bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct neural substrates of receptive and responsive aspects of empathy in patients with neurodegenerative disease
Authors: Sollberger Marc , Toller Gianina , Miller Bruce L. , Rankin Katherine
Published: December 2020

Background

The way we interact with each other is influenced by how we perceive and evaluate socioemotional signals and adapt our interpersonal behavior to them (Lieberman, 2007). In this study, we investigated the neurostructural substrates of two key aspects of interpersonal behavior: socioemotional sensitivity and behavioral self‐management, using a neurodegenerative disease lesion model.

Method

Socioemotional sensitivity and behavioral self‐management were measured by obtaining informant reports from two subscales of the Revised Self‐Monitoring Scale (RSMS)(Lennox & Wolfe, 1984). Scores were correlated with structural volume using voxel‐based morphometry. The study enrolled 360 participants, including 251 patients diagnosed with one of five neurodegenerative disease syndromes causing diverse structural brain changes (77 behavioral variant frontotemporal dementia, 30 semantic variant primary progressive aphasia, 33 non‐fluent variant primary progressive aphasia, 57 progressive supranuclear palsy, and 54 Alzheimer’s disease) and 109 neurologically healthy older controls.

Result

Sensitivity to others’ social cues was significantly predicted by volume in predominantly right‐hemispheric paralimbic ventro‐anterior‐ and mesio‐temporal regions, some of which are known to support auditory and visual social signal reading, while the remaining regions were part of the frontotemporal semantic appraisal network (Yeo, et al., 2011), involved in making social evaluations. In contrast, capacity to make behavioral adjustments in response to social cues was uniquely predicted by volume in predominantly right‐hemispheric neocortical frontal regions that comprise the cingulo‐opercular stable task control network (Dosenbach, et al., 2007), involved in maintaining attention during socioemotional tasks.

Conclusion

Our results clarify how receptive and responsive aspects of empathy rely on distinct, predominantly right‐hemispheric anterior fronto‐temporal brain regions, largely comprising two intrinsically connected networks including the semantic appraisal and cingulo‐opercular task control networks, along with right temporal structures mediating person perception. The fidelity with which this questionnaire method revealed these specific brain networks shows that standardized informant reports are valuable tools in assessing the complex socioemotional constructs involved in empathy. Lastly, the specificity of these brain‐behavior correlations provides further evidence that observable, measurable patterns of decreased empathy in patients with brain disorders can be a direct result of differently localized brain lesions.
Imaging dopamine system transporter activity and connectivity in Alzheimer’s dementia
Authors: Caminiti Silvia , Sala Arianna , Pilotto Andrea , Presotto Luca , Garibotto Valentina , D'Amelio Marcello , Liguori Claudio , Mercuri Nicola , Padovani Alessandro , Perani Daniela
Published: December 2020

Background

Neuropsychiatric symptoms and cognitive deficits in Alzheimer’s Disease (AD) dementia can be related to changes in the brain dopamine (DA) system. In order to investigate whether and how the DA pathways, namely the nigrostriatal and mesocortico‐limbic, are involved in the pathophysiology of AD, we relied on imaging measures of DA transporter activity, using [123I]FP‐CIT SPECT. We tested (i) presence and degree of alterations in the ventral and dorsal dopamine structures and their major cortical targets; (ii) presence of alterations in DA molecular connectivity within the two DA pathways.

Methods

Sixteen amyloid‐positive subjects with amnestic mild cognitive impairment (aMCI), twenty‐two amyloid‐positive patients with probable Alzheimer’s dementia (AD) and seventy‐two healthy controls, were selected from three centres. Each subjects underwent an [123I]FP‐CIT SPECT scan. The subcortical/cortical dopaminergic structures showed significant tracer binding, as compared to the reference region, and were thus selected for further analyses, which included the assessment of regional differences in [123I]FP‐CIT bindings, via MANCOVA and differences in molecular connectivity within the dopamine pathways via partial‐correlation analysis, among the three groups. Gender, age and reconstruction method were included as nuisance covariates in all statistical analyses. Results deemed significant at p<0.05, following Bonferroni correction for multiple comparisons.

Results

The assessment of DA transporter activity demonstrated a significant reduction in aMCI subjects and AD patients in subcortical and cortical targets of the ventro‐tegmental area, namely the ventral striatum and hippocampus, bilaterally, and the middle cingulate gyrus. Within the nigrostriatal projections, only the dorsal caudate was affected, bilaterally. Molecular connectivity measures demonstrated a widespread loss of inter‐connections among targets of the ventro‐striatal pathway only, with a sparing of the nigrostriatal projections.

Conclusions

The selective and significant decrease in dopaminergic transporter activity in the ventro‐striatal subcortical/cortical dopaminergic regions is indicative of an axonal degeneration starting from the projections arising from the dopaminergic ventro‐tegmental brainstem nuclei, and involving the mesolimbic pathways. Our data, consistent with previous post‐mortem evidence [1], support the involvement of the ventral dopaminergic system in AD, since the prodromal phases. The mesolimbic subcortical/cortical DA alterations might play a role in the pathophysiology of memory function and neuropsychiatric symptoms in AD.
TRPML1: A novel therapeutic target to remediate endolysosomal pathology in Alzheimer’s disease
Authors: Somogyi Aleksandra , Kirkham Emily D. , Lloyd‐Evans Emyr , Allen Nicholas D. , Anderson Karen E. , Hawkins Phillip T. , Sims Rebecca , Boland Barry , O'Neill Cora
Published: December 2020

Background

TRPML1 (transient receptor potential channel mucolipin 1) is an essential endosomal‐lysosomal Ca2+ channel whose loss of function can cause neurodegeneration. Defects in the endosomal‐autophagic‐lysosomal (EAL) are a primary feature of Alzheimer’s disease (AD) pathogenesis, and many late‐onset AD (LOAD) risk genes, including APOE4, functionally converge on the EAL system, although the underlying mechanisms remain unclear. Dysfunctional TRPML1 activity has been reported in genetic models of AD involving cells deficient in presenilin 1. Here, we hypothesised that TRPML1 malfunction underlies EAL defects in LOAD, and can be therapeutically targeted to remediate EAL defects in LOAD.

Method

Cell and molecular approaches were employed to investigate the integrity of endolysosomes in LOAD (n = 10) and matched control (n = 10) post‐mortem brain, and in APOE isoform expressing human cortical neurons derived from induced pluripotent stems cells. TRPML1 activity was manipulated in primary neurons to determine whether blocking TRPML1 could recreate EAL defects evident in LOAD and whether TRPML1 could be targeted therapeutically to protect against EAL defects in LOAD.

Result

We identified perinuclear clustering of enlarged LAMP‐1‐positive endolysosomes in post‐mortem LOAD hippocampal neurons, indicative of TRMPL1 dysregulation. Our results reveal for the first time that TRPML1 activity was significantly reduced in APOE4 expressing human cortical neurons derived from induced pluripotent stems cells, resulting in elevated endolysosomal Ca2+ content. Furthermore, depletion of the TRPML1 agonist, PI(3,5)P2 in primary neurons using YM201636, recreated many features of AD endolysosomal neuropathology. This included endolysosomal swelling, accumulation of autophagic vacuoles (AVs), and increased endolysosomal Ca2+ accumulation. Strikingly, the re‐activation of TRPML1 in YM201636‐treated cultures, using the synthetic small molecule agonist ML‐SA1, restored endolysosomal Ca2+ pool to its normal size, mitigated endolysosomal swelling, prevented the accumulation of AVs, and increased levels of non‐pathogenic alpha‐secretase derived C‐terminal fragments of the amyloid precursor protein (APP).

Conclusion

Together, these finding implicate defects in TRPML1 in LOAD and present TRPML1 as a novel potential therapeutic target to remediate endolysosomal pathology in AD.
Plasma neurofilament light chain (NFL) is differentially associated with neuropsychological test performance among non‐Hispanic whites and hispanic, Mexican Americans: A HABLE study
Authors: Petersen Melissa , Hall James R. , Mozdbar Sima , Johnson Leigh Ann , Yaffe Kristine , Braskie Meredith N , King Kevin , Toga Arthur W. , O'Bryant Sid ,   the HABLE Research Team
Published: December 2020

Background

Neurofilament light chain (NfL) has been examined as a biomarker of Alzheimer’s disease (AD) due to its link with neurodegeneration. Among a community sample of Mexican Americans, NfL was found to be inversely related to processing speed, attention, executive functioning, and memory among those with normal cognition (NC) as well as those with mild cognitive impairment (MCI). This study aimed to validate prior work and examine if the relationship between NfL and cognition differed by ethnicity when split by diagnostic status.

Method

Data were analyzed on n= 503 non‐Hispanic white (n=363 NC; n= 140 impaired cognition [MCI +dementia]) and n=357 Mexican American (n=187 NC; n=169 impaired cognition [MCI +dementia]) participants enrolled in a study of health disparities. Plasma NfL were assayed using Simoa. Neuropsychological test battery included Trail Making Test Part A and B, FAS, Animal Naming, Spanish and English Verbal Learning Test (Immediate and Delayed Recall), and Digit Symbol Substitution. Linear regression models analyzed cognitive test performance as the dependent variable while NfL was included as the independent variable. Covariates included age, gender, and education. Regression models were run separately for each cognitive test. Analyses were split by both ethnicity and diagnosis.

Result

Among non‐Hispanic whites with normal cognition, NfL was related to poorer neuropsychological test performance across measures of attention, processing speed, verbal fluency (FAS), and immediate memory. Among those with impaired cognition, NfL was associated with poorer performance across neuropsychological measures of attention, processing speed, executive functioning, and verbal fluency (animal naming). Among Hispanic, Mexican Americans with normal cognition, NfL was only found to be associated with poorer neuropsychological test performance on a measure of verbal fluency (animal naming). NfL was not found to be associated with any cognitive domain examined for Hispanic, Mexican Americans with impaired cognition.

Conclusion

These findings highlight that biomarkers associated with AD, such as NfL, likely differ by ethnicity. This corresponds with our prior work that has shown lower rates of APOEe4 and amyloid among Hispanic, Mexican Americans. This further supports the need to examine more closely underlying biological mechanisms of neurodegenerative conditions among minority populations such as Hispanic, Mexican Americans.
Influence of amyloid‐beta isoforms in different in vitro models
Authors: Van Bulck Michiel , Gräler Markus , Castillo Ana Maria Pérez , Braeuer Anja
Published: December 2020

Background

Alzheimer disease (AD) is a complex multifactorial neurodegenerative disorder, characterized by mild cognitive impairment and late dementia. Understanding and treatment of AD is one of the greatest challenges in modern medicine. The pathological brain features includes formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, leading to neuronal cell death. The underlying process, onset and progression are not yet elucidated, although impaired neurogenesis, synaptic dysfunction, and dysregulation of lipid metabolism are known to be involved. Homeostatic balance of Amyloid‐beta (Aβ) peptide during normal brain development and function, are depending on soluble or insoluble isoforms, aggregation state, developmental stage of the brain and concentration of Aβ peptide. Physiological and pathophysiological features of Aβ peptide remain controversial due to complexity, inconsistency and contradictory results. Investigating the effect of low concentration of human synthetic Aβ isoforms on adult neurogenesis, synaptic plasticity, and alteration of lipid metabolism might help better understanding the biochemical pathways in AD.

Method

We performed immunofluorescence, high performance thin layer chromatography, and mass spectrometry analyses on hippocampal neurons, glial cells and neurospheres treated with and without low concentration (1µM) of human synthetic Aβ40 and Aβ42 for 3‐12 hours.

Result

Preliminary results of neurospheres treated with Aβ40 and Aβ42 showed altered levels in stem cell differentiation towards neuronal phenotype. The hippocampal neurons showed synaptic loss after 3‐12 hours. Lipid analysis showed altered levels of phospholipids (e.g. Phosphatidylcholine, Phosphatidylserine) and sphingolipids in hippocampal neurons after 3‐12 hours of Aβ40 and Aβ42 treatment compared to glial cells. Glial cells showed altering lipid levels after 3 hours of Aβ42 treatment and 12 hours for both Aβ40 and Aβ42 treatment.

Conclusion

Preliminary results showed that treatment with low concentration of Aβ40 and Aβ42 might have neurotrophic effect on stem cell differentiation and synaptic loss on hippocampal neurons. Lipid profiles showed altering levels in phospholipids and sphingolipids in both glial cells and hippocampal neurons. These results will have potential impact in a better understanding, finding of new biomarkers for diagnostics, and developing new therapeutics for AD.
Development of an ultrasensitive multiplex assay for simultaneous detection of Aβ1‐42, Aβ1‐40, GFAP and NF‐L in blood
Authors: Shan Dandan , Holdridge Marcella , Chang Lei , Stoops Erik , Verberk Inge M.W. , van Der Flier Wiesje , Teunissen Charlotte E. , Ball Andrew J.
Published: December 2020

Background

Previous work (1) has described plasma amyloid, GFAP and NF‐L as predictors of Alzheimer’s pathology. Here we build on the Amyblood 1‐42/1‐40 Simoa assay (1,2) where GFAP and NF‐L, as indicators of astrogliosis and neurodegeneration, further added to the prediction for Aβ PET imaging or diagnosis. We report a Simoa multiplex assay that simultaneously measures Aβ1‐42, Aβ1‐40, GFAP and NF‐L in blood.

Methods

A 4‐plex immunoassay was designed using Simoa technology. A monoclonal capture antibody specific for each analyte was attached to one of four different fluorescent dye‐encoded beads. Antibodies against Aβ1‐42 and Aβ1‐40 were from ADx (clones 21F12 and 2G3 as capture; 3D6 as detector), NF‐L and GFAP antibodies were as supplied in Quanterix commercial kits. The assay was further evaluated for its analytical performance, including analyte detectability in commercially‐sourced human plasma (n=20) and CSF (n=10) from healthy controls, and for discrimination between AD patient and control plasma (each n=10) from the Alzheimer Center Amsterdam.

Results

Assay calibration ranges were 0.041‐30pg/mL (Aβ1‐42), 0.016‐12pg/mL (Aβ1‐40), 6.86‐5000pg/mL (GFAP), and 0.686‐500pg/mL (NF‐L). Lower Limits of detection were 0.148pg/mL (Aβ1‐42), 0.084pg/mL (Aβ1‐40), 1.66pg/mL (GFAP), 0.157pg/mL (NF‐light). Limits of quantification for assay prototype were 0.381pg/mL (Aβ1‐42), 0.125pg/mL (Aβ1‐40), 4.99pg/mL (GFAP), 0.493pg/mL (NF‐light). In parallelism studies, mean recovery of serially diluted endogenous plasma and CSF (each n=4) was within 80‐120%. Grand mean recovery of expected spike concentration was within 70‐130% (n=4). The assay has 100% detectability for all four analytes in both plasma and CSF samples. NF‐L and GFAP concentrations increased in AD samples (respectively p<0.05 and 0.01) while the Aβ 42/40 ratio decreased (p<0.05) in AD samples versus healthy donors.

Conclusions

This multiplex Simoa assay accurately and specifically measure four biomarkers simultaneously in plasma and CSF, providing a new tool to quantify Aβ1‐42, Aβ1‐40, GFAP and NF‐L. Ongoing studies using a larger cohort of clinical samples will determine the potential clinical utility of this assay. References: (1)Verberk et al, Plasma amyloid, GFAP and NfL as predictors of Alzheimer’s pathology (AAIC 2019). (2)Stoops et al, Characterization and Transfer of a Novel Plasma Aβ1‐42/ Aβ1‐40 Simoa Assay for integration into the clinic (AAIC 2019).
An in silico target‐specific drug repurposing approach for autism
Authors: Marisse Lakshmi Prasanna , Sree G.N.S. Hema , Rajalekshmi Saraswathy Ganesan
Published: December 2020

Background

Autism a most disabling heterogenous neuro‐developmental disorder with vast heritability is exemplified by impaired social interaction, communication, motor function, cognition, restricted and repetitive stereotyped behaviors. The inability to identify risk factors and genetic variants associated with the pathogenesis has attributed to its complexity. The current research of autism is only focused on symptomatic relief rather than cure. This dearth in research for specific drugs aids in unwinding druggable targets via drug repurposing.

Method

The GEO dataset GSE22507 from National Centre for Biotechnology Information (NCBI) comprising the microarray data of 67 autistic children and 47 controls was selected. Increasing paternal age, an established risk factor for the development of autism was later considered for computing the median age of fathers in to young fathers, old fathers and total age. This data was analyzed through Geo2 Enrichr for retrieving significant differential expressed genes (DEG’s) which were processed for functional enrichment analysis though Database for Annotation Visualization and Integrated Discovery tool. Subsequently, protein‐protein interactions were constructed between DEG’s and literature derived genes using Search Tool for Retrieval of Interacting Genes. The common genes amongst the groups were identified and considered as potential targets. Selected targets and their respective drugs acquired from FDA were subjected to molecular docking studies through Extra Precision (XP) mode in Glide tool of Schrodinger drug design suite (version 10.7). The shortlisted targets were ranked and evaluated to energy calculations via MM‐GBSA.

Result

Protein‐protein interaction for all the groups revealed FOS a proto‐oncogene as the potential target. Drugs that are found to possess the best docking score and glide energy were further subjected to MM‐GBSA studies. Compounds exhibiting top binding free energies (∆G) i.e., ‐60 k.cal/mol are selected for literature survey. This survey revealed the affinity of 6 drugs namely, Pranlukast, Bemotrizinol, Ceforanid, Dasabuvir, Flavin Adenine Dinucleotide drugs. These drugs were not reported in literature for autism.

Conclusion

The FOS target should be validated further along with the aforementioned drugs in in vitro and in vivo to identify potential targets for a devastating disease like autism.
Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer’s disease risk in humans
Authors: Ma Yiyi , Yu Lei , Olah Marta , Smith Rebecca G. , Pishva Ehsan , Menon Vilas , Lunnon Katie , Bennett David A. , Klein Hans‐Ulrich , De Jager Philip L.
Published: December 2020

Background

Not all APOE ε4 carriers who survive to advanced age develop Alzheimer’s disease (AD); factors attenuating the ε4 risk on AD may exist.

Method

Guided by the top ε4‐attenuating signals from methylome‐wide association analyses (N = 572, ε4+ and ε4‐) of neurofibrillary tangles and neuritic plaques, we conducted a meta‐analysis for pathological AD within the ε4+ subgroups (N = 235) across four independent collections of brains. Cortical RNA‐seq and microglial morphology measurements were used in functional analyses.

Result

Three out of the four significant CpG sites were captured by one principle component (PC1), which interacts with ε4 on AD, and is associated with expressions of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 59% (OR = 2.41, 95%CI = [1.64,3.52], P = 7.40 × 10−6).

Conclusion

An epigenomic factor associated with a reduced proportion of activated microglia appears to attenuate the risk of ε4 on AD.
Brain amyloid accumulation and glucose hypometabolism in Chinese Alzheimer’s disease population
Authors: Ren Shuhua , Huang Qi , Jiang Donglang , Huang Lin , Wang Ying , Guan Yihui , Guo Qihao , Xie Fang
Published: December 2020

Background

Amyloid is the main pathology for Alzheimer’s disease (AD), amyloid and glucose metabolism alternation are very important to investigate the progress of Alzheimer’s disease. However, not so many results were reported in Chinese population. In this study, we try to figure out the brain structure, function alternation and brain network alternation in Chinese subjective cognitive decline (SCD), mild cognition impairment (MCI) and Alzheimer’s disease (AD) from the data of Chinese preclinical Alzheimer’s disease (C‐PAS), which is initiated by us.

Method

200 participants were enrolled in this study, including 93 normal cognition (NC) healthy volunteers, 37 SCD, 34 MCI and 36 AD patients.6 types of neuropsychological tests from 3 cognitive domains and MMSE, Moca B were performed. FDG and amyloid PET (18F‐Flortabetapir) were conducted in these participants. 18F‐FDG and 18F‐Flortabetapir PET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space. To assess the regional pattern of the 4 group, one‐way ANOVA followed by two sample t test for post hoc analysis were performed, The statistical level was set at p<0.05 with FDR correction and a minimum cluster extent Ke>20 voxels.

Results

In Chinese population, changed glucosemetabolism were present in Superior temporalcortex, inferior temporal cortex, superior occipital cortex, precuneus, frontal cortex, supra‐marginal gyrus, anterior cingulate cortex, insula in a multiple comparison of AD MCI, SCD, and NC. And amyloid plaque were found in temporal cortex, frontal cortex, middle occipital cortex, inferior parietal cortex, insular, lingual gyrus, calcarine fissure and surrounding cortex, cingulate gyrus, fusiform gyrus, gyrus rectus, angular gyrus in these participants. Most of these changes were from AD patients, but slight hypometabolism, and amyloid accumulation were found among NC, SCD, MCI.

Conclusion

Cortex and cingulate gyrus were the main regions for amyloid accumulation and glucose hypometabolism for Chinese AD patients. However, slight change was observed in NC, SCD, MCI participants.
Undulating changes in human plasma proteome profiles across the lifespan are linked to disease
Authors: Lehallier Benoit , Gate David , Schaum Nicholas , Nanasi Tibor , Lee Song Eun , Yousef Hanadie , Losada Patricia Moran , Berdnik Daniela , Keller Andreas , Verghese Joe , Sathyan Sanish , Franceschi Claudio , Milman Sofiya , Barzilai Nir , Wyss‐Coray Tony
Published: December 2020

Background

Aging is a predominant risk factor for numerous chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, which supports a hypothesis that age‐related molecular changes in blood could provide novel insights into age‐related disease biology.

Method

We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18‐95 years old) using an aptamer‐based platform.

Result

We identified a proteomic clock that can be used to predict chronological age. Deviations from this plasma proteomic clock are correlated with changes in clinical and functional parameters in healthy subjects and AD patients from the Addneuromed cohort have an older proteomic age than their chronologic age (n=641). We are currently expanding this analysis to 881 healthy controls, MCI and AD subjects of the EMIF‐AD consortium. Thus, this panel of proteins can be used to assess the relative health of an individual and to measure healthspan, analogous to epigenetic clocks based on DNA methylation patterns. In addition, we describe a 46‐protein aging signature that is conserved in humans and mice, allowing deeper investigation of translational aging interventions in mice. Finally, we developed a novel bioinformatics approach, which uncovered marked non‐linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age‐related diseases and phenotypic traits.

Conclusion

This new approach to the study of aging led to the identification of unexpected signatures and pathways, which might offer potential targets for age‐related diseases. Our results also have strong implications for the development of diagnostic and prognostic tests. Indeed, the undulating nature of the aging plasma proteome and its interactions with diseases has to be considered when developing proteomic signatures for diagnostic purposes. Such reliable tests are still urgently needed for Alzheimer’s disease.
Effects of magnetic nanoparticle hyperthermia on the disruption of beta‐amyloid and microglia‐mediated inflammation
Authors: Dyne Eric , Li Junfeng , Cawood Meghan , Yu Bing , Huang Songping , Kim Min‐Ho
Published: December 2020

Background

Insoluble and aggregated forms of beta‐amyloid peptides (Aβ) were shown to contribute to chronic inflammation in Alzheimer’s disease, in large part due to an impaired ability of microglial cells to clear Aβ when they form insoluble large aggregates. The objective of this study is to validate whether the application of mild magnetic nanoparticle (MNP) hyperthermia, which can generate heat on the surface of MNPs selectively attached to the Aβ aggregates to a remotely applied alternating magnetic field (AMF), is sufficient to disaggregate Aβ plaques and if then, can this alter the phagocytic and inflammatory responses of microglial cells towards the clearance of Aβ plaques.

Methods

Aggregated Aβ peptides were prepared by incubating beta‐amyloid1‐42 peptides for 16 h, which resulted in 2‐10 um size of Aβ. Varying concentrations (1‐3 mg/mL) of MNPs (20 nm, paramagnetic nanoparticles) were added to the wells containing Aβ fibrils and incubated for 2 h, The samples were then treated with an AMF for 10 min duration at a field strength of 30 kA/m. The extent of Aβ disruption was assessed by using dynamic light scattering particle analysis and ultrastructure microscopy. The fragmented Aβ samples received with MNP/AMF were subsequently treated to the culture of human microglial cells (C20 cell line and HMC3 cell line (CRL‐3304™)), and changes in expression of pro‐ and anti‐inflammatory genes as well as phagocytic activity were quantified.

Results

The application of MNP/AMF for 10 min resulted in disaggregation of Aβ into smaller fragments, which was positively related to MNP concentration. The expression of pro‐inflammatory genes, IL‐1β and TNF‐α, in microglial cells were increased in the presence of large aggregate of Aβ plaques compared to an untreated control. However, the responses were significantly attenuated when cells were treated with Aβ plaques treated with MNP/AMF, which was associated with an increase in the uptake of Ab by microglia.

Conclusions

Our results demonstrate that a localized heating of magnetic nanoparticles localized around Aβ plaques is enough to disrupt the chemical bonds between beta‐amyloid plaques by destabilizing the aggregates, which could promote the functional activity of microglial cells towards clearance of beta‐amyloid debris, eliciting the attenuation of pro‐inflammatory signaling.
The effect of age on tau burden is dependent on amyloid status in late‐onset Alzheimer's disease
Authors: Ottoy Julie , Kang Min Su , Savard Melissa , Mathotaarachchi Sulantha , Pascoal Tharick A. , Chamoun Mira , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

Growing evidence suggests that middle‐aged subjects with early‐onset AD show higher tau burden and more rapid tau accumulation compared to elderly. Here, we aim to investigate the effects of age, the greatest risk factor in AD, on amyloid, tau, and neuroinflammation in late‐onset AD. We hypothesized the independent effect of age on amyloid and neuroinflammation. However, the effect of age on tau would depend on amyloid load in AD.

Method

A total of 106 participants (66 A‐T‐, age 20‐86y; 40 A+T‐/A+T+, age 65‐84y) from the TRIAD cohort underwent static 40‐60min 18F‐AZD4694, 90‐110min 18F‐MK620, and 60‐90min 11C‐PBR28 SUVR, as well as MOCA and CDR‐SOB cognitive testing. All images were normalized to the ADNI template, and used cerebellar gray matter as the reference region. The effects of age on amyloid, tau, or neuroinflammation, as well as the interactive effect between age and AT status based on linear regression models. Last, the age‐dependent effect of amyloid, tau, or neuroinflammation on cognition is investigated. All models were corrected for sex, APOE, education, and remaining PET variables.

Result

We showed a positive main effect of age on amyloid (p<0.001) or neuroinflammation (p=0.05) while no interactive effect between age and AT status was observed. However, a significant interaction between age and AT status on tau in Braakstage1‐2 (p=0.01), Braakstage3‐4 (p=0.001), and Braakstage5‐6 (p=0.002) were observed (Figure1). In relation to cognition, younger subjects with higher tau load performed worse on cognitive testing as shown by a significant negative interaction between age and tau on MOCA. In contrast, age and amyloid showed a positive interactive effect on cognition.

Conclusion

Our study demonstrated that the age and amyloid or neuroinflammation have a positive association irrespective of the disease status. However, the effect of age on tau deposition depends on the amyloid load such that the presence of pathologic Ab leads to greater tau burden at younger age and worse cognition in late‐onset AD. This supports the framework where tau burden depends on amyloid load following the Ab cascade hypothesis.
Prevalence of subjective cognitive decline higher among transgender and gender nonbinary adults in the U.S., 2016‐2018
Authors: Lambrou Nickolas H , Gleason Carey E , Cicero Ethan , Flatt Jason D
Published: December 2020

Background

Subjective cognitive decline (SCD), or self‐reported cognitive problems may represent an early sign of Alzheimer’s disease. Little is known about SCD prevalence among gender minorities (GM), or those who do not identify as cisgender (e.g., transgender and gender nonbinary people). The term cisgender refers to individuals whose gender identity is aligned with the sex they were assigned at birth.

Methods

We examined data from 11 U.S. states administering both optional SCD and GM modules of the Behavioral Risk Factor Surveillance System (BRFSS) between 2016‐2018. The annual BRFSS survey used random digit dialing via cellphones and landlines to assess the health and health behaviors of U.S. adults. Of those aged ≥45 years (N=59,690), 408 respondents identified as a GM. SCD represented reports of confusion or memory loss happening more often or worsening during the previous 12 months. Multivariable logistic regression was used to examine associations between GM identity and SCD adjusting for demographic characteristics.

Results

GM adults were more likely to report SCD (15%) compared to cisgender adults (10%; p < 0.001). Among GMs, 14% of transgender adults and nearly 17% of gender nonbinary adults reported SCD. After accounting for demographic characteristics, GMs were 37% more likely to report SCD compared to cisgender adults (Adjusted Odds Ratio = 1.37; 95% Confidence Interval = 1.04, 1.80). GMs with SCD were significantly more likely to report giving up day‐to‐day activities (50% vs. 34%), needing assistance with day‐to‐day activities (50% vs. 30%), and being unable to work or participate in social activities (42% vs. 31%) compared to cisgender adults. In addition, GMs with SCD were significantly more likely to report difficulties in obtaining caregiving or help with day‐to‐day activities (22% vs. 13%) compared to cisgender adults.

Conclusions

This is among the first population‐based studies to explore SCD with transgender and gender nonbinary adults. Given the higher rates of SCD in GM adults compared to their cisgender counterparts; additional research specifically focused on GM identities, psychosocial factors, and cognitive health is recommended. Efforts aimed at screening for Alzheimer’s and developing tailored interventions and care services should be considered.
Clostridium shows a higher abundance in less neurovascular and neurodegenerative changes: A microbiome‐wide association study
Authors: Karamujić‐Čomić Hata , Ahmad Shahzad , Radjabzadeh Djawad , Bonnechere Bruno , Kaddurah‐Daouk Rima F. , Kraaij Robert , Ikram M. Arfan , Amin Najaf , van Duijn Cornelia M.
Published: December 2020

Background

There is an important interplay between the gut microbiome and brain, commonly known as the gut‐brain‐axis. Several studies addressed the role of the microbiome in neurologic diseases. Here, we studied the role of microbiota in cognitive function, neurovascular changes, and neurodegenerative changes in the general population.

Method

In the population‐based Rotterdam Study, we studied the association between microbial taxa and cognitive function in 1,184 participants and the association between microbial taxa and neurovascular and neurodegenerative traits, measured on brain magnetic resonance imaging, in 1,241 participants. Gut microbiota were profiled using 16 s rRNA gene sequencing. We used linear regression analysis to study these associations and adjusted for major confounders, i.e., age, sex, technical covariates, medication use, alcohol, smoking, body mass index, and hypertension.

Result

We found that the genus Clostridium sensu stricto 1 showed a higher abundance in participants with better cognitive function (beta(β)(standard error(SE)) 0.023(0.01), p = 3.22 × 10−2), larger global brain volume (β(SE) 0.0019(0.0006), p = 1.83 × 10−3), less white matter hyperintensities (β(SE) ‐0.024(0.007), p = 5.38 × 10−4), and smaller lateral ventricular volume (β(SE) ‐0.013(0.005), p = 1.81 × 10−2). The family Clostridiaceae 1 also showed a higher abundance in these traits, with the same direction of effect and very similar effect estimates. The class Clostridia, order Clostridiales, family Christensenellaceae, and genus Christensenellaceae R7 group showed a higher abundance in better cognition. Of note is that the agreement of our findings with those of studies of Alzheimer’s disease is high.

Conclusion

Clostridium shows a higher abundance in less neurovascular changes, in less neurodegenerative changes, and in better cognition. We find that different microbiota are associated to neurovascular and neurodegenerative pathology.
Cerebral microbleeds on 7 Tesla MRI in preclinical Alzheimer’s disease: The Medea‐7T study
Authors: Zwartbol Maarten H.T. , Ghaznawi Rashid , Blom Kim , Kuijf Hugo J. , Witkamp Theo , Hendrikse Jeroen , Geerlings Mirjam I.
Published: December 2020

Background

Subjective cognitive decline is increasingly being viewed as an early cognitive marker of preclinical Alzheimer’s disease (AD). Studies have recommended including AD biomarkers to increase the specificity of subjective cognitive decline, because of its etiological heterogeneity. We studied the prevalence and burden of cerebral microbleeds in persons with normal cognition, subjective memory impairment, cognitive impairment, and a clinical diagnosis mild cognitive impairment (MCI) or AD.

Methods

Data are from 386 participants (68±9 years, 30% women) included in the Medea‐7T cohort, a diverse cohort of persons with normal cognition, patients with a history of vascular disease, and memory clinic patients. A 7T brain MRI was performed in all participants. Four cognitive stages were defined: 1) normal cognition (n=196); 2) subjective memory impairment (n=78); 3) cognitive impairment (defined as <1.5 SD below age, sex, and education adjusted Z‐scores in any cognitive domain within the study sample) (n=57); 4) MCI/AD diagnosed according to international criteria (n=36). CMBs were visually rated on 7T MRI according to established criteria. Age‐ and sex‐adjusted log‐binomial regression was performed to examine the association between the cognitive stages and presence of CMBs (yes vs. no).

Results

Overall microbleed prevalence was 61%, with estimates per cognitive stage: normal cognitive function 60%, SCD 73%, cognitive impairment 55%, MCI and AD 47% (Figure 1). Age‐ and sex‐adjusted log‐binomial regression showed that—compared with the normal group—differences in microbleed prevalence were not statistically significant. Nonetheless, SCD showed an increased risk of CMBs (RR=1.18; 95% CI, 0.99‐1.41; p=0.06), whereas MCI/AD showed a decreased risk (RR=0.68; 95% CI, 0.45‐1.02; p=0.06), both approaching statistical significance.

Conclusion

In this study, cerebral microbleeds on 7T MRI were highly prevalent in older persons with normal cognition, subjective memory impairment, and MCI/AD. Differences observed between groups may reflect differences in underlying dominant etiology.
Transcutaneous vagus nerve stimulation increases locus coeruleus function and memory performance in older individuals
Authors: Jacobs Heidi I.L. , Priovoulos Nikos , Riphagen Joost M , Poser Benedikt A. , Napadow Vitaly , Uludag Kamil , Sclocco Roberta , Ivanov Dimo , Verhey Frans R.J.
Published: December 2020

Background

Animal studies reported that vagus nerve stimulation increases noradrenalin release in target areas of the locus coeruleus (LC). Furthermore, after stimulation, animals exhibited improved retention performance. Evidence for memory improvement using transcutaneous vagus nerve stimulation (tVNS), a non‐invasive alternative, is scarce. Given that the LC is affected by tau pathology early in life, we aimed to examine 1) whether tVNS can improve memory performance in older individuals and 2) whether tVNS targets the LC in older individuals.

Method

Two separate cross‐over single‐blind randomized studies were performed. In study one, 30 healthy older individuals (Mean age:60.57 years, 50% male) underwent tVNS and Sham during face‐name learning. Bias‐corrected scores across the experimental conditions were analyzed using a repeated measures ANOVA. In study two, 16 older individuals (median age:71.15 years, 56% male) underwent respiratory‐gated tVNS and Sham during 2 sessions of 7T fMRI involving a face‐name learning task. The bias‐corrected behavioral scores were compared using LME. The BOLD data were motion, distortion and ICA‐FIX denoised and we fitted a GLM for stimulation on> stimulation off within session, within participant (tVNS>Sham). The group‐average tVNS effect was estimated. For the LC, we performed analyses within a small volume search space at p<0.05. For the rest of the brain, cluster‐wise correction was applied.

Result

Both studies demonstrated higher scores on the memory task during tVNS as compared to the sham condition (tVNS versus Sham, p=0.037, Cohen’s d=0.35) but effect sizes were greater for the respiratory gated tVNS experiment (tVNS versus Sham: p=0.04, Cohen’s d=0.55). The BOLD map showed bilateral activation of the caudal LC during tVNS compared to Sham (peak z‐value=3.44). Positive clusters (tVNS>Sham) were also observed in several regions, including the prefrontal and temporal cortex, insula, thalamus, hippocampus and putamen. Negative clusters were observed in the basolateral amygdala and cornu ammonis 1.

Conclusion

In older individuals, alterations in the functioning of the locus coeruleus network may mediate the positive effects of tVNS on memory performance in older individuals. Our previous work demonstrated that noradrenalin‐dysregulation was associated with greater tau. Future work will explore the efficacy and disease‐modifying potential of tVNS in cognitively impaired individuals.
Trajectories of decline in cognitively complex everyday activities across the Alzheimer’s disease continuum
Authors: Dubbelman Mark A. , Jutten Roos J. , Farias Sarah Tomaszewski , Amariglio Rebecca , Buckley Rachel F. , Visser Pieter Jelle , Rentz Dorene M. , Johnson Keith A. , Properzi Michael J. , Schultz Aaron P. , Donovan Nancy , Gatchel Jennifer R. , Teunissen Charlotte E. , Van Berckel Bart N.M. , van Der Flier Wiesje , Sperling Reisa A. , Papp Kathryn V. , Scheltens Philip , Marshall Gad A. , Sikkes Sietske A.M.
Published: December 2020

Background

Assessment of daily functioning may be used to capture clinically meaningful decline in Alzheimer’s disease (AD). In this multi‐center study, we aimed to investigate ‘instrumental activities of daily living’ (IADL) trajectories along the AD disease continuum from no symptoms to overt dementia, as defined in the 2018 National Institute on Aging – Alzheimer’s Association research framework (Jack et al., 2018).

Method

A total of 1,557 individuals with longitudinal IADL data (72.1±8 years; 41% female; mean follow‐up 2.4±2 years) were selected from memory clinics and community‐based cohorts (Harvard Aging Brain Study, ADNI, National Alzheimer’s Coordinating Center, Amsterdam Dementia Cohort and EMIF‐AD PreclinAD and 90+). Amyloid positivity was determined at baseline using positron emission tomography or cerebrospinal fluid. Amyloid positive individuals (n=980) were classified into four NIA‐AA clinical stages based on cut‐offs on measures of subjective cognitive decline and cognitive functioning (Table 1, independent of IADL measures). Amyloid negative individuals without memory impairment or complaints (n=577) served as a control group. Everyday functioning was assessed using study‐partner‐based questionnaires as available in the different cohorts: the Everyday Cognition, Functional Activities Questionnaire and Amsterdam IADL Questionnaire. To allow comparison between the instruments, scores were standardized into Z‐scores using baseline means and standard deviations in the control group. Changes over time were analyzed using linear mixed models with random intercepts and slopes.

Result

Baseline characteristics and distribution of individuals across stages can be found in Table 2. Baseline Z‐scores did not differ between amyloid negatives and stage 1; baseline Z‐scores were significantly lower in each following stage. A decline in function was found across the AD continuum, which accelerated along the clinical stages (Figure 1 and Table 3). From stage 2 onwards, IADL decline was faster compared to controls (β=‐0.085, 95% confidence interval = [‐0.116, ‐0.053], adjusted for age, sex, and education; Table 3).

Conclusion

Our results suggest that AD‐related functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive stage in people with amyloid pathology. These findings were robust across different cohorts, and can be used to inform participant selection and trial design for AD clinical trials.
Mild behavioral impairment is associated with atrophy in Alzheimer's disease‐related regions in non‐demented older adults
Authors: Matuskova Veronika , Ismail Zahinoor , Nikolai Tomas , Markova Hana , Cechova Katerina , Laczó Jan , Nedelska Zuzana , Lerch Ondrej , Hort Jakub , Vyhnalek Martin
Published: December 2020

Background

Mild behavioral impairment (MBI) is a recently developed diagnostic concept describing late‐onset persistent neuropsychiatric symptoms (NPS) in older adults without dementia. Few studies to date investigated associations of MBI with structural brain changes. Our aim was to explore structural correlates of NPS in a non‐demented memory clinic sample using the Mild Behavioral Impairment Checklist (MBI‐C) that has been developed to measure MBI.

Method

116 non‐demented older adults from the Czech Brain Aging Study presenting with subjective cognitive concerns underwent a neurological, comprehensive neuropsychological examination and brain MRI and were classified as subjective cognitive decline (n=37, MMSE=29.30±0.88) or mild cognitive impairment (n=79, MMSE=26.82±2.51). The Czech version of MBI‐C was administered to participants´ informants. 1.5T MRI with T1‐weighted 3‐dimensional images and FreeSurfer 5.3. algorithm was used to measure a priori selected brain regions: thicknesses of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and entorhinal cortex (ERC) and hippocampal volume (HV) adjusted for total intracranial volume. The volumetric measures were averaged between the two hemispheres. The associations of the MBI‐C total score and five domain scores with the aforementioned regions were assessed within the whole sample using covariate‐adjusted Spearman Rank correlations.

Result

Significant associations of MBI‐C total score were found with HV (rho=‐.225, p=.016), ERC (rho=‐.284, p=.002) and OFC (rho=‐.214, p=.023) while controlling for sex, age and education. Both latter associations remained significant after controlling also for MMSE. We found associations of HV with both motivation (rho=‐.248, p=.008) and impulse dyscontrol scores (rho=‐.240, p=.011), ERC with impulse dyscontrol (rho=‐.368, p<.001) and OFC with motivation score (rho=‐.201, p=.033). No other associations were observed.

Conclusion

NPS (particularly in motivation and impulse dyscontrol domains) detected by the MBI‐C in non‐demented older adults are associated with structural changes in typical Alzheimer´s disease‐related regions. This provides supportive evidence for MBI as an early manifestation of AD.