bluuebunny/crossref_metadata_2025_split huggingface dataset:
INPP5D is associated with tau seeding and tau pathogenesis
Authors: Oblak Adrian L , Soni Disha , Lee‐Gosselin Audrey , Lin Peter Bor‐Chian , Reeves Cristian A Lasagna 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia characterized by extracellular amyloid deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau aggregates. GWAS studies have identified variants in several inflammatory genes as significant risk factors for AD, highlighting that neuroinflammation is a critical, underlying pathological component in AD. INPP5D, a family member of Src homology 2 domain containing inositol 5' polyphosphatases (SHIPs), is an AD risk gene related to innate immunity in late‐onset AD (LOAD). Inpp5d plays a role in regulating signal transduction initiated by immune cell surface receptors. INPP5D binds receptor ITIMs, competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P¬2, thereby limiting downstream signaling. We previously reported that Inpp5d expression is increased in LOAD and is positively correlated with amyloid burden. However, the relationship of Inpp5d in tau pathology remains unclear. We hypothesize that inhibiting INPP5D will release the break and increase microglial function.MethodsTo assess the role of Inpp5d in tau pathology, we performed a fluorescence resonance energy transfer (FRET) assay on human‐AD brains obtained from NCRAD. We also crossed a mouse model deficient in Inpp5d (Inpp5d+/−) with a PS19 model of tau pathology and measured tau phosphorylation and transcriptomics. Primary microglia were utilized to measure microglial internalization of Tau.ResultsIn human AD‐ brains, increased tau seeding was positively correlated with Inpp5d expression. Furthermore, in PS19 mice, Inpp5d protein expression was upregulated and positively correlated with phosphorylated tau (S202, Thr205). Utilizing the NanoString nCounter assay, we found an upregulation of the immune‐related and cell migration related genes in PS19.Inpp5d+/‐ mice compared to PS19 mice. Primary microglia from Inpp5d+/− mice released increased tau internalization compared to WT microglia.ConclusionOur findings confirmed that elevated Inpp5d expression in human‐AD subjects is recapitulated in PS19 mice and correlated with increased tau pathology. In PS19.Inpp5d+/‐ mice we found alterations in immune related and cell migration related pathways suggesting that Inpp5d modulates the disease progression through these pathways. Furthermore, pathogenesis may be modulated through increased internalization of tau. Together these results suggest that therapeutic interventions aimed at reducing Inpp5d may be beneficial in tauopathies.
The role of transcranial direct current stimulation in improving learning and memory performances of patients with mild cognitive impairment and mild Alzheimer’s disease: a functional magnetic resonance imaging study
Authors: Joshi Himanshu , Roy Ashika Anne , Havanur Setu , Rangarajan Subhashini K , Sreeraj Vanteemar S , Sinha Preeti , Narayanan Mariyappa , Janakiprasad Keshav K , Alladi Survana , Sinha Sanjib , Saini Jitender , PT Sivakumar , Varghese Mathew , Venkatasubramanian Ganesan , John John P 
Published: December 2023

AbstractBackgroundTranscranial direct current stimulation (tDCS) is a safe non‐invasive brain stimulation (NIBS) procedure which helps to stimulate a particular region of interest by modulating the neuronal firing rate, thereby modulating the cognitive functioning. The tDCS intervention is known to show improvement on memory recall and recognition in patients with mild cognitive impairment (MCI) and mild Alzheimer’s Disease (mild AD)MethodWe investigated the effect of anodal stimulation at the left dorsolateral prefrontal cortex (DLPFC) and cathodal stimulation at the right supra‐orbital area in patients with MCI (n = 18) and mild AD (n = 20) (Refer Table 1), after due approval from Institute Ethics Committee NIMHANS. Both baseline and post‐intervention assessments for a single patient were administered by the different assessors allocated randomly using NIMHANS neuropsychological battery for elderly (NNB‐E). Two resting state functional magnetic resonance imaging (rsfMRI) acquisitions, before and after the ten sessions of tDCS, each session lasting 20 minutes. A spherical mask of 5 mm diameter was chosen a priori on the left middle frontal gyrus (LMFG) as a seed for performing seed based functional connectivity (sbFC) analysis using default preprocessing pipeline and pre‐post analysis setup in CONN 18b toolbox.ResultThe combined sample of patients with MCI and mild AD showed significant improvement in word list learning trial 3 (pre tDCS 5.85 (1.59); post tDCS 6.63 (1.67); Z = 3.586, p<0.0001) and delayed recall (pre tDCS 1.50 (1.88); post tDCS 2.45 (2.33); Z = 3.656, p<0.0001) scores using NNB‐E. The sbFC analysis showed significantly reduced functional connectivity between left MFG (the region of anodal stimulation) and posterior cingulate cortex (PCC) as well as precuneus cortex (cluster‐level extent threshold p‐FDR <0.05) after tDCS. Post‐hoc tests showed that these reductions after tDCS intervention were also found to be significantly associated with attention and auditory verbal learning memory scores (Refer Figure 1 and Table 2).ConclusionThe tDCS intervention helped reducing the functional connectivity at rest, which was responsible for compensatory neuronal processes found in early AD. These findings unravel the therapeutic role of tDCS by enhancing auditory verbal memory performance and altering the functional connectivity at PCC and precuneus cortex in earlier stages of AD.
Molecular analysis of nasal secretion to identify Alzheimer’s disease
Authors: Nicoló Marion San , Wunderlich Hilary , Peters Oliver , Grimmer Timo , Frölich Lutz , Metzler Richard , Schaepe Arno , Mertzig Sabine , Hallermayer Klaus , Waltenberger Harald , Heydler Thomas , Haack Mareike 
Published: December 2023

AbstractBackgroundIncreasing clinical evidence shows significant drainage of cerebrospinal fluid (CSF) and its metabolites along the olfactory route into the nose. Nasal secretion‐based analysis of key Alzheimer biomarkers was compared to CSF‐based analysis in different cohorts.MethodWe conducted a multicenter, prospective cohort study involving patients with cognitive impairment and availability of CSF measurement of the 4 AD‐specific proteins. Cohorts were defined based on CSF biomarker classification following NIA‐AA ATN research diagnostic framework and clinical findings. Nasal secretion (NS) was collected from the vicinity of the olfactory cleft. [NosetestAD] was performed for subsequent in vitro analysis.ResultFor this analysis, 39 patients with cognitive impairment were included at 3 university clinics in Germany. The nasal sampling procedure [noseabsorb] is painless (VAS 2 ±1.7) and yields a high sample volume (mean 450 μl). [NosetestAD] allows for precise quantification in size and relative protein amount of AD biomarkers pTau181, total Tau, Amyloid‐ß1‐40 and Amyloid‐ß1‐42. By using an automated protein separation and immunodetection system, we are able to generate a protein specific biomarker signature for all 4 AD‐associated proteins (pTau, tTau, Aß42,Aß40) characterizing parameters such as oligomerization state and relative protein amount. Further, a highly significant discrimination of amyloid pathology (A+ vs. A‐) was achieved with an AUC of 0.94 and p‐value <0.001.ConclusionNasal secretion constitutes a safe, minimally invasive access to CSF. Therefore, it is highly suitable for detection and monitoring of AD relevant biomarkers. Within a cohort of patients with cognitive impairment A+ patients can be distinguished from A‐ patients based on their diseases state specific individual protein‐specific biomarker signatures and the different levels of oligomeric or monomeric structures. Thus, our proprietary diagnostic platform, detects and assesses a broad panel of brain derived biomarkers simultaneously and allows for intraindividual monitoring and possibly disease staging in nasal secretion.
TDP‐43 dysregulation and STMN‐2 mis‐splicing upon proteasomal inhibition in potential iPSC‐derived neuronal ALS model
Authors: Ritsma Laila , Bsibsi Malika , Popalzij Abeera , Sancerni Sara Compte , de Kraa Esther , Magnani Dario , Turner Amanda , Oosterveen Tony , Fisher David F , Iovino Mariangela , Vlaming Marijn 
Published: December 2023

AbstractBackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. Many ALS cases are associated with nuclear‐to‐cytosolic mislocalization and phosphorylation of the transactivation response DNA binding protein (TDP)‐431. This is caused by several mutations such as M337V in the TAR DNA binding protein (TARDBP) gene1. In addition, proteasomal degradation is often affected, resulting in aggregation of TDP‐432. TDP‐43 is involved in many mRNA processes, and its depletion results in mis‐splicing of the neuronal growth associated factor, stathmin 2 (STMN‐2)3. This mis‐splicing contributes to axonal degeneration. To model the ALS phenotypes in vitro, proteasomal inhibition is often used to trigger TDP‐43‐associated phenotypes2.MethodsIn this report we assessed if homozygous or heterozygous CRISPR‐edited TPD‐43 M337V mutations in induced pluripotent stem cell (iPSC)‐derived glutamatergic neurons, generated by bit.bio using the opti‐ox technology4‐5, alone, or in combination with an MG‐132 proteasomal inhibition trigger, would result in TDP‐43 mislocalization and/or STMN‐2 splicing, and could therefore be used as an ALS‐relevant disease model. This was assessed in highly mature (DIV21), and less mature (DIV7) neurons.ResultsImmunocytochemistry, high‐content imaging, and automated image analysis were used for visualization, localization, and quantification of proteins of interest in individual cells. Here, increase in TDP‐43 mislocalization, phosphorylation (and aggregation) was observed upon acute proteasomal inhibition in all cell lines compared to their respective untreated sample, with more extreme phenotypes on DIV7. More interestingly, the homozygous M337V cell line D5 showed showed TDP‐43 associated phenotypes in untreated conditions at DIV7. Digital droplet PCR was used to evaluate mRNA expression, using absolute quantification of nucleic acid molecules. This showed decrease of full length STMN‐2 and the generation of truncated STMN‐2 upon MG‐132 treatment in most cell lines. Additionally, preliminary functional data generated using Multi Electrode Arrays (MEA) showed that all neuronal lines demonstrated formation of synchronous activity at late stage of maturation, suggesting these neurons are electrophysiologically active and amenable to functional studies.ConclusionThese results suggest that wildtype and mutant clones show TDP‐43 dysregulation and mis‐splicing of STMN‐2 upon acute proteasomal inhibition, thus establishing an ALS relevant phenotype that can be used for in vitro drug discovery.
Transcranial Magnetic Stimulation improves language and language network functional connectivity in a patient with logopenic Primary Progressive Aphasia
Authors: Touroutoglou Alexandra , Katsumi Yuta , Jones Amelia , Hochberg Daisy , Quimby Megan , Wong Bonnie , Carvalho Nicole , Brickhouse Michael , Dickerson Brad C. , Eldaief Mark C. 
Published: December 2023

AbstractBackgroundPrimary progressive aphasia (PPA) refers to a group of neurodegenerative disorders characterized by early language impairments. Neuroimaging evidence suggests that language networks anchored in prefrontal, temporal and parietal cortices are selectively affected in these syndromes. Focal neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), are able to change resting‐state functional connectivity in a network‐specific manner.MethodHere, we characterized the language network of a patient with logopenic PPA and targeted this network in an individualized manner with high frequency (20Hz) rTMS and with sham rTMS. We used detailed language testing and resting‐state functional connectivity MRI as outcome measures.ResultThe patient’s language performance improved following active but not sham rTMS. This was accompanied by increased functional connectivity in the patient’s individually characterized language network after active but not sham rTMS.ConclusionThis case report supports further controlled clinical trials of individually‐targeted rTMS in PPA.
Hsp40 molecular chaperones are potent regulators of tau seeding and accumulation
Authors: Esquivel Abigail R. , Hill Shannon E. , Blair Laura J. 
Published: December 2023

AbstractBackgroundThe misfolding of the microtubule associated protein tau is associated with Alzheimer’s disease and other tauopathies. In tauopathies, aberrant tau spreads through synaptically connected regions of the brain by templating the misfold of endogenous tau. Work from our group and others has identified molecular chaperones as regulators of tau accumulation and toxicity, but many tau regulators have yet to be identified.MethodWe performed a screen of members from seven major chaperone families using Tau RD P301S FRET Biosensor cells. Hits were assessed by secondary knockdown studies in cultured cells and validated in tau expressing primary neurons. Additional in vitro experiments to dissect the mechanism of activity are ongoing, which will be followed by in vivo studies.ResultOur data support the use of Tau RD P301S FRET Biosensor cells as a robust screening tool to identify known and novel tau regulators. The Hsp40 family is enriched with tau regulators, including some not previously known to affect tau. Studies are ongoing to determine how these proteins alter tau levels.ConclusionMultiple members of the Hsp40 family regulate tau accumulation.
Developing Training for MyChart Use for Older Persons with Mild Cognitive Impairment
Authors: Loizos Maria , Chin Shehan , Umpierre Mari , Inala Sanjana , Sewell Margaret , Neugroschl Judith A. , Sano Mary 
Published: December 2023

AbstractBackgroundMyChart, a mechanism for sharing personal health information and communication among patients and healthcare providers is well received but underutilized by older adults, especially those with Mild Cognitive Impairment (MCI). Difficulty using or accessing technology coupled with rapid changes in portals may negatively impact a patient’s ability to effectively manage their health concerns. We report the initial phase of a study in older adults using focus groups to 1) determine the nature of user difficulties and knowledge gaps, and explore the preferred training methods (in person, virtual, manual), 2) develop a MyChart training module based on focus group data, and 3) assess the feasibility of providing training to improve MyChart use amongst older adults with MCI.MethodWe conducted three focus groups with older adults with MCI. Groups were held from August‐November 2022 and consisted of 15 participants both familiar and unfamiliar with MyChart. Focus groups were conducted virtually, and participants were asked open ended questions regarding user difficulties, knowledge gaps, and preferred training methods. Sessions were recorded, transcribed, and later analyzed utilizing thematic analysis. Focus groups continued until saturation was reached.ResultWe approached 84 ADRC participants to get 15 needed to reach saturation. 1) Technology and Health: participants acknowledged technology could be used positively to control health 2) MyChart: participants reported positive view of MyChart as a way to communicate with doctors and manage medical information 3) Difficulty with MyChart: participants stated there was no clear way to get help if needed to make appointments or find medical information 4) Learning technology: participants reported a preference for verbal teaching methods such as a video (over solely manualized teaching) that could be slowed down and stressed the importance of repetition of information.ConclusionThe use of direct patient feedback was positive in that we discovered that older adults with MCI are open to use MyChart to monitor their health but have clear preferences on how to learn and get support with the technology.
Analysis of human endogenous retrovirus in Alzheimer’s disease and Frontotemporal dementia affected tissues
Authors: Fort‐Aznar Laura ,   Unitat d’Alzheimer i altres trastorns cognitius
Published: December 2023

AbstractBackgroundHuman Endogenous Retroviruses (HERVs), normally dormant within the eukaryotic genome, can be awaken by environmental factors that may induce neurodegeneration via brain inflammation and epigenetic dysregulation. We investigated different HERVs transcripts using blood and post‐mortem brain samples from genetic and sporadic Alzheimer’s disease (gAD and sAD) and Frontotemporal Dementia (sFTD and gFTD) patients, using quantitative PCR (RT‐qPCR) and microarray techniques. Only HERV‐K env transcript was upregulated in sporadic AD in blood. Genome‐wide DNA methylation data analysis revealed hypermethylation in several genes involved in HERVs machinery, including APOBEC3, CDK6, E2F5, PRODH and SLC4A8 in AD and FTD when compared to healthy controls in post‐mortem brain tissue. In summary, our preliminary findings suggest that HERVs may be implicated in AD and FTD neuropathogenesis.MethodRNA samples were obtained from sAD (n = 63), gAD (n = 10), sFTD (n = 46), gFTD (n = 15) and healthy controls (n = 39). Post‐mortem tissue (prefrontal cortex) from sAD (n = 10), gAD (n = 10), sFTD (n = 10), gFTD (n = 15) and healthy controls (n = 17). Quantification of different HERVs were measured by qRT‐PCR. Transcript levels within each of the samples were quantitated and normalized using the reference genes actin and GAPDH. 64 subjects were studied with Infinium MethylationEPIC array. Samples comprised healthy controls (n = 5), sAD (n = 5), gAD (n = 5), gFTD (n = 15) and sFTD (n = 10).ResultHERV‐K env transcript was increased in blood from sAD compared to healthy controls (p = 0.0044). No other HERV transcript was found to be significantly upregulated in sporadic and genetic AD and FTD. Microarray analysis from AD and FTD patients revealed hypermethylation in APOBEC3, E2F5, in all groups and CDK6, PRODH and SLC4A8 in FTD when compared to healthy controls in post‐mortem brain tissue.ConclusionIn this study we found that HERV‐K env transcript was upregulated in sAD from blood, which could be useful as a potential clinical biomarker. Future studies targeting the env protein should be performed to confirm the results found in this preliminary study. Hypermethylation of different genes involved in HERVs machinery suggest a different pathomechanism between AD and FTD that might help to differentiate them. Future functional studies for APOBEC3, CDK6, E2F5, PRODH and SLC4A8 could reveal the underlying biological mechanism leading to HERV activation.
Soluble biomarkers of Alzheimer’s disease in plasma vary according to quantity of blood CNS derived extracellular vesicles
Authors: Boyer Emilien , Kienlen‐Campard Pascal , Hanseeuw Bernard J 
Published: December 2023

AbstractBackgroundHallmark proteins pathogenic in Alzheimer’s disease (AD), amyloid and tau, can now be quantified in plasma samples using single‐molecule array (SIMOA). However, proteins are not only circulating in plasma, but are also present in nervous system‐derived extracellular vesicles (NDBEs) secreted by neurons in the plasma. We aim to quantify plasmatic NBDEs to evaluate whether their number or content are modified in symptomatic AD.MethodPlasma samples were obtained in clinically normal (CN) participants (N = 76, sex ratio F/M = 1.5, mean age 57.5 ± 16.3, Apoε4 positive n = 31, Apoε4 negative n = 43). Quantification of amyloid 42 – 40 peptides and total‐Tau protein was achieved with SIMOA multiplex analysis. For relative quantification of NDBEs circulating in plasma, we used DELFIA ELISA immunoassay with anti‐neuronal cell adhesion molecule (NCAM1) antibody. EVs content analysis was done with SIMOA Neurology 3‐plex A multiplex (t‐tau, Aβ42 and Aβ40).ResultWe observed that the relative amount of NDBEs in plasma was correlated with circulating Aβ42 (p < 0.0001, R² 0.2699) and t‐tau (p < 0.0001, R² 0.2753) such that greater numbers of NBDEs were associated with lower concentrations of proteins in circulating plasma. Content in Aβ42, Aβ40 and t‐Tau of NDBEs was higher in individuals with high amount of NDBEs circulating (Aβ42 (p < 0.05, R² = 0.18), Aβ40 (p < 0.05, R² = 0.18) and t‐tau (p < 0.03, R² = 0.17)).ConclusionThe number of NBDEs is negatively associated with the concentrations of these proteins, suggesting that these proteins are encapsulated in NBDEs. Latest results regarding NDBEs content seems to confirm this hypothesis with significant higher biomarkers concentrations in individuals with high amount of plasmatic NDBEs.
Older adults participation and adoption among a lifestyle‐based multidomain dementia prevention program
Authors: Pérez Ana Laura Isidro , Martínez‐Galindo Joyce Graciela , Salinas‐Contreras Rosa Maria , Sosa‐Ortiz Ana Luisa 
Published: December 2023

AbstractBackgroundOlder adult participation in lifestyle‐based programs has been described round 80%. (Lee et al., 2018). Participation at dementia prevention programs has been influenced by age, gender, marital status, and interest in receiving health education (Coley et al., 2021). The aim of this study is to evaluate the participation and adoption of lifestyle changes of older adults in a multidomain dementia prevention program from the LatAm Fingers Initiative, in MexicoMethodhealthy cognitive older adults between 60 to 77 years old were recruited. 148 pre‐screenings were done to complete a 100 participants sample, all of them were randomized between Systematic (SIG) (supervised participation) or Flexible FIG (educational advises) Lifestyle Intervention groups (50 per group). Participation is defined as attendance to educational session for physical, nutritional, cognitive and cardiovascular health plus attendance to physical activities, diary diet delivery, and 48 levels per week of cognitive online activities through 6‐months. Participation was classified as low, moderate, and high.ResultMean age was 70.06 (±5.4) years old, and 70.8% participants were females. From 48 participants of the systematic group (SIG) there were two dropouts because problems for traveling, and work. 45% of the SIG, are participating on the four intervention domains. 40 participants are currently at the physical activity intervention. From them high participation and adoption of physical activity was 52.5%, moderate participation was 37.5% and low, 10%. From Nutritional intervention are 26 participants who showed high participation at 57.7%, 11.5% moderate and 30.8%, low. The 21 participants that are at the Cognitive intervention stage, 33.3% had high participation, 52.4% moderate and 14.3% low participation. From the 18 participants at the health intervention stage, 94.4% participants had high participation and 5.6% low.Conclusionfrom this preliminary data, we found that the in the SIG the participation rates, are moderate to high. Physical, nutritional, and cardiovascular health activities showed more than 50% of participation rate. Also, nutritional domain showed the lowest percentage of participation among the four interventions.