito Kengo ,   BATON study group
Published: June 2023

Background

Recent advances in blood‐based biomarkers have shown promising abilities to estimate brain pathological statuses related to amyloid‐β (Aβ) deposition, phosphorylated tau deposition, and neurodegeneration using minimally invasive methods. The objective of this study was to evaluate the potential of blood‐based ATN classification, by analyzing relevance of plasma biomarkers to imaging biomarkers.

Method

There were 161 subjects, consisting of 62 cognitively normal (CN), 13 MCI, 40 Alzheimer’s dementia (AD) and 46 non‐Alzheimer’s dementia (non‐AD) individuals. Plasma Aβ composite biomarker was measured using immunoprecipitation‐mass spectrometry assay by combining plasma ratios of APP669‐711/Aβ1‐42 and Aβ1‐40/Aβ1‐42. Plasma levels of p‐tau 181, glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were measured using the SimoaⓇ platform. PiB‐PET, THK5351‐PET, FDG‐PET and structural MRI images, and their representative semiquantitative values; PiB‐SUVR, THK‐SUVR, FDG‐PET scores (representing the degree of AD‐like glucose hypometabolism), and VSRAD® scores (representing the degree of medial temporal atrophy), respectively, were used to analyze the relationships with the plasma biomarkers.

Result

The ROC analyses showed that AUCs of plasma Aβ composite, p‐tau 181, GFAP and NfL to discriminate Aβ status (PiB‐positive vs. negative) were 0.934, 0.835, 0.720 and 0.583, respectively. Whereas AUCs of those to discriminate clinical status (CN/MCI vs. dementia) were 0.649, 0.655, 0.800 and 0.803, respectively. Correlations to PiB‐SUVR were stronger in Aβ composite (r = 0.657) and p‐tau 181 (r = 0.551). Both p‐tau and GFAP showed higher correlations to THK‐SUVR (r = 0.444 and 0.416, respectively), and to FDG‐PET scores (r = 0.533 and 0.541, respectively) compared with other biomarkers. Correlations to VSRAD scores were only significant in NfL (r = 0.319). NfL also showed the highest correlation to MMSE scores (r = ‐0.583) (all the above r values were p < 0.001). These results were supported by multiple regression analyses between each imaging data and each plasma biomarker values using SPM8 adjusting for age and sex.

Conclusion

The results demonstrated reasonable relationships between the plasma biomarkers and imaging biomarkers, suggesting clinical utility of blood‐based ATN classification. GFAP and NfL are expected to reflect different aspects of neurodegeneration like FDG‐PET and structural MRI.
Subjective cognitive concerns differ by race/ethnicity among einstein aging study (EAS) participants: Implications for assessment and interpretation of self‐perceived cognitive functioning
Authors: Katz Mindy J. , Qin Jiyue , Wang Cuiling , Rabin Laura
Published: June 2023

Background

Subjective cognitive concerns (SCC) play an important role in the identification of preclinical dementia, especially among individuals who have experienced health disparities. It is critical to discern differential patterns of SCC endorsement among racially/ethnically diverse groups to enhance the ability to accurately capture current and future cognitive status. Moreover, it is important to determine whether the association of SCCs and objective neuropsychological test scores vary by racial/ethnic background.

Method

Using data from the EAS, a longitudinal community residing cohort aged 70+, SCCs were captured using an expanded version of the Cognitive Change Index (CCI‐40), which taps multiple cognitive domains. Objective cognition was measured using the FCSRT and tests from the Uniform Data Set, Neuropsychological Battery (UDSNB3.0). Linear regression models evaluated racial/ethnic differences in SCC at baseline. Additional models for objective cognition examined its association with SCC adjusting for racial/ethnic groups, and furthermore the interaction effects between race/ethnicity and SCC. Covariates included demographics, depressive symptoms, income, and co‐morbidities.

Result

We included 313 participants of non‐Hispanic (NH) White (47%), NH Black (40%) and Hispanic/Latino (13%) racial/ethnic groups who were not demented at baseline. NH Blacks and Hispanic/Latino participants reported significantly more SCC than NH Whites after adjusting for covariates. Higher CCI‐40 scores were associated with worse FCSRT free recall and Trail Making Test Part B performing, adjusting for race and other covariates. When interactions between race/ethnicity and CCI‐40 were included, higher levels of SCC were associated with lower MoCA and FCSRT free recall scores for NH Whites but not for NH Blacks.

Conclusion

Stronger perceptions of self‐reported cognitive decline do not necessarily correspond to worse performance on memory and global cognitive tasks for all racial groups. Although racial/ethnic differences were found in levels of SCC, it is important to investigate factors that may influence self‐perceived cognitive functioning for specific groups (e.g., health status, social support), and the consequential impact on access to healthcare settings (where assessment and diagnosis typically occur). In addition, researchers should consider diversity variables when setting cut points on self‐report questionnaires to enhance diagnostic sensitivity and inform optimal assessment and monitoring needs.
A joint model of network spread and selective vulnerability explains tau pathology spread in Alzheimer’s disease mouse models
Authors: Torok Justin , Raj Ashish
Published: June 2023

Background

The propagation and spread of pathology in Alzheimer’s disease (AD) results from the interplay of many complex biological processes. Two key hypotheses have been proposed to help explain the characteristic Braak stageing patterns that define typical AD tau pathology1: network spread, which posits that trans‐synaptic spread of tau determines how pathology progresses2, and selective vulnerability, which states that the regions most affected by tau pathology contain high densities of cell types particularly sensitive to the presence of tau3. Here we explore the explanatory power of each hypothesis in the context of mouse tauopathy models.

Methods

We implemented a mathematical network spread model that extends the Network Diffusion Model2 by adding a linear accumulation term (sNDM). We also utilized the cell type distributions recently made available by the MISS algorithm, which deconvolves spatial transcriptomic data into cell type densities using scRNAseq information4. We fit the sNDM to the Iba, et al. PS19 tauopathy model seeded at the hippocampus5 (IbaHippInj) and the Hurtado, et al. unseeded PS19/PDAPP model6 (Hurtado).

Results

We find that although network spread is the single‐best correlate of tau pathology, there are many cell types that are highly correlated at the regional level, particularly Layer‐2/3 glutamatergic neurons and Lamp5‐expressing GABAergic neurons (Figure 1). A combined linear model using sNDM predictions and these two cell types (Figure 2) yields higher R2 values than the sNDM predictions alone (Figure 3).

Conclusion

We demonstrate that both the network spread and selective vulnerability hypotheses contribute meaningful information for explaining tau pathology in mouse models, indicating that more sophisticated modeling approaches taking into account the full biological complexity of AD have more explanatory power.

References:

1. Braak, H. & Braak, E. Acta Neuropathol. 82, 239‐259 (1991).

2. Raj, A., Kuceyeski, A. & Weiner, M. Neuron (2012).

3. Fu, H., Hardy, J. & Duff, K. E. Nat. Neurosci. 21, 1350‐1358 (2018).

4. Mezias, C., Torok, J., Maia, P. D., Markley, E. & Raj, A. PNAS. (In press).

5. Iba, M. et al. J. Neurosci. 33, 1024‐1037 (2013).

6. Hurtado, D. E. et al. Am. J. Pathol. 177, E4376–E4385 (2010).
Characteristics of peripheral immune system in a novel AppNL‐G‐F knock‐in mouse model of Alzheimer’s disease
Authors: Gera Ruchi , Mitra Sumonto , Tambaro Simone , Nilsson Per , Eriksdotter Maria
Published: June 2023

Background

Increasing epidemiological, clinical, and experimental evidence suggests that Alzheimer’s disease (AD) pathogenesis is closely associated with systemic abnormalities, including dynamic processes in the peripheral immune compartment and inflammation1,2,3. Recent reports in transgenic AD animal models propose a role of dysregulated peripheral immune system in memory impairment4,5. In this regard, the contribution of peripheral immune response in driving different pathological stages in AD is less understood. Therefore, utilizing a novel App knock‐in mouse model (AppNL‐G‐F) exhibiting robust Aβ pathology, neuroinflammation and memory impairment, we have explored the relation of Aβ pathology development in the brain with alterations in the peripheral immune compartment.

Method

Using flowcytometry, we characterized the AppNL‐G‐F mice at different stages of Aβ pathology (early‐plaque: 3‐month‐old; plaque + early memory impairment: 7‐month‐old; late stages: 12‐month‐old) and investigated the distribution and activation status of various peripheral immune cells in splenic primary cells.

Result

Among various immune cells from innate immunity including macrophages, natural killer and dendritic cells, there was a significant increase in macrophage number in AppNL‐G‐F mice. While percent distribution of B cells from adaptive immunity was reduced (as observed in AD patients2), no significant changes in total T cell distribution following 3, 7 and 12‐months of age compared to wild‐type controls was observed. B cells showed reduced activation examined by CD69 and PD‐L1 expression in 7 and 12‐months old AppNL‐G‐F mice. Among T cell subsets, CD4, CD8 and regulatory T (Treg) cell distribution in AppNL‐G‐F mice was comparable to control mice in all age groups. However, there was rise in follicular T helper (Tfh) cells at 3‐month of age, with altered activation molecule ICOS expression in AppNL‐G‐Fmice.

Conclusion

These findings in AD mice model show a reduction in B cell and their activation status during aggressive Aβ plaque deposition in brain, reflecting their possible contribution in Aβ pathology reinforcing the importance of further investigation. Our data suggest a possible role of Tfh cell in early stage of Aβ pathology. An altered Tfh cell activation may answer the impaired protective antibody production from B cells reported in AD6,7. The observed increase in macrophages in the peripheral system during Aβ pathology development demands further investigation.
Evaluating a patient engagement program within a national research network
Authors: Bethell Jennifer , McGilton Katherine S , Snowball Ellen ,   Engagement of People with Lived Experience of Dementia (EPLED) Advisory Group
Published: June 2023

Background

The Engagement of People with Lived Experience of Dementia (EPLED) is a program within the Canadian Consortium on Neurodegeneration in Aging (CCNA). The role of EPLED is to enable those with lived experience of dementia – persons with dementia and their care partners (i.e., friends, family and caregivers) – to be meaningfully and actively involved in the CCNA research process. The EPLED Advisory Group is composed of people with lived experience of dementia.

Method

The EPLED researchers, Advisory Group and program staff worked to develop an approach to evaluate EPLED activities. Evaluation will include capturing quantitative data on Advisory Group activities (e.g., number and nature of projects) as well as Advisory Group and CCNA perspectives on the engagement activity. Existing resources were used to identify key domains and Advisory Group members were invited to share their perspectives on the most relevant questions, including by voting on existing questions or suggesting their own. Ultimately, the Patient Engagement in Research Scale (PEIRS‐22) was selected to capture Advisory Group perspectives, but with two additional questions, from the full (37‐item) PEIRS and free‐text questions. EPLED also developed a short questionnaire for CCNA researchers to evaluate their experience working with Advisory Group members, including questions related to timing, objectives, engagement, collaboration and impact. Both questionnaires were transferred to Google Forms for online data collection.

Result

We will present the EPLED program evaluation plan and data from the first year of activities. We will describe the nature of the Advisory Group’s work as well as the perceptions from members and researchers.

Conclusion

Patient engagement in research is becoming more widespread and, for some research funding, an expectation. Our evaluation plan will be used to improve the EPLED program and plan future activities. Our results may also help other patient partners, researchers and research organisations to develop and implement their own activities.
Loss of apolipoprotein E exacerbates microglial and astrocyte reactivity to sustained systemic glucocerebrosidase inhibition
Authors: Connolly Kyle J , Hallett Penelope J , Isacson Ole
Published: June 2023

Background

Increased lipid storage is observed within the brains of patients with Alzheimer’s disease (AD). Genetic risk factors for AD involved in lipid processing include APOE, ABCA7 and TREM2. Lipid transport between neurons and glia is induced by mitochondrial stress and NMDA‐induced excitotoxicity in vitro and is dependent on glial apolipoprotein E (ApoE) expression. Therefore, this suggests that lipid transport between neurons and glia of the brain by ApoE and intracellular lipid processing are critical cellular adaptations to stress. This in turn suggests that insufficient ApoE activity may underpin the elevated lipid storage associated with neurodegenerative diseases.

Method

To determine whether ApoE function is required for cellular adaptation to increased lipid load relevant to dementia, 3‐month‐old WT and ApoE‐KO mice received daily intraperitoneal injections of the glucocerebrosidase inhibitor, CBE, for 18 d. Animals were sacrificed 1 d after the final dose and perfused with paraformaldehyde for immunohistochemistry, or were perfused with saline and dissected to isolate the cortex, hippocampus and substantia nigra for biochemical analysis by Western blot. Microglial and astrocyte reactivity to CBE were assessed by Iba1 and GFAP immunohistochemistry respectively.

Result

Microglial reactivity was greater in the dentate gyrus, substantia nigra and cortical layer V in ApoE‐KO mice after 18 d CBE, relative to WT. Loss of ApoE also elevated astrocyte reactivity in the dentate gyrus, substantia nigra and cortical layer V after 18 d CBE. Ongoing analyses into the molecular and cellular consequences of prolonged CBE include changes in lipid transport, tau phosphorylation, lysosome biogenesis, autophagy and proteostasis, to determine how loss of ApoE function may impact cellular adaptation to intracellular lipid formation resulting from sustained glucocerebrosidase inhibition.

Conclusion

The exacerbated glial activation in ApoE‐KO animals receiving CBE suggests that ApoE expression and function may, in part, determine the capacity of neuron‐glia networks to overcome damaging stimuli. When ApoE function is insufficient, failed resolution of lipids may then lead to persistent damage and degeneration. Therefore, characterizing the consequences of limited lipid clearance on the adaptation to rising lipid load is highly relevant to understanding how failure to overcome increased lipid storage contributes to neurodegenerative processes in AD.
Methods in Prioritizing Pathways and Targets from Expression Data
Authors: Turkes Emir , Duff Karen E
Published: June 2023

Background

Expression datasets, such as those from RNAseq and mass‐spec platforms, have been growing at an everincreasing rate and are relevant to a wide variety of diseases, however, it remains challenging to yield interpretable and actionable results. In this poster, we present novel computational methods that attempt to resolve this issues and demonstrate their use in several Alzheimer’s Disease datasets.

Method

Two publicaly available datasets were used for this analysis: a post‐mortem single‐nucleus RNAseq dataset from the entorhinal cortex of Alzheimer’s Disease and non‐demented donors (Leng et al., 2021, Nature Neuroscience) and a post‐mortem single‐soma RNAseq dataset from the prefrontal cortex of Alzheimer’s Disease donors where tangle‐bearing neurons were sorted prior to sequencing (Otero‐Garcia et al., 2020, bioRxiv). In brief, our method, which we have named GeneFunnel, firstly optimizes filtering steps and statistical correctness (such as pseudobulking) to yield robust gene set enrichment results. Gene set enrichment is then used to guide prioritization of differentially expressed genes using hierarchial clustering and graph theory, focusing especially on the overlap of genes between gene sets.

Result

Using several forms of visualization, we demonstrate how GeneFunnel can create a clear and succint overview of the processes involved in Alzheimer’s Disease. As the name implies, the results are made intuitively explorable, effectively facilitating a “funnel” that allows inspection at broad and narrow levels of depth.

Conclusion

We show a novel approach to tackling large and complex expression datasets, demonstrating its utility in summarizing key molecular changes that take place in Alzheimer’s Disease.
The interaction between psychological resilience and perceived stress in relation to memory performance in middle‐aged adults
Authors: Franks Katherine H. , Buckley Rachel F. , Lim Yen Ying , Pase Matthew P.
Published: June 2023

Background

High levels of perceived stress are associated with an increased risk of late‐life dementia. As such, it is important to investigate resources that might protect against the negative effects of stress, particularly in midlife when dementia is still preventable. One potential resource is an individual’s psychological resilience (i.e., their ability to cope with stress). The aim of this study was to investigate if the effect of perceived stress on memory depends on an individual’s level of resilience in a middle‐aged sample enriched for a family history of dementia.

Method

Participants (n = 1148) enrolled in the community‐based Healthy Brain Project aged 40‐71 (78% female, 61% with a family history of dementia) completed the Perceived Stress Scale, the Connor‐Davidson Resilience Scale, and the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning task. A two‐way ANCOVA was conducted to assess the interaction between perceived stress (low/high by median split) and psychological resilience (low/high by median split) on associative memory performance, while controlling for age and years of education. Simple main effects were Bonferroni adjusted.

Result

There was a statistically significant interaction between resilience and perceived stress on associative memory performance when controlling for age and education, F(1, 1142), 8.631, p = .003, partial h2 = .008. Bonferroni‐adjusted comparisons indicated that for individuals with low levels of resilience, associative memory was significantly poorer for those reporting high levels of stress relative to low levels of stress (mean difference = ‐0.31, 95% CI = ‐0.44 – ‐0.17, p < .001, Cohen’s d = 0.38). However, for individuals with high levels of resilience, associative memory performance between individuals reporting high and low levels of stress was comparable (mean difference = ‐0.01, 95% CI = ‐0.16 – 0.13, p = .857, Cohen’s d = 0.02).

Conclusion

Individuals with low levels of resilience might be more susceptible to the negative effect of stress on memory than those with high levels of resilience. Further research is needed to explore whether boosting an individual’s resilience to stress can help mitigate cognitive decline and reduce dementia risk.
Prediction of multiple neuropathologic changes from features available during life
Authors: Phongpreecha Thanaphong , De Francesco Davide , Chang Alan , Thuraiappah Melan , Becker Martin , Ravindra Neal , Berson Eloise , Espinosa Camilo , Mataraso Samson , Godrich Dana , Beecham Gary W. , Aghaeepour Nima , Montine Thomas J.
Published: June 2023

Background

Neuropathologic changes are central for both understanding of the patients’ brains and making the definitive diagnosis of dementia‐related diseases. However, many of them are only obtainable post‐mortem. To make this information available while an individual is still alive, this study developed machine learning models that predict neuropathologic changes based on features obtainable during life.

Method

The multi‐site post‐mortem data (n∼5000) was obtained from National Alzheimer’s Coordinating Center. A multitask long‐short term memory‐based neural network architecture was developed with custom loss to predict the 13 neuropathologic changes from features during life measured longitudinally. The performance of the model was evaluated using entire unseen sites as test sets. Evaluation metrics include area under receiver’s operating curve (AUROC) and area under precision recall curve (AUPRC).

Result

The model was able to predict Alzheimer’s Disease neuropathologic changes (ADNC) and any Alzheimer’s‐related pathologies, such as Braak score, with great sensitivity, specificity, and precision (for example AUROC = 0.85; AUPRC = 0.96 for ADNC). Apart from these, the model can also predict hippocampal sclerosis accurately (AUROC = 0.79; AUPRC = 0.80) and Lewy Body disease at higher precision than clinician’s diagnosis. Model interpretation shows patterns in neuropsychological tests that are predictive of pathologic changes. Additionally, model error analysis revealed factors, such as resilient case ratios, that explain variation in performance between sites.

Conclusion

Patterns of measurable features during life can be used by machine learning to predict ADNC, hippocampal sclerosis, and to lesser extent Lewy Body.
Variants near X‐Chromosome Genes NLGN4X and PTCHD1 are Significantly Associated with Alzheimer’s Disease Risk
Authors: Chung Jaeyoon , Sun Xinyu , Schmidt Michael A. , Song Yeunjoo E. , Grunin Michelle , Palmer Ellen L , Bush William S. , Naj Adam C. , Rajabli Farid , Hamilton‐Nelson Kara L. , Zhang Xiaoling , Leung Yuk Yee , Wang Li‐San , Mayeux Richard , Schellenberg Gerard D. , Vance Margaret A. , Haines Jonathan L. , Farrer Lindsay A. , Kunkle Brian W. , Martin Eden R.
Published: June 2023

Background

Genome‐wide association studies (GWAS) for AD have identified numerous associated loci but have been focused only on the autosomes. We sought to identify novel AD‐associated genes on X‐Chromosome (X‐Chr).

Method

We evaluated the association of AD with X‐Chr variants in GWAS datasets assembled by the Alzheimer Disease Genetics Consortium including 26,322 non‐Hispanic White (NHW) individuals using logistic regression models with covariates for age, sex and principal components of ancestry. The number of independent SNPs in X‐Chr was calculated by linkage disequilibrium pruning yielding a study‐wide significance threshold of P<7.58×10−7. Genes near SNPs surpassing this threshold were further evaluated by expression quantitative trait locus (eQTL) in the BRAINEAC database and differential gene expression analyses using RNA‐seq data obtained from autopsied brains contained (GEO: GSE44772 and GSE33000). We also tested association of AD with missense or splicing variants with minor allele count (MAC)≥10 in the same genes using GENESIS and whole exome sequencing (WES) data obtained by the Alzheimer Disease Sequencing Project (ADSP) for 11,172 NHWs.

Result

We identified novel associations with variants near NLGN4X (rs34056759; minor allele frequency [MAF] = 0.15, OR = 1.15, P = 5.14×10−7) and PTCHD1 (rs5970663; MAF = 0.30, OR = 1.13, P = 8.26×10−7). The rs5970663 risk allele C was significantly associated with increased expression of PTCHD1 in the medulla region, and PTCHD1 expression was significantly higher in AD cases than in controls in the prefrontal cortex (P<2.1×10−8) and visual cortex (P<2.3×10−4). Rs34056759 was not associated with NLGN4X expression, but NLGN4X expression was significantly lower in AD cases compared to controls in the prefrontal cortex (P<8.7×10−7). A rare PTCHD1 variant (rs201933353; MAF = 0.001) was nominally associated with AD among 6,318 women (OR = 3.72, P = 0.06).

Conclusion

We identified novel associations of AD with X‐Chr variants near NLGN4X and PTCHD1, loci that were previously associated with autism spectrum disorder. We plan to replicate, fine‐map, and annotate the candidate loci identified in this study using large whole genome sequencing ADSP datasets.
Functional brain networks reorganization in the absence of medial temporal lobe structures: an example of neuroplasticity
Authors: Peña‐Gomez Cleofé , Akinci Muge , Young Peter , Öhman Fredrik , Palpatzis Eleni , Studahl Marie , Arenaza‐Urquijo Eider M , Schöll Michael
Published: June 2023

Background

Medial temporal lobe structures are particularly vulnerable in age‐related neurodegenerative diseases. Here, we investigated the brain reorganization that allows maintaining relatively normal global cognitive functioning in patients with herpes simplex encephalitis (HSE) – an infectious neurological disease ‐ with marked focal atrophy most pronounced in the medial temporal lobes, particularly the hippocampus. Using rs‐fMRI we (i) characterized the patterns of functional network organization, and (ii) compared the intra‐/interhemispheric functional connectivity (FC) within each patient.

Method

A total of nine HSE patients were included (see Table 1), four of them were affected mainly in the left (LH) and five in the right (RH) hemisphere. The rs‐fMRI data were acquired after a long‐term follow‐up (median 16 years) of the disease and were preprocessed using the AFNI software. For each patient, using different brain parcellations, we computed the intra‐ and inter‐FC strength for each hemisphere separately, yielding four measures of intra‐FC
LH/RH
and inter‐FC
LH/RH
. We grouped the subjects according to their lesion‐side and their performance (low, high) in a memory task.

Result

We observed, regardless of the lesion side, a highly variable pattern of disrupted FC in each patient. Left‐lesioned patients showed high intra‐FCLH/RH particularly in the precuneus/posterior cingulate (PPC) and the angular gyrus while right‐lesioned patients exhibited a high inter‐FCRH in the medial prefrontal cortex (MPFC) and PPC regions. Both left and right‐lesioned showed decreased intra‐FCLH/RH in ventral medial temporal areas, more pronounced in the left‐lesioned patients (Figure1). Right‐lesioned individuals who showed a pattern of inter‐FC within the right MPF and PPC performed consistently higher on the memory task (percentiles > 50) (Figure2).

Conclusion

The substantial HSE‐induced medial temporal lobe lesions induce a global network reorganization. However, the side of the lesion seems to determine a specific pattern of network reorganization that is associated with differential cognitive performance. Left‐lesioned patients exhibited high PPC intra‐ and inter‐FCLH/RH and low memory performance while the right‐lesioned exhibited a high inter‐FCRH on the PPC and MPFC and better memory performance. Left lesions may result in nonadaptive brain reorganizations, however, right lesions, when linked to prefrontal brain reorganizations, may result in cognitive benefits and therefore be adaptive.
2021 Annual Report of Japanese Brain Bank Network for Neuroscience Research
Authors: Murayama Shigeo , Saito Yuko , Takao Masaki , Kaneda Daita , Mihara Ban
Published: June 2023

Background

Japanese Brain Bank Network for Neuroscience Research (JBBNNR) was established in 2001, whose reader is the Brain Bank for Aging Research (BBAR), the first and only Japanese Brain Bank dedicated for aging and dementia research.

Method

BBAR recruited all the members of the Japanese Society of Neuropathology to establish JBBNNR, funded by MEXT in 2001, on the following four conditions: open resource, to organize brain donation system, to share quality control including neuropathological method and to combine clinical longitudinal studies like US ADNI. National Center of Neurology and Psychiatry (NCNP), Mihara Memorial Hospital and Fukushimura Hospital joined JBBNNR. In 2020, Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders (BBNNPD) joined JBBNNR. JBBNNR was established in United Graduate Shool of Child Development, Osaka University and was the first brain bank system in all the universities of Japan.

Result

In 2021, the pandemic of COVID‐19 seriously influenced recovery of postmortem brains via dramatic decrease of autopsy. JBBNNR promoted brain donation and began effort to include legal autopsy for Japanese equivalent of suicide bank and autism brain net in US. The main barrier resides in cultural respect of suicide in Japan, which makes it difficult to obtain the deceased first kin of relatives' consent for brain donation. The solid public support system for autism promised long life without accident and makes it difficult to recover autism brains through forensic pathology. A goog news is that BBNNPD proposed cloud funding in Osaka for the research of neurodevelopmental disorders and intractable neurological disorders and successfuly received donation of ten million yen. The main target of JBBNNR is Alzheimer disease and contributed clinical trials of amyloid pet in Japan. JBBNNR is based on full autopsy and reported that one third of geriatric population contained Lewy body pathology in the body. BBAR received the best reserch presentation award from the Japanese Society of Dementia Research about correlationg of in vivo PIB PET and postmortem Abeta deposition with shor interval.

Conclusion

JBBNNR continued to contribute neuroscience research, focused AD and dementia, in Japan.
Relationship between MTA visual scale scores and hippocampal volume measured by a medical device in patients from a multicentric memory clinic population
Authors: Longo Clarisse , Cavedo Enrica , Gordon Elizabeth , Samper‐Gonzales Jorge , Schwarz Adam J. ,   MEMENTO Study group
Published: June 2023

Background

The medial temporal lobe (MTL), including the hippocampus, undergoes atrophy in patients with Alzheimer’s disease (AD). Visual rating of medial temporal lobe atrophy (MTA) is often performed in the assessment of patients with cognitive impairment. Calculation of hippocampal volumes (HV) can also be achieved by multiple automated and semi‐automated methods using T1‐weighted MR images. The current study investigated the relationship between HV and z‐scores calculated by an automated method, included in the QyScore® medical device, and visual MTA rating scores using Scheltens’ scale in a multicentric memory clinic population at baseline.

Method

1959 participants from the MEMENTO cohort (Age 71.02 +/‐ 8.61, 1218 Female, MMSE 27.95 +/‐ 1.91) had 3DT1 MRI scans analyzed with QyScore®, an FDA‐approved and CE‐marked image analysis software. HV are reported in mL, corrected for % Intra Cranial Volume (ICV), and in z‐scores calculated relative to a cognitively normal population. 814 had amyloid status from CSF or PET, of which 216 were Amyloid+. Correlation between MTA scores and quantitative HV measurements was ascertained by Spearman’s rank correlation.

Result

There was a significant negative correlation between MTA scores and HV in %ICV (Left ‐0.62, p<0.001; Right ‐0.59, p<0.001) and z‐scores (Left ‐0.47, p<0.001; Right ‐0.43 p<0.001) for the total sample, as well as in Amyloid+ individuals HV in %ICV (Left ‐0.63 p<0.001, Right ‐0.58 p<0.001) and z‐scores (Left ‐0.50 p<0.001, Right ‐0.47 p<0.001). The correlation was also strong when separated by clinical diagnosis: patients with Subjective Cognitive Complaint (SCC, N = 306, AGE: 69.82 +/‐ 8.03, 196 female, MMSE: 28.86 +/‐ 1.17) and MCI (N = 1646, Age: 71.23 +/‐ 8.71, 1018 Female, MMSE: 27.79 +/‐ 1.95) presented MTA scores correlated both with HV in %ICV (Right = ‐0.47 p<0.001, Left = ‐0.50 p<0.001 for SCC; Right = ‐0.60 p<0.001, Left = ‐0.63 p<0.001 for MCI) and z‐scores (Right = ‐0.26 p<0.001, Left = ‐0.33 p<0.001 for SCC; Right = 0.44 p<0.001, Left = ‐0.49 p<0.001 for MCI).

Conclusion

The automated quantification of ICV‐corrected HV and z‐scores were well‐correlated to MTA scores. QyScore® z‐scores may improve specificity in patients with cognitive impairment, by providing automated quantification of hippocampal atrophy directly compared with healthy ageing.