bluuebunny/crossref_metadata_2025_split huggingface dataset:
Positive clinical outcomes in two phase 2a studies: ADAS‐COG in Alzheimer’s and MDS‐UPDRS in Parkinson’s patients plus markers of toxic cascade that leads to nerve cell death
Authors: Maccecchini Maria L. , Hernandez Priscilla , Liow Kore , Zetterberg Henrik , Chen Michael 
Published: December 2021

AbstractBackgroundOverexpression of neurotoxic proteins drives dysregulation of axonal transport, inflammation, nerve cell death, and loss of function. By inhibiting translation of amyloid precursor protein, tau and alpha‐synuclein our drug has been shown in animal models to restore axonal transport, lower inflammation and protect nerve cells and to restore full function in 7 animal models ‐ Down Syndrome [Chen 2020], Alzheimer’s [Teich 2018], stroke [Turcato 2018], traumatic brain injury [Chesselet], Parkinson’s [Kuo 2019], frontotemporal dementia [Davies], and acute glaucoma [Sundstrom]. We showed safety in over 130 healthy and sick people [Maccecchini 2012].MethodsWe are conducting a 2‐part double‐blind, placebo‐controlled phase 2a study in 14 AD and 14 PD patients, collected blood, CSF, conducted safety evaluations and psychometric tests. The patients were treated for 25 days. At the end of the study again safety, psychometric tests, blood and CSF. The plasma and CSF samples are being analyzed for AD and PD specific biomarkers, markers of axonal transport, inflammation, neurodegeneration and synapse health. The second part of the study is enrolling an additional 40 patients with the same study design.ResultsIn AD patients, we are reporting statistically significant improvements in a number of ADAS‐Cog variables: Number of Cancellations, Word Recall, Commands, Spoken Language, Remembering Test Instructions, and ADAS‐Cog 11. In PD patients, we also see statistically significant improvements in speed, coordination and motor function. The first step of the toxic cascade to have been measured is inflammation. Specific markers measured are: YKL40, sTREM2 and GFAP. The statistical significance holds whether the levels are compared within at 0 and at 25 days or between placebo treated and Posiphen treated at 25 days.ConclusionsWe showed that our drug improves cognition in AD and motor function in PD. The PD data is substantiated by the lowering of inflammatory markers. We are in the process of showing that by lowering more than one neurotoxic protein, our drug reverses the toxic cascade that leads to nerve cell death and loss of function. We still have a lot of markers to measure in CSF and plasma and expect to finish by July.
Overcoming social isolation: A dementia‐ friendly guide to adapt during a global pandemic
Authors: Tokarczuk Pam 
Published: December 2021

AbstractBackgroundThe pandemic left millions of families with the unsustainable burden of tending to their loved ones’ cognitive, emotional, physical and spiritual wellbeing. Without the tools, training or expertise, they simply cannot fulfill this responsibility on their own. Dementia care experts, despite the heavy regulations placed on them, offer these families their only true window of hope. Learn how to flip the script during these harrowing times. We will examine how care providers can help families overcome these devastating hardships by giving them and their loved ones the tools they need to stay connected.
Investigating the role of Synaptotagmin‐1 at ribbon synapses
Authors: Jamal Armaan , Markert Sebastian , Watanabe Shigeki 
Published: December 2021

AbstractBackgroundPhotoreceptors possess a specialized form of proteinaceous electron‐dense projection: the synaptic ribbon that exhibits graded neurotransmitter release. The molecular mechanism underlying graded release is unknown. Data suggests that synaptic vesicles at ribbon synapses undergo homotypic compound fusion where vesicles may only travel a short distance to the neighboring vesicles and fuse with each other around the ribbons1. Here we demonstrate that Synaptotagmin‐1 (Syt1) functions in compound fusion as it promotes full formation of the SNARE complex fusion machinery in response to calcium influx2. A better understanding of synaptic ribbon communication proteins may lead to novel drug targets to aid in therapeutic designMethodSyt1 knock‐down (KD) was developed using a CRISPRi system in Danio rerio larvae (n=100) and incubated for 5 days. Flash‐and‐freeze electron microscopy was performed on the Syt1 KD line and controls (n=100) by stimulating and freezing the samples at time points 0, 3, 6, 9 and 15 milliseconds after exposure to light for 30 seconds. Samples were fixed in epoxy resin and viewed under TEM. Blind analysis using ImageJ was performed to identify the presence of any compound fusion.ResultMean compound fusion frequency was highest at the 6ms and 9ms time points in Danio rerio controls. At the 6ms timepoint, compound fusion was seen at the middle of the ribbon and at 9ms, compound fusion was seen closer to the base. Prevalence of compound fusion was significantly reduced at the 6ms and 9ms time points in the Syt1 KD compared to controls.ConclusionSyt1 is can mediate compound fusion on a millisecond timescale during exocytosis.1. Matthews G, Sterling P. Evidence That Vesicles Undergo Compound Fusion on the Synaptic Ribbon. J Neurosci. 2008;28(21):5403‐5411. doi:10.1523/JNEUROSCI.0935‐08.20082. Chicka MC, Hui E, Liu H, Chapman ER. Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+. Nat Struct Mol Biol. 2008;15(8):827‐835. doi:10.1038/nsmb.1463
Characteristics of referrals to national assessment for eligibility into the Specialist Dementia Care Program (SDCP) in Australia
Authors: Atee Mustafa , Morris Thomas , Macfarlane Stephen , Cunningham Colm 
Published: December 2021

AbstractBackgroundDementia is a progressive neurodegenerative disease that is characterized by the presence of behaviors and psychological symptoms (BPSD), such as agitation and hallucinations. BPSD frequently have considerable negative social and clinical outcomes, such as inappropriate drug therapy, caregiver distress, institutionalization, and reduced quality of life. Thus, dementia requires significant care and support, particularly in the advanced stages. A new initiative funded by the Australian Government; the Specialist Dementia Care Programs (SDCPs) provide a person‐centered, multidisciplinary care within special accommodation units for people with severe dementia (up to 12 months) who cannot be cared for by mainstream aged care services. Eligibility assessments for SDCP’s placements are conducted by Dementia Support Australia (DSA) through its national Needs Based Assessment (NBA) program (Figure 1). This study describes the referral characteristics of the NBA program.MethodsNBA referrals were deemed eligible for admission to SDCPs if they had: (1) behaviors primarily linked to dementia; (2) severe or very severe BPSD (e.g., aggression, severe agitation); and (3) proved intractable to adequate trials of treatment. Eligibility assessments were completed by a dedicated team of NBA consultants and psychogeriatricians. Demographic data of referrals were described for the period November 2019‐June 2021.ResultsOf the 471 referrals (age: 76.0 ± 8.3 y; 69.1% males) received during the specified period, 273 (58.0%) had an NBA assessment. Of these, two‐thirds (n = 178, 65.2%) were found eligible for SDCP placement. Eligible referrals (age: 74.6 ± 7.6 y; 72.3% males) had Alzheimer’s disease (n = 93, 52.2%), mixed dementia (n = 27, 15.2%), frontotemporal dementia (n = 17, 9.6%), vascular dementia (n = 14, 7.9%), and dementia with Lewy bodies (n = 8, 4.5%). Most eligible cases were referred from residential aged care homes (RACH; n = 70, 39.8%), hospitals (n = 55, 31.3%) and mental health services (n = 27, 15.3%) because of physical aggression (64.0%).ConclusionsTypical characteristics of eligible NBA referrals to an SDSP placement (i.e., people with severe‐to‐very severe BPSD that require extensive support) included being male, aged on average 75 years old, resided in RACH, physically aggressive towards others, and had Alzheimer’s disease.
Diabetes is associated with poorer allocentric processing compared to non‐diabetic participants in the EPAD LCS cohort
Authors: Gregory Sarah 
Published: December 2021

AbstractBackgroundDementia and type 2 diabetes mellitus (T2D) are prevalent disorders in older adults, and increasingly T2D is recognized as a robust predictor of cognitive impairment, decline and dementia. Older adults with T2D experience global cognitive decline at a rate that is double those without T2D over a 5‐year period. With regard to specific cognitive domains, associations between T2D and pre‐diabetic levels of insulin resistance are most commonly reported with both episodic memory and decreased executive function, including verbal fluency, working memory, processing speed, cognitive flexibility, and cognitive control. Identification of those living with diabetes at risk for cognitive decline is critically important for early intervention.MethodWe used the EPAD LCS vIMI baseline dataset (n=1324, excluding participants with missing data). Our primary outcome measure was performance on the Four Mountains Test (4MT), a measure of allocentric processing. Diabetes was recorded in the medical history. Covariates were age, sex, years of education, family history, APOE status, pTau and Aβ1‐42. Our statistical analysis approach was linear regression.ResultThere were 90 participants with diabetes included in the sample. Their mean score on the 4MT was 8.32 (±2.32) correct (out of 15) compared to 9.24 (±2.60) for participants without diabetes. In uncorrected models, diabetes was significantly associated with worse 4MT total scores (β=‐0.92, p=0.001). This relationship remained significant in a fully adjusted model including sex, age, education, family history of dementia and APOE status (β=‐0.71, p=0.0017). There was no significant interaction between diabetes and APOE status. pTau was significantly higher in participants with diabetes compared to those without. Including pTau and Aβ1‐42 in the fully adjusted model further attenuated it but it remained significant (β: ‐0.62, p=0.02)ConclusionIndividuals with diabetes performed worse on the 4MT compared to those without diabetes in the EPAD LCS v.IMI dataset. Novel cognitive tests, such as the 4MT, may be appropriate to identify early cognitive changes in this high‐risk group. Future research will investigate longitudinal associations between diabetes and 4MT performance over multiple visits.
APOE, TOMM40, and Sex Interactions on Neural Network Connectivity
Authors: Li Tianqi , Pappas Colleen , Le Scott T , Wang Qian , Klinedinst Brandon S , Larsen Brittany A , Pollpeter Amy , Lee Ling Yi , Lutz Michael W , Gottschalk William Kirby , Swerdlow Russell H , Nho Kwangsik , Willette Auriel A 
Published: December 2021

AbstractBackgroundThe Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The Translocase of Outer Mitochondrial Membrane‐40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 (‘650) G vs. A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE.
MethodWe examined 21 orthogonal neural networks among 8,222 middle‐aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 ‘650 genotypes, and if age and sex acted as moderatorsResultAPOE ε4 was associated with less strength in multiple networks, while ‘650 G vs. A carriage was related to more language comprehension network strength. In APOE ε4 carriers, ‘650 G‐carriage led to less network strength with increasing age, while in non G‐carriers this was only seen in women but not men.ConclusionTOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.
Deletion of the SPAG9 gene cause autosomal‐recessive intellectual disability
Authors: Acosta‐Baena Natalia , Tejada‐Moreno Johanna A. , García Alejandro Mejía , Caro María Antonieta , ‐Lanau Carlos Andrés Villegas , Bedoya‐Berrío Gabriel 
Published: December 2021

AbstractBackgroundIntellectual disability (ID) is the limitation of intellectual functioning and adaptive behavior before 18 years of age. In a consanguineous family of 149 members, this disease is expressed in 9 individuals. Here, we report one branch of a family tree with three siblings, presenting severe ID, delayed speech development, cataracts, strabismus, gait disturbance, cerebellar syndrome, seizures in one of them, and eyelid ptosis in two. Brain magnetic resonance imaging (MRI) with hippocampal malrotation, brain atrophy and white matter hyperintensities in all cases. Thinning of the corpus callosum in two of them.MethodWe conducted whole exome sequencing analysis in nine subjects from one multigenerational family of Colombian origin. The study was carried out at the University of Antioquia,Colombia with the approval of the ethics committee. A medical, neurological, neuropsychological examination and brain MRI were performed in all cases.ResultWe identified a single nucleotide deletion in the SPAG9 gene, which codes for the JIP4 protein. The frameshift generates a premature stop codon (p.Tyr914Ter). The deletion is classified as pathogenic, according to the ACMG / AMP guidelines. The variant co‐segregated in the respective family as an autosomal recessive trait.ConclusionJIP 4 has two functions: As scaffold protein that potentiates the p38 MAPK signaling cascade under stress conditions and as dynein‐dynactin motor adapter for lysosomal retrograde flow, regulating the constitutive transport of lysosomes. Both functions could be associated in the disease mechanism. The absence of JIP 4 may be responsible for the disease in the family, altering neuronal homeostasis.
Ca2+/Calcineurin‐mediated release of exosomal miR‐23a regulates astrocyte‐neuron cross‐talk and protects against neuroinflammation and neurodegeneration
Authors: Bhattacharyya Pallabi , Biswas Subhas Chandra 
Published: December 2021

AbstractBackgroundAstrocyte dysfunction and associated neuroinflammation is well implicated in various neurodegenerative disorders like Alzheimer’s (AD) and Parkinson’s diseases (PD). Importantly, Ca2+/Calcineurin signaling is reported to induce astrocyte dysfunction in AD (1) but very little is known regarding PD. So, our objective was to study the role of Ca2+/Calcineurin signaling in astrocyte‐neuron cross‐talk during PD‐related neuroinflammation which is unreported till date.Method1.Mammalian cell culture 2.Immunoblotting. 3.qRT‐PCR. 4.Exosome isolation. 5.Intracellular Ca2+ measurement. 6.Transfection (miRNA mimics). 7. 3’UTR cloning. 8.Luciferase assay.ResultWe treated human astrocytic 1321N1 cells with Rotenone, a neuro‐toxin known to induce PD‐associated neuroinflammation (2). At the dose of Rotenone which caused about 40% death in 24 hrs, simultaneous activation of the Ca2+‐dependent protein phosphatase Calcineurin and intracellular surge in the Ca2+ levels were also observed. Now, miR‐23a is an anti‐apoptotic miRNA and Calcineurin/NFAT‐mediated upregulation of miR‐23a has been reported in cardiac hypertrophy (3). Surprisingly, in our study, Rotenone caused a Calcineurin‐mediated decrease of intracellular miR‐23a levels in astrocytes. Now this decrease, we found, was due to a concomitant release of miR‐23a via exosomes. Can this anti‐apoptotic miR‐23a released by astrocytes protect the neurons? To answer this, we treated neuronal SH‐SY5Y cells with Rotenone and found that the pro‐apoptotic protein PUMA was upregulated although the miR‐23a levels remained unchanged. Interestingly, over‐expression of miR‐23a caused attenuation of the Rotenone‐mediated death in neurons. PUMA being a predicted target of miR‐23a, we cloned the 3’UTR of PUMA and subsequent luciferase assay revealed that indeed PUMA is a direct target of miR‐23a under our experimental conditions.ConclusionOur results suggest a novel mechanism by which Ca2+/Calcineurin‐mediated release of miR‐23a through exosomes regulates astrocyte‐neuron cross‐talk and plays a probable role in protection against neuroinflammation and neurodegeneration.References:1.Sompol P. et al. Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ‐Bearing Mice. J Neurosci. 2017 Jun 21;37(25):6132‐6148. 2.Javed, H., Azimullah, S., Abul Khair, S.B. et al. Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci 17, 58 (2016). https://doi.org/10.1186/s12868‐016‐0293‐4. 3.Lin Z. et al. miR‐23a functions downstream of NFATc3 to regulate cardiac hypertrophy. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12103‐8.
Investigating changes in the proteostasis capabilities of iPSC‐neurons during development and in FTD using iPSC‐neurons with MAPT mutations
Authors: Lines Georgie , Arber Charles , Preza Elisavet , Leckey Claire Alexandra , Myeku Natura , Casey Jackie M. , Perkinton Michael , Wray Selina 
Published: December 2021

AbstractBackgroundMutations in microtubule‐associated protein tau (MAPT) gene are causative of Frontotemporal Dementia (FTD). Many of the features associated with the development of tau pathology, e.g high levels of tau phosphorylation, are also present in early development. iPSC‐neurons have gene expression signatures similar to fetal neurons, and iPSC‐neurons with MAPT mutations do not develop tau aggregates. We hypothesise that iPSC‐neurons are resistant to developing tau aggregates due to high activity levels of the proteostasis network during early development. To test this hypothesis, we investigated the levels of proteasome subunits in developing iPSC derived neurons and measured the proteasome activity of iPSC‐neurons throughout development. To test whether manipulation of proteostasis in iPSC‐neurons could lead to tau pathology we treated cells with a proteasome inhibitor, and measured changes in total and phosphorylated tau, proteasome subunits and autophagy regulators.MethodsHuman cortical neurons were derived from isogenic iPSCs with the following MAPT genotypes: WT, 10+16 monoallelic, 10+16 biallelic and 10+16/P301S biallelic. RNA and protein analysis of proteasome subunits was performed by qPCR and Western blot at during neuronal development (DIV 0, 10, 30 and 100) and after proteasome inhibition treatments.ResultsWe show that proteasome activity decreases during the differentiation of iPSCs to cortical neurons, accompanied by a reduction in levels of the proteasome regulatory subunits Rpt6 and Rpn6. Proteasome inhibition in WT neurons does not lead to a significant change in total or phosphorylated tau levels but resulted in an increase in the autophagy associated protein BAG3, together with an induction of tau cleaved by caspase‐3 at Asp421.ConclusionProteasome activity decreases during the differentiation of iPSCs into neurons, which may be due to a reduction in in proteasome regulators. Our results suggest that proteasome inhibition causes an increase in tau cleavage which may be preferentially cleared through the autophagy pathway. The ability of these ‘fetal‐like’ neurons to adapt and upregulate their protein clearance system may be enhanced compared to FTD brain tissue. In ongoing work we are investigating proteasome expression and activity in FTD post‐mortem tissue as well as the localisation and interactions of tau and the proteasome after proteasome inhibition treatments.
Identification of pharmacodynamics readouts through acute dosing of a small molecule inhibitor of tau self‐association in a tauopathy mouse model
Authors: Patel Dhruv R. , Sussman Chaya , Greco Mindy , Cheesman Edward H. , Lopez Patricia , Davidowitz Eliot J. , Moe James G. 
Published: December 2021

AbstractBackgroundThe accumulation of tau aggregates correlates with and facilitates disease progression in pure and mixed tauopathies such as Progressive Supranuclear Palsy and Alzheimer’s disease. However, a disease‐modifying‐therapeutic targeting tau aggregation has not yet shown success in the clinic. Our target approach is highly differentiated from other programs that are focused on inhibiting tau aggregation and all downstream cascades. We have selected and optimized small molecules capable of targeting tau self‐association (TSA), the first and rate‐limiting step in tau aggregation. We have demonstrated the efficacy of our lead TSA inhibitor in two mouse models of tauopathy (htau mice; tau‐P301L‐JNPL3 mice) in preventive and therapeutic studies. Treatment with the lead TSA inhibitor blocked tau self‐association and formation of large tau aggregates, reduced overall tau accumulation, and rescued impaired motor function in aged mice with pre‐existing tau aggregates. IND‐enabling studies for the lead TSA inhibitor are completing, and a FDA submission is planned for Q1 2022. In this study, we aim to identify acute measures of efficacy in aged homozygous female tau‐P301L‐JNPL3 mice that will be used to model Pharmacokinetics (PK)/Pharmacodynamics (PD) relationship of our TSA inhibitors.MethodsAcute dose range‐finding (ADRF) study was performed using multiple routes of administration. C57BL/6 mice (n=30) were either administered vehicle or a single dose of a selected TSA inhibitor ranging from 2 to 200 mg/kg (n = 3 mice/gender/group). Biospecimens were collected at Cmax. PK studies in C57BL/6 mice will be performed with and without fasting to determine the food effects on bioavailability.ResultsSerum and brain homogenate samples from the ADRF study are being analyzed to evaluate TSA inhibitor concentrations by LC‐MS/MS. These results will be used to select the dose and route of administration for PK studies in 9 months‐old homozygous female JNPL3 mice. To determine the selective dose for PD evaluations, PK studies will be performed using three doses. Some of the PD measures that will be evaluated are tau self‐association, tau hyperphosphorylation, and motor behavior.ConclusionsUnderstanding PK/PD relationship will be crucial for determining appropriate dosing and target engagement biomarkers in subsequent Phase‐1b studies.