bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug repurposing for Alzheimer’s disease: Selective serotonin reuptake inhibitors
Authors: Rao Praveen P. Nekkar , Tin Gary , Mohamed Tarek , Shakeri Arash , Pham Amy Trinh
Published: December 2020

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder which affects more than 50 million people across the globe. Unfortunately, the current pharmacotherapy options are very limited and provide only symptomatic relief. Several drug discovery efforts to treat AD have failed in the clinical trials which is a setback in discovering novel anti‐AD therapies. Considering the cost, time and risks involved in bringing a new drug from the bench‐to‐bedside, drug repurposing or discovering novel therapeutic indications for drugs already in the market is an attractive alternative to find novel AD therapies. Targeting the amyloid (Aβ) cascade event in AD is one of the several potential targets to develop novel anti‐AD agents. Our studies looked at the possibility of repurposing marketed selective serotonin reuptake inhibitors (SSRIs) fluvoxamine, fluoxetine, paroxetine, sertraline and escitalopram in AD and investigated their anti‐Aβ aggregation properties.

Method

Experiments conducted include fluorescence aggregation kinetics using the dye thioflavin T (ThT), determining Aβ morphology in the presence and absence of SSRIs by transmission electron microscopy (TEM) and computational modeling using the software Discovery Studio Structure‐Based‐Design.

Result

These experiments demonstrated that among the SSRIs tested, paroxetine in particular was able to prevent the aggregation of both Aβ40 and Aβ42 peptides. Computational studies were used to understand the interactions of paroxetine with Aβ40 and Aβ42 oligomer and fibrils models.

Conclusion

These studies suggest that the antidepressant paroxetine has the potential to target the amyloid cascade in AD. Further studies are required to determine the suitability of repurposing paroxetine to treat AD.
Association of the motoric cognitive risk syndrome with levels of perceived social support
Authors: Felix Nicole , Ayers Emmeline , Verghese Joe , Blumen Helena M
Published: December 2020

Background

The Motoric Cognitive Risk (MCR) Syndrome is a pre‐dementia syndrome characterized by slow gait and cognitive complaints that predicts dementia. It remains unclear whether decreased levels of social support predict MCR. Our goal is to assess the risk of developing MCR as a function of varying levels of self‐reported social support in the categories of: (a) emotional/information support (b) tangible support (c) affectionate support and (d) positive social interactions.

Methods

Our prospective cohort study sampled male and female older adults between 65 and 96 years old, with a mean age of 77, and with no MCR or dementia at baseline. We calculated MCR incidence based on participants’ levels of perceived social support with adjustments for age, sex, race/ethnicity, years of education, global health score, geriatric depression scale score, and marital status. Cox regression analyses were used to estimate hazard ratios with 95% confidence intervals across a one to seven‐year time span and a median follow‐up time of 2.5 years.

Results

Thirty‐eight participants (9.8%) developed MCR. Increased tangible support decreased the risk of MCR by 30.9% [aHR:0.691, 95% CI (.523‐.915), p=0.010]. A higher overall social support score also decreased the risk of MCR by 33.8% [aHR: 0.662, 95% CI (.456‐.962), p=0.031]. The other categories of social support as well as the Social Network Index (SNI) scores were not significantly associated with a decreased risk of MCR (p>.05).

Conclusions

Increased social support, especially tangible support, may prove protective against MCR, dementia and other forms of cognitive decline.
Dementia prevalence in Torres Strait communities
Authors: Strivens Edward , Russell Sarah G , Quigley Rachel , Sagigi Betty , Miller Gavin
Published: December 2020

Background

Dementia prevalence in Aboriginal communities is amongst the highest in the world, with rates up to three to five times higher than the wider Australian community being reported. Risk factors identified included age, male gender, lack of formal education, smoking, stroke, epilepsy, head injury, poor mobility, falls, and incontinence. However, Australia has two culturally distinct Indigenous populations, and it is not known if Torres Strait Islander peoples, who comprise 10% of all Indigenous Australians, share this increased risk of dementia. The aim of this study was to assess dementia prevalence in the Torres Strait and investigate factors associated with dementia risk.

Method

A total of 322 residents living in the Torres Strait in Far North Queensland (94% Indigenous) participated in a comprehensive diagnostic Geriatrician assessment. Mean age of the sample was 64.58 (SD11.2, range 41‐93) and 37.3% were male. All had some formal education (30.6% primary school only). Using consensus diagnosis, participants were diagnosed with dementia, cognitive impairment no dementia or normal cognition according to DSM IV criteria.

Results

Consistent with findings in Aboriginal communities, the prevalence of dementia in the sample was 2.94 times higher than the wider Australian population. Over 14% of the sample were diagnosed with dementia and a further 21% with Cognitive Impairment No Dementia. Preliminary results showed that age, education, hypertension, heart disease, chronic kidney disease, previous stroke, falls risk and pain were associated with dementia in this sample.

Conclusion

Torres Strait Islander peoples share an increased risk of dementia seen in Aboriginal Australians compared to the wider community but have a distinct pattern of risk factors. This highlights the need for tailored interventions to address this increased dementia risk for different Indigenous communities.
Variability in working memory performance on mobile devices is sensitive to mild cognitive impairment: Results from the Einstein Aging Study
Authors: Cerino Eric S. , Hyun Jinshil , Hakun Jonathan G. , Roque Nelson A. , Lipton Richard B. , Sliwinski Martin J.
Published: December 2020

Background

Most prior research on distinguishing cognitive impairment from healthy controls focuses on measuring mean‐level of cognitive performance on one or relatively few assessments, ignoring potentially valuable information about variability. Within‐person variability in cognitive performance is emerging as a promising indicator of mild cognitive impairment (MCI) and dementia. The limited research on this topic, however, typically examines speeded responses and variability transpiring across moments during a single test administration. The current study extends prior work by using ecological momentary assessments (EMA) to examine cognitive status differences in variability across hours and days in three dimensions of working memory (WM): object‐location binding, object‐feature binding, and spatial WM.

Method

In a sample of 243 systematically recruited, community‐dwelling adults age 70+ from the Einstein Aging Study (Mean age=77.46 years, SD=5.13), we identified 68 individuals meeting Jak‐Bondi criteria for MCI and 175 cognitively normal controls (Table 1). All participants performed object‐location binding, object‐feature binding, and spatial WM tasks on a smartphone up to four times daily for 14 days, totaling up to 56 assessments per person. We employed heterogeneous variance models using log‐linear prediction of residual variance to simultaneously assess MCI differences in mean performance and within‐person variability. Models adjusted for linear trends across assessments and study days, as well as age, education, gender, and ethnicity (Table 2; Figure 1).

Results

For mean performance, individuals with MCI exhibited worse performance than healthy controls in measures of object‐location binding (Est.=0.14, SE=0.02, p<.001), object‐feature binding (Est.=‐0.27, SE=0.04, p<.001), and spatial WM (Est.=0.90, SE=0.20, p<.001). For variability across assessments, individuals with MCI exhibited greater within‐person variability than controls in object‐location binding (Est.=0.89, SE=0.03, p<.001) and object‐feature binding (Est.=0.37, SE=0.03, p<.001) performance. Variability in spatial WM performance did not vary as a function of cognitive status (Est.=0.02, SE=0.03, p=.63).

Conclusion

Results suggest both mean and variability in performance are sensitive to MCI and exhibit dissociative patterns by WM dimension. Variability in object‐location and object‐feature binding performance may provide specific detection of MCI. The 14‐day smartphone‐based EMA offers novel opportunity to leverage performance variability across frequent assessments for identifying early clinical manifestations of cognitive impairment.
Proteomic analysis of microglia during LPS‐induced acute neuroinflammation
Authors: Cartier Anna , Yeung Bertrand , Moyron‐Quiroz Juan , Gao Qing , Hunag Tse Shun , Nazor Kristopher , Tan Miguel
Published: December 2020

Background

Dysregulation of microglia function is associated with neuroinflammation. A major limitation in understanding microglial contribution to cellular processes and their role in disease has been the lack of tools to specifically distinguish these cells from other myeloid cells.

Method

We generated and validated a rat monoclonal antibody against a highly selective microglia marker P2RY12. We utilized LPS administration as a model for neuroinflammation to assess alterations in P2RY12 expression, a homeostatic protein. To gain better understanding of microglial function, we assessed their proteomic profile using BioLegend’s proprietary technology, TotalSeq™, which allows simultaneous analysis of both the transcriptome and proteome at the single‐cell level.

Result

Mice were injected with either PBS, low or high dosages of LPS daily for 4 days after which microglia were harvested from the brain. Isolated cells were co‐stained with CD11b, CX3CR1, and P2RY12 as general markers for microglia. Flow cytometric quantification using live cells showed a significant increase in CD11b+ expression in both low and high dose LPS treated mice compared to the control untreated group. Low and high dose LPS injections led to a significant reduction in P2RY12 and CX3CR1 expression in these cells. These data are consistent with a decrease in P2RY12 expression under inflammatory conditions. We utilized a panel of 200 antibody‐oligonucleotide conjugates from our TotalSeq™ platform, including P2RY12, CD11b, CD45, and CX3CR1, to analyze differentially expressed proteins under normal and LPS‐induced inflammation in mice.

Conclusion

These studies help elucidate the diversity and physiology of microglia, and potentially aid in the discovery of novel markers in response to neuroinflammation. Our future goal is to extend our studies and use our platform to assess alternations in microglial response in neurodegeneration.
Effect of interferon regulatory factor 5 in LPS‐induced neuro‐inflammation
Authors: Fan Ziqi
Published: December 2020

Background

Activated microglia plays a central role in neuro‐inflammation in central nervous system (CNS), which is involved in the progress of disease. Interferon regulatory factor 5 (IRF5) has been well established relating to inflammatory responses and is highly expressed in M1 macrophage in periphery, the role of which in the CNS remains elusive.

Method

Down‐regulation of IRF5 by siRNA in C57/BL6 mice and BV2 microglial cells was employed. Lipopolysaccharide (LPS) challenge activates the response of neuro‐inflammation, Pro‐inflammatory cytokines were evaluated by ELISA, western blot, and real‐time PCR.

Result

LPS induced the activation of microglia, which co‐localized with the significantly increase expression of IRF5. Down‐regulation of IRF5 significantly quenched the pro‐inflammatory responses. The levels of pro‐inflammatory cytokine TNF‐α, IL‐1βand IL‐6 were significantly up‐regulated at 4h after LPS treatment, which were reduced with the down‐regulation of IRF5. However, LPS did not up‐regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS induced inflammation does not involve IRF5 signaling.

Conclusion

IRF5 plays an important role in the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. BV2 microglia is not an ideal cell line for the studies involves IRF5.
Prediction of clinical diagnosis of Alzheimer’s disease, vascular, mixed, and all‐cause dementia by a polygenic risk score and APOE status in a community‐based cohort prospectively followed over 17 years
Authors: Stocker Hannah , Perna Laura , Weigl Korbinian , Möllers Tobias , Thomsen Hauke , Schöttker Ben , Holleczek Bernd , Rujescu Dan , Brenner Hermann
Published: December 2020

Background

The strongest genetic risk factor for Alzheimer’s disease (AD) is the ε4 allele of Apolipoprotein E (APOE4) and recent genome‐wide association (GWA) meta‐analyses have confirmed additional associated genetic loci with smaller effects. The aim of this study was to investigate the ability of an AD polygenic risk score (PRS) and APOE status to predict clinical diagnosis of AD, vascular (VD), mixed (MD), and all‐cause dementia in a community‐based cohort prospectively followed over 17 years and secondarily across age, sex and education strata.

Method

A PRS encompassing genetic variants reaching genome‐wide significant associations to AD (excluding APOE) from the most recent genome‐wide association meta‐analysis data was calculated and APOE status was determined in 5 351 participants. During follow‐up, 109, 113, 59, and 366 participants were diagnosed with AD, VD, MD, and all‐cause dementia, respectively. Prediction ability of AD, VD, MD, and all‐cause dementia by the PRS and APOE was assessed by multiple logistic regression and receiver operating characteristic curve analyses.

Result

The PRS per standard deviation increase in score and APOE4 (≥ 1 e4 allele) positivity were significantly associated with greater odds of AD (PRS OR, 95% CI: 1.70, 1.45‐2.03; APOE4 OR, 95% CI: 3.21, 2.14‐4.80) and AD prediction accuracy was significantly improved when adding the PRS to a base model of age, sex and education (ASE) (c‐statistics: ASE, 0.772; ASE+PRS, 0.809).

Conclusion

The PRS enriched the ability of APOE4 to discern AD with stronger associations than to VD, MD, or all‐cause dementia in a prospective community‐based cohort.
A brain penetrant progranulin biotherapeutic rescues lysosomal and inflammatory phenotypes in the brain of GRN knockout mice
Authors: Logan Todd , DeVos Sarah , Simon Matthew J. , Davis Sonnet , Wang Junhua , Low Ray , Huang Fen , Rajendra Yashas , Prorok Rachel , Sun Elizabeth , Rana Anil , Hsiao‐Nakamoto Jennifer , Mosesova Sofia , Zhu Yuda , Cherf Gerald M. , Lengerich Bettina , Bhalla Akhil , Kim Do Jin , Chan Darren , Duque Joseph , Tran Hai , Lenser Melina , Nguyen Hoang , Chau Roni , Earr Timothy , Kariolis Mihalis S. , Monroe Kathryn M. , Sanchez Pascal E. , Dennis Mark S. , Henne Kirk R. , Gunasekaran Kannan , Astarita Giuseppe , Watts Ryan J. , Sweeney Zachary K. , Lewcock Joseph W. , Srivastava Ankita , Di Paolo Gilbert
Published: December 2020

Background

Heterozygous loss of function (LOF) mutations in GRN cause frontotemporal dementia (FTD), a neurodegenerative disorder associated with lysosomal dysfunction, TDP‐43 pathology and inflammation in the CNS. Additionally, homozygous LOF mutations cause neuronal ceroid lipofuscinosis, a lysosomal storage disorder. GRN encodes progranulin (PGRN), a soluble protein that is most abundantly expressed in microglia, where it localizes to lysosomes and can undergo secretion. Although the precise function of PGRN is unknown, growing evidence suggests that it regulates lysosomal function, inflammatory responses and promotes neuronal survival. Accordingly, PGRN LOF models are associated with lysosomal defects, hyperinflammatory responses, and decreased neuronal viability, both in vitro and in vivo. Because GRN‐FTD patients exhibit reduced levels of PGRN in biofluids and tissues, including the brain, a protein replacement therapy analogous to enzyme replacement therapy and capable of crossing the blood brain barrier (BBB) more efficiently may represent a powerful approach to slow or prevent disease progression.

Method

Here we describe a novel therapeutic for increasing brain penetrance of PGRN, referred to as Protein Transport Vehicle (PTV):PGRN. PTV:PGRN consists of recombinant human PGRN fused to a modified Fc domain engineered to bind to the human transferrin receptor (huTfR), thus facilitating receptor‐mediated transcytosis across the BBB.

Result

We found that extracellular applications of PTV:PGRN rescue a range of Grn KO cell phenotypes in vitro, including lysosomal proteolysis and alteration in the levels of bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid involved in lysosomal lipid catabolism. Intravenously administered PTV:PGRN showed increased acute brain exposure in huTfR knock‐in (TfRmu/hu) mice relative to a regular Fc:PGRN fusion that does not bind to huTfR. Importantly, low doses of PTV:PGRN, but not Fc:PGRN, fully corrected lysosomal lipid alterations, including BMP deficiency, as well as inflammatory markers in the brain of Grn KO x TfRmu/hu mice.

Conclusion

Our data suggest that PTV:PGRN may represent a viable therapeutic strategy for the treatment of GRN‐FTD and potentially other disorders associated with PGRN deficiency.
Selective targeting of plaque‐associated microglia through systemic dendrimer administration in an Alzheimer’s disease model
Authors: Henningfield Caden M. , Cleland Jeffrey L. , Sharma Rishi , Green Kim N
Published: December 2020

Background

In Alzheimer’s disease (AD) microglia surround extracellular plaques and mount a sustained inflammatory response. Microglial elimination studies, as well as targeted microglial gene deletion studies, have suggested that this sustained microglial response to plaques contributes to the pathogenesis of the disease, including in plaque homeostasis, as well as contributing to synaptic and neuronal loss. The ability to specifically target plaque associated microglia would afford a powerful tool and potential therapeutic avenue. To that end, we sought proof of principle to target plaque associated microglia while leaving other microglia unaffected, via systemically administered Cy5 labelled hydroxyl dendrimers.

Method

To specifically target plaque associated microglia, we performed intraperitoneal injections with hydroxyl dendrimers conjugated to a Cy5 fluorophore into 5xFAD mice. Dendrimers are symmetric and highly branched molecules which are selectively endocytosed by reactive cells at sites of inflammation. To test whether we could alter plaque associated microglia phenotypes via peripheral drug administration, we next injected 5xFAD mice intraperitoneally with hydroxyl dendrimers conjugated to N‐acetyl cysteine, OP‐101, which has demonstrated ability to cause normalization of reactive microglia in several animal models.

Result

Here, we find that hydroxyl dendrimers are selectively taken up by reactive microglia surrounding plaques in the brain parenchyma of 5xFAD mice. The hydroxyl dendrimers co‐localize with lysosomal (CD68+) puncta in the microglia and do not co‐localize with neurons, astrocytes, or oligodendrocytes. The impact of OP‐101 on microglia in the 5xFAD mouse as measured by RNAseq will also be presented.

Conclusion

These data provide evidence that hydroxyl dendrimers are specifically taken up by reactive microglia rather than other central nervous system cells. This study demonstrated that systemic administration of hydroxyl dendrimers is a sufficient tool to target plaque associated microglia, demonstrating the potential for hydroxyl dendrimer‐based therapeutics in AD.
In‐vivo imaging of locus coeruleus integrity at ultra‐high field: A feasibility study
Authors: Pievani Michela , Jelescu Ileana O , Jorge Joao , Reynaud Olivier , Andryszak Paulina , Garibotto Valentina , Jovicich Jorge , Frisoni Giovanni B
Published: December 2020

Background

Increasing evidence suggests that neurodegeneration of the locus coeruleus (LC) is an early pathological feature of Alzheimer’s Disease (AD). However, assessment of the LC in‐vivo is hampered by its small size. Here we test the feasibility of characterizing LC’s integrity in‐vivo using ultra‐high field MRI.

Method

Eight young controls (age: 23+3y, education: 17+2y) and 9 elderly subjects from the Geneva memory clinic cohort (age: 74+7y, education: 16+3y; MMSE: 26+2; diagnosis: 1 cognitively normal, 7 cognitively impaired; biomarker profile: 63% A+, 14% T+) underwent MRI on a 7T Siemens Magnetom scanner, including magnetization transfer (MT; voxel: 0.43x0.43x0.5mm) and diffusion tensor imaging (DTI; voxel: 1.3x1.3x1.4mm). A MT template was generated from all the MT images with the Advanced Normalization Tools software. A LC map was extracted from the template with semi‐automated intensity thresholding. Individual MT and DTI images were warped to the MT template of the LC to measure: LC contrast ratio (CR) on MT; fractional anisotropy (FA) and mean diffusivity (MD) on DTI. These metrics were compared between groups and hemispheres using non‐parametric tests.

Result

The LC volume (MT template) was 62mm3, spanning 15mm rostro‐caudally. Elderly showed higher CR than younger subjects (median [IQR]: 23 [21‐28] vs 15 [12‐19], p=0.008 on Mann Whitney U test). This difference was detected along most of the rostro‐caudal LC axis (significance differences over 77% of the LC axis). In both younger and older subjects, the CR was greater in the left vs. right hemisphere (p=0.018 and p=0.015 respectively, Wilcoxon signed‐rank test). MD was more heterogeneous and overall higher in the LC of elderly compared to younger subjects (median [IQR]: 1.7 [0.7‐2.4] vs 0.94 [0.86‐1.02], p=0.023 on Mann Whitney U test). FA showed neither group nor hemisphere differences.

Conclusion

These findings are consistent with previous LC literature at 3T. We confirmed that LC signal increases with age and reported a hemisphere asymmetry in LC signal. Microstructure atrophy with age is suggested by increased diffusivity. Data acquisition is ongoing with the aim to evaluate MT, DTI and fMRI differences across cognitively normal, AD and non‐AD impaired groups. Funding: H2020‐EU.3.1.1 (grant ID:667375), Swiss National Science Foundation (SNF‐320030_169876).
Effects of iron and/or inflammation on regional brain magnetic resonance imaging T1 and T2 in an Alzheimer’s disease mouse model
Authors: Aljuhani Manal , Ashraf Azhaar , Kislitsyna Elena , Anjum Rifah , Hubens Chantal , Parkes Harry , So Po‐Wah
Published: December 2020

Background

Both iron dyshomeostasis and neuroinflammation feature in Alzheimer’s disease (AD)1,2, the former thought to induce neuronal death via oxidative stress3,4. Interestingly, iron metabolism can be modulated by neuroinflammation5. Here, we investigate the effects of systemic iron or neuroinflammation (induced by lipopolysaccharide, LPS), and possible synergies in an AD mouse model (5xFAD) using in vivo magnetic resonance imaging (MRI).

Method

AD mice were given iron (II) sulphate or saline, with or without LPS pretreatment (see Figure 1). A month after the final iron treatment, brain MRI was performed at 9.4T. MRI‐T1 and ‐T2 values from the hippocampus (ventral and dorsal; Hippven and Hippdor, respectively) and various cortices (prefrontal, somatosensory and motor cortex; PFC, SSC and MC, respectively) were obtained. Group differences were assessed using ANOVA and Tukey’s post‐testing with significance at p<0.05.

Result

Iron is paramagnetic and lowers MRI‐T26. Iron reduced T2 in the SSC compared to saline but not in other regions, remaining low even with LPS pre‐treatment (Figure 2). While T2 was generally decreased in the PFC, LPS pre‐treatment significantly increased T2, possibly by attenuating iron deposition. Interestingly, LPS reduced T2 in the Hippven and this was alleviated by combined treatment with iron, suggesting increased iron deposition due to microglia activation during inflammation5 which is attenuated by iron‐inhibition of cellular iron importation7. T1 is also reduced by iron although T1 is less sensitive than T26 and relates more to water content, e.g. oedema8. Indeed, iron treatment reduced T1 in the Hippven and PFC but T1 was similar in the other regions (Figure 2). In the Hippven, PFC, SSC and MC, LPS only or iron+LPS treatments increased T1 when compared to the iron only group, suggesting LPS may induce oedema and counteract the iron‐induced T1 reductions.

Conclusion

Changes in T2 suggests iron deposition in different brain areas with iron or LPS treatment, that is counteracted when LPS and iron treatments are combined. Similarly, selective T1‐changes observed in the hippocampus and cortices are also attenuated by combined LPS and iron treatment. Specific iron‐neuroinflammation interactions occur in different brain regions, not necessarily synergistically and further investigations are needed.
Identification of α4β2 nAChR interaction site with Aβ42 and development of tetrapeptide capable of breaking this interaction
Authors: Barykin Evgeny , Garifulina Alexandra , Adzhubei Alexei , Shelukhina Irina , Kozin Sergey A. , Mitkevich Vladimir , Tsetlin Victor , Makarov Alexander
Published: December 2020

Background

Cholinergic dysfunction in Alzheimer’s disease may arise from selective death of cholinergic neurons caused by the interaction of Aβ peptide with nicotinic acetylcholine receptors (nAChRs). Thereby, compounds that prevent the interaction of Aβ with nAChRs are needed to address the cholinergic deficit. Here, we identify the interaction site between Aβ42 and one of the two most abundant nicotinic receptors ‐ α4β2 nAChR. Further, we propose a tetrapeptide that prevents this interaction and serves as a potential therapeutic to counteract the cholinergic deficit in AD.

Method

Sequence analysis was used to identify the binding site of Aβ42 to α4β2 nAChR (35HAEE38). Surface plasmon resonance was utilized to evaluate the interaction between HAEE peptide and Aβ16. A complex of human α4β2 nAChR with Aβ42 was modeled with bioinformatics approaches. Human α4β2 nAChR was expressed in X. laevis oocytes. The receptor currents in the presence of Aβ42 and HAEE were studied with a two‐electrode voltage clamp.

Result

Analysis of α4β2 nAChR sequence showed that N‐terminal fragment 35HAEE38 of the α4 subunit is ionic complementary to 11EVHH14 in Aβ, suggesting it to be a potential site of the interaction. Synthetic HAEE peptide demonstrated binding to Aβ16, and molecular modeling confirmed that interaction of Aβ42 with α4β2 nAChR can occur via 11EVHH14:35HAEE38 interface. Pre‐incubation with Aβ42 reduced the amplitude of ACh‐evoked response in α4β2 nAChR‐transfected X. laevis oocytes by 20% and increased the leakage current in oocytes. Co‐incubation of Aβ42 with HAEE tetrapeptide reduced the degree of inhibition. Washout of Aβ42 with HAEE‐containing solution restored the current amplitude and reduced the leakage current.

Conclusion

35HAEE38 is a potential binding site for Aβ42 on α4β2 nAChR. HAEE tetrapeptide corresponding to this site restores inhibition of α4β2 nAChR by Aβ42 opening a potential therapeutic avenue for cholinergic dysfunction in AD.

Supported by RSF grant #19‐74‐30007.
Cortical thickness of parahippocampal gyrus discriminates mild cognitive impairment (MCI) groups with different profiles of CSF biomarkers
Authors: Fernández Miguel Ángel Rivas , Aldrey‐Vázquez Jose M. , Lojo‐Seoane Cristina , Lindín Mónica , Pías‐Peleteiro Juan M. , Vieites Ana Nieto , Zurrón Montserrat , Domínguez‐Vivero Clara , Campos‐Magdaleno Maria , Pereiro Arturo X. , Díaz Fernando
Published: December 2020

Background

Mild cognitive impairment (MCI), clinically considered an intermediate state between the cognitive changes of normal aging and early dementia (Petersen, 2016), progress frequently to Alzheimer´s clinical syndrome. Alzheimer Disease (AD) biomarkers are used to evaluate the etiology and progression of MCI. In this study, we evaluated whether MCI participants with different profiles of CSF biomarkers (proposed by the National Institute on Aging and Alzheimer's Association ‐Jack et al., 2018‐) show differences in cortical thickness measures of the parahippocampal gyrus subregions.

Method

Seventy‐eight patients from the Compostela Aging Study diagnosed as MCI according to the Petersen criteria (Petersen, 2004; Albert et al., 2011) underwent neuropsychological assessment, CSF (β‐amyloid, p‐tau and t‐tau), and MRI cortical thickness measures of the parahippocampal gyrus. Subcortical segmentation of T1‐weighted MR images was conducted with FreeSurfer (6.0 version) using the “recon‐all” pipeline to obtain the mean thickness measures of the parahippocampal and the entorhinal cortex of each participant. Participants were classified into four groups according to CSF biomarkers: Group 1: Normal AD with MCI; Group 2: Alzheimer’s pathologic change with MCI; Group 3: Alzheimer’s disease with MCI (Prodromal AD); and Group 4: non‐Alzheimer’s pathologic change with MCI. General lineal models were performed to evaluate Group differences in the cortical thickness measures.

Results

The MCI Group 1 showed significantly higher cortical thickness than: a) Group 3 in right and left parahippocampal cortex, and b) Group 2 in right entorhinal cortex (Table 1 and Figure 1). No other significant differences were obtained.

Conclusions

The MCI CSF profile groups 3 (“prodromal AD”) and 2 (“Alzheimer´s pathologic change”) showed significant parahippocampal gyrus atrophy compared with MCI group 1 (“normal AD”). These results support MCI profiles proposed by Jack et al. (2018). Moreover, considering the degeneration of medial temporal lobe in AD, the aforementioned changes might have an AD diagnostic and prognostic value for both MCI groups.
CSF1R inhibitor abrogates tau propagation exacerbated in APPNL‐G‐F knock‐in mice but enhances fibrillar beta‐amyloidosis and dystrophic neurite formation in the brain
Authors: Clayton Kevin , Delpech Jean Christophe , Herron Shawn , Saito Takashi , Ikezu Seiko , Saido Takaomi C. , Ikezu Tsuneya
Published: December 2020

Background

Microglia are the primary innate immune cells in the brain. They can phagocytose apoptotic neurons and dystrophic neurites containing aggregated and phosphorylated tau (p‐tau) in tauopathies, and possibly spread pathological tau via extracellular vesicles (EVs) release. Proteinopathic stress like amyloid plaque accumulation can transform microglia into a neurodegenerative phenotype (MGnD), possessing enhanced phagocytic and exocytotic functions. Thus, MGnD could exacerbate tau spreading throughout the brain. To determine the role of MGnD on tau propagation, we employed microglia depletion in adeno‐associated virus (AAV)‐mediated tau propagation mouse models.

Method

C57BL/6 (WT) and APPNL‐G‐F mice were fed with a CSF1R inhibitor (PLX5622) or control chow for one month before and after stereotaxic injections of AAV2/6‐SYN1‐P301Ltau expressing P301L tau mutant into the medial entorhinal cortex (MEC) at 5 months of age. Propagation of tau to the dentate granular cells of the hippocampus, amyloid plaque formation, and association of microglia and p‐tau with plaques were assessed by immunohistochemistry after one month. MGnD and homeostatic microglia were separately isolated from APPNL‐G‐F mouse brains by FACS and evaluated for expression of EV marker molecules.

Result

FACS data showed higher percentage of Clec7a (MGnD marker)‐positive microglia (20.8%) in APPNL‐G‐F compared to WT. Immunohistochemistry of APPNL‐G‐F mouse brains revealed strong positivity of Clec7a+ microglia surrounding both amyloid plaques and plaque‐associated p‐tau. APPNL‐G‐F mice exhibited approximately a 10‐fold increase in tau propagation compared to WT mice. Strikingly, PLX5622 treatment, which depleted ∼ 99% of microglia, showed 74 and 87% reduction of tau propagation in WT and APPNL‐G‐F groups, respectively. Contrarily, PLX5622 treatment increased intensity of plaque associated p‐tau along with increased size and number of amyloid plaques in the APPNL‐G‐F mice, suggesting their regulation by MGnD. Gene expression of EV markers, CD9 and CD63, was upregulated in Clec7a+ microglia compared to Clec7– microglia isolated from APPNL‐G‐F mice, suggesting enhanced microglial EV synthesis. This was further supported by the significant colocalization of Tsg101, an exosome marker, in Clec7a+ MGnD.

Conclusion

Tau propagation may be influenced by engulfment of pathological tau seeds by microglia and secretion through EVs, which is exacerbated in MGnD in APPNL‐G‐F mice and mitigated by PLX5622 treatment.
Correlation between cerebrospinal fluid and blood neurofilament light protein: A systematic review and meta‐analysis
Authors: von Widekind Sophia , Alagaratnam Jasmini , de Francesco Davide , Underwood Jonathan , Winston Alan , Zetterberg Henrik , Fidler Sarah
Published: December 2020

Background

Cerebrospinal fluid (CSF) neurofilament light protein (NfL) is a sensitive biomarker of central nervous system neuro‐axonal injury. A novel assay measuring blood NfL has been developed, avoiding the need for CSF sampling. Several studies have published correlations between CSF and blood NfL, but the pooled correlation is unknown. This meta‐analysis aims to determine the pooled correlation coefficient estimate between CSF and blood NfL, and to stratify by correlation technique and blood NfL assay.

Method

We searched Medline, Embase and Web of Science for published manuscripts in English, from their inception to July 9, 2019, according to PRISMA guidelines. We included studies reporting the correlation between CSF and blood (plasma/serum) NfL. We then conducted a random‐effects meta‐analysis to calculate the pooled correlation coefficient estimate, accounting for correlation technique and assay used. Heterogeneity was assessed using the Cochran Q test. In sensitivity analyses, we calculated the pooled correlation coefficient estimate according to whether Spearman’s rank or Pearson’s correlation coefficient was reported (where unspecified, Pearson’s correlation was imputed), and according to blood NfL assay: single‐molecule array digital immunoassay (Simoa), electrochemiluminescence (ECL) or enzyme‐linked immunosorbent assay (ELISA).

Result

Data were extracted from 37 articles, including 3797 individuals. 23 studies reported Spearman’s rank and 10 studies reported Pearson’s correlation coefficient; correlation technique was unspecified in 4 studies. 29 studies used Simoa, 7 ECL and 1 ELISA. Results from the overall meta‐analysis demonstrated that the pooled correlation coefficient estimate for CSF and blood NfL was r=0.72, 95% confidence interval 0.56‐0.83, p<0.001 (Figure 1). Heterogeneity was significant: Q=206.2, p<0.0001. In sensitivity analyses, for studies quoting Spearman’s rank, the pooled estimate was r=0.66, p<0.001, while the pooled estimate was r=0.76, p<0.001 for studies quoting Pearson’s correlation. When stratified by blood NfL assay, the pooled correlation coefficient was similar for Simoa and ECL (r=0.70, p<0.001 and r=0.73, p<0.001, respectively), but weaker for ELISA (r=0.35, p=0.272).

Conclusion

Strong correlations are demonstrated between CSF and blood NfL, especially with Simoa and ECL blood NfL assays. Simoa is the preferred blood NfL assay due to its low detection limit, and this meta‐analysis supports blood NfL measured using Simoa, as a surrogate measure of CSF NfL.
Scalable diagnostic screening of mild cognitive impairment using AI dialogue agent
Authors: Tang Fengyi , Uchendu Ikechukwu , Wang Fei , Dodge Hiroko H , Zhou Jiayu
Published: December 2020

Background

The search for early biomarkers of mild cognitive impairment (MCI) has been central to Alzheimer's Disease (AD) and the dementia research community in recent years. While there exist in‐vivo biomarkers (e.g., beta‐amyloid and tau) that can serve as indicators of pathological progression toward AD, biomarker screenings are prohibitively expensive to scale if widely used among pre‐symptomatic individuals in the outpatient setting. Behavior and social markers such as language, speech, and conversational behaviors reflect cognitive changes that may precede physical changes and offer a much more cost‐effective option for preclinical MCI detection, especially if they can be extracted from a non‐clinical setting.

Method

We developed a prototype AI conversational agent that conducts screening conversations with participants. Specifically, this AI agent must learn to ask the right sequence of questions to distinguishing the conversational characteristics of the participants with MCI from those with normal cognition. Using transcribed data obtained from recorded conversational interactions between participants and trained interviewers generated in a recently completed clinical trial, and applying supervised learning models to these data, we developed a novel reinforcement learning (RL) pipeline and a dialogue simulation environment to train an efficient dialogue agent to explore a range of semi‐structured questions. We train and validate our AI dialogue agent based on transcribed data from a randomized controlled behavioral intervention study, where we use the transcribed data from 41 subjects (14 MCI, 27 NL). Each subject has an average of 35 turns of dialogue on average.

Result

The results show that while using only a few turns of conversation, our framework can significantly outperform state‐of‐the‐art supervised learning approaches used in a past study. An AI agent of 30 turns of dialogue achieves over 0.853 Area Under the Receiver Operating Characteristic Curves (AUC) and 0.809 AUC with 20 turns, as compared to 0.811 AUC with the full dialogue turns.

Conclusion

Our dialogue‐based AI agent presents a step toward using AI to extend clinical care beyond the classical hospital and clinical settings, where we find that AI‐generated dialogues produce more predictive linguistic markers.
The API Generation program: Umibecestat treatment and discontinuation effects on hippocampal and whole brain volumes in the overall population and amyloid‐negative APOE4 homozygotes
Authors: Reiman Eric M. , Tariot Pierre N. , Borowsky Beth , Liu Fonda , Riviere Marie‐Emmanuelle , Rouzade‐Dominguez Marie‐Laure , Cazorla Pilar , Quinn Matt , Ricart Javier , Langbaum Jessica B. , Viglietta Vissia , Sui Yihan , Caputo Angelika , Graf Ana , Seneca Nicholas , Neumann Ulf , Eichenlaub Udo , Chien Yuchen , Arkuszewski Michal , Piccard Hernan , Quarg Peter
Published: December 2020

Background

In addition to early mild non‐progressive cognitive worsening, BACE inhibitors have been associated with early non‐progressive reductions in hippocampal and whole brain volume in trial participants with elevated amyloid (A+, Egan et al, 2019). We have begun to evaluate the effects of umibecestat treatment and discontinuation on cognitively unimpaired amyloid‐positive (A+) and A‐ APOE4 homozygotes and A+ heterozygotes, testing the hypotheses that BACE inhibitor‐related hippocampal and whole brain shrinkage is apparent soon after treatment initiation, non‐progressive, limited to A+ participants, and reversible following discontinuation.

Method

The API Generation Program had begun to evaluate umibecestat in 1,623 cognitively unimpaired 60‐75 year‐old participants including 921 A+ APOE4 heterozygotes and 702 homozygotes (A+ or A‐).Following randomization, volumetric brain MRIs were scheduled at month 6, month 12 and then annually. After discontinuation of study medication, participants continued to be assessed under double‐blind conditions, and MRIs were acquired within 3 months after the last dose. We investigated 6‐month hippocampal and whole brain volume changes and their relationship to RBANS immediate, delayed and total memory score changes; and we plan to investigate the persistence or reversibility of these changes within 3 months of discontinuation after study completion in Q2 2020.

Result

Umibecestat was associated with significant 6‐month hippocampal and whole brain shrinkage in the aggregate APOE4 homozygote and A+ heterozygote group, but not in the A‐ homozygotes. While an early non‐progressive worsening in RBANS immediate, delayed, and total memory scores (Graf et al, AAIC 2020 submitted) was seen in the overall population as well as in A‐ HMs, we failed to demonstrate any significant association between brain shrinkage and cognitive worsening in the overall group (R2 coefficient <0.1) in the active treatment group for any of the visits (on‐ and off‐ treatment).

Conclusion

BACE inhibitor‐related brain shrinkage appears to be early, non‐progressive, related to pre‐existing amyloid plaque burden, and unrelated to its cognitive worsening. Pending findings will help to clarify the extent to which it is also reversible. Together, our cognitive and MRI findings could help to assess potential benefits versus risks of BACE inhibitors in future prevention trials.
First‐in‐human studies of MW01‐6‐189WH, a brain‐penetrant, anti‐neuroinflammatory, small molecule drug candidate: Phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic studies in healthy adult volunteers
Authors: Van Eldik Linda J. , Roy Saktimayee M. , Guptill Jeffrey T.
Published: December 2020

Background

Acute brain injuries, such as intracerebral hemorrhage (ICH) or traumatic brain injury (TBI), are major medical problems that cause considerable mortality and morbidity in older individuals. In addition to the initial injury, secondary neuroinflammatory events can further damage the brain and lead to increased risk of neurologic complications, including Alzheimer’s disease (AD) and related dementias (ADRD). A specific aspect of neuroinflammation, injury‐induced proinflammatory cytokine overproduction from abnormally activated glia, has been linked to subsequent neurological damage and cognitive deficits in both acute and chronic CNS disorders. Despite advances in our understanding of these molecular neuroinflammatory mechanisms, approved therapeutics that target this pathological process are lacking. To address this need, we developed a CNS‐penetrant, small molecule drug candidate, MW01‐6‐189WH (=MW189), that selectively attenuates stressor‐induced proinflammatory cytokine overproduction. MW189 is efficacious at low doses in animal models of AD, TBI and ICH. Based on promising drug‐like properties, preclinical efficacy, and excellent safety profile, an intravenous formulation of MW189 was developed and tested in phase 1 human studies.

Methods

Phase 1 studies were done to evaluate safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of MW189 in healthy adults. A pilot pharmacodynamic study administering low dose endotoxin to induce a systemic inflammatory response was done to evaluate effects of a single dose of MW189 on plasma cytokine levels.

Results

MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. No clinically concerning changes were seen in vital signs, ECGs, physical or neurological examinations, or safety laboratory results. PK analysis showed dose‐proportional increases in MW189 plasma concentrations after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. In the pilot pharmacodynamic study, MW189 treatment resulted in lower plasma levels of the proinflammatory cytokine TNFα and higher levels of the anti‐inflammatory cytokine IL‐10 compared to placebo treatment, suggesting engagement of pharmacological mechanism.

Conclusion

Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute CNS injury, AD/ADRD, or other disorders involving dysregulated neuroinflammation as a driver of disease progression.
Let’s CHAT – Dementia: Primary care model of care to optimise detection and management of dementia in Aboriginal and Torres Strait Islander older people: Determination of the risk factor profile in this population
Authors: Hughson Jo‐Anne , Flicker Leon , Smith Kate , Bradley Kate , Belfrage Mary , Strivens Edward , Bessarab Dawn , Atkinson David , Radford Kylie , Russell Sarah G , Quigley Rachel , Allan Wendy , Malay Roslyn , Sullivan Kylie , Ducker Belinda , LoGiudice Dina
Published: December 2020

Background

Rates of dementia and cognitive impairment in Australian Aboriginal and Torres Strait Islander populations are 3‐5 times higher than in the overall population. In addition, under‐detection of these conditions has been consistently confirmed, particularly in primary care. A national co‐design project called the Let’s CHAT (Community Health Approach To) Dementia aims to optimise detection rates and management of dementia and cognitive impairment in Indigenous primary care contexts. This will occur through the co‐development of a model of care, and outcome measures include data profiling the dementia risk of older Indigenous persons and current management of patients with confirmed or suspected cognitive impairment or dementia

Method

Six‐monthly medical record audits of patients aged 50 and over recording: basic demographic information, presence of dementia risk factors, current care practices in relation to dementia and co‐morbid conditions of ageing.

Result

Audits were conducted on patients (n=1675) in 12 primary health services across Australia. The mean age of patients was 60.3 (8.3). The top ten risk factors documented overall were: hypertension (50.9%), polypharmacy (46.7%), current smoking (43%), diabetes (42.9%), dyslipidaemia (41.1%), obesity (35%), depression (30%), mental health concerns (25.9%) cardiovascular disease (25.6.%) and low physical activity (19.1%), but there was some inter‐service variation in risk factor profiles. Documented evidence of health service assessment for, and investigation of, cognitive impairment was limited. Use and type of diagnostic tools varied widely between services (e.g. MMSE used with 0.6%‐45.9% of sample, KICA (culturally appropriate cognitive assessment tool) used with 0.0%‐5.0% of sample). Diagnoses of dementia and cognitive impairment (combined = 3.8%) are well below known prevalence rates in these populations (∼20%), although there is variation from service to service (range = 0.8% ‐8.9%).

Conclusion

The audit data confirm low rates of detection and low levels of assessment activity for cognitive impairment and dementia in Indigenous primary care contexts, while the population displays a high risk for developing these conditions. These findings underscore the need for more focus on detection activities in primary health care, as well as reinforcing the importance of preventive health care strategies.