bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isoform‐dependent neurotoxicity of the Alzheimer disease risk factor BIN1
Authors: Lambert Erwan , Abdelfettah Farida , Barois Nicolas , Vandekerkhove Dirk , Hermant Xavier , Ayral Anne‐Marie , Davoine Lindsay , Dupont Cloe , Lafont Frank , Amouyel Philippe , Chapuis Julien , Verstreken Patrik , Dermaut Bart , Lambert Jean‐Charles , Dourlen Pierre 
Published: December 2020

AbstractBackgroundUsing genome‐wide association studies, BIN1 was identified as the most associated risk gene for Alzheimer’s Disease (AD) after APOE. A 3bp insertion allele was shown to increase BIN1 expression in human brains and AD risk. BIN1 has more than 10 isoforms and the contribution of BIN1 and its isoforms to AD pathogenesis remains unclear. The aim of this work was to assess the neurotoxicity of BIN1 isoforms and understand the underlying mechanisms.MethodWe generated Drosophila transgenic lines expressing brain, muscular and ubiquitous human BIN1 isoforms 1, 8 and 9 respectively. We analyzed BIN1 isoform neurotoxicity using cornea neutralization, immunofluorescence, electrophysiology and electron microscopy in the fly eye photoreceptor neurons.ResultWe showed that adult eye‐specific expression of the brain BIN1 isoform 1 (BIN1‐1) resulted in an age‐dependent loss of photoreceptor neurons. Interestingly, the effect was specific of this isoform only. We tested truncated BIN1‐1 forms and showed that the BIN1‐1‐specific CLAP domain is necessary for the BIN1‐1 induced neurodegeneration. This domain is involved in endocytosis and vesicular trafficking. In addition, photoreceptor neuron degeneration was characterized by a strong accumulation of vesicles with endosomal markers suggesting a blockade of the endosome‐lysosome pathway. We further found that modulation of Rab5, Rab4 and Rab11, involved at the level of the early and recycling endosomes, abrogated photoreceptor degeneration, indicating that BIN1‐1 toxicity is due to the blockade of the endosome‐lysosome pathway likely at the level of early endosomes. Finally, as endosomes are involved in synaptic vesicles formation and postsynaptic receptor recycling, we tested the electrophysiological consequences of BIN1‐1 expression. Although not affected in young flies, we observed that expression of BIN1‐1 affected early photoreceptor neuron synaptic transmission.ConclusionAltogether, these results show that an increase of the BIN1 isoform 1 impairs the endosome‐lysosome pathway, thereby affecting synaptic transmission and inducing neurodegeneration. Interestingly, enlarged endosomes have been shown to be one of the first cytopathological markers of the disease and synaptic transmission is affected early in AD pathogenesis. These results suggest that an increase in BIN1 isoform1 could contribute to early steps of Alzheimer’s disease.
Protective genetic variants in the MS4A gene cluster modulate microglial activity
Authors: Deming Yuetiva , Filipello Fabia , Cignarella Francesca , Suárez‐Calvet Marc , Morenas‐Rodríguez Estrella , Van Hulle Carol A. , Jonaitis Erin M. , Blennow Kaj , Zetterberg Henrik , Asthana Sanjay , Johnson Sterling C. , Carlsson Cynthia M. , Bendlin Barbara B. , Engelman Corinne D. , Ewers Michael , Haass Christian , Benitez Bruno , Karch Celeste M. , Piccio Laura , Cruchaga Carlos 
Published: December 2020

AbstractBackgroundVariants within the gene‐rich membrane‐spanning 4‐domains subfamily A (MS4A) gene region have been associated with increased or reduced risk for Alzheimer's disease (AD) by large genome‐wide association studies (GWAS). Although MS4A family members are known to be cell membrane proteins implicated in immunity, their role in AD pathogenesis has remained elusive. Another transmembrane protein with a key role in immunity is the triggering receptor expressed on myeloid cells 2 (TREM2) and low frequency variants in TREM2 have been associated with AD risk. Soluble TREM2 (sTREM2) measured in cerebrospinal fluid (CSF) has also been associated with AD. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of these immune‐related genes in AD may reveal important pathological mechanisms and identify distinct therapeutic targets.MethodWe measured sTREM2 in CSF samples obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 813) and used GWAS to identify genetic modifiers of CSF sTREM2. Bioinformatics approaches and RNAseq were used to identify expression quantitative trait locus (eQTL) effects. Finally, the genetic findings were functionally validated in human macrophages by lentivirus‐mediated overexpression and antibody knockdown.ResultCommon variants in the MS4A gene region were associated with CSF sTREM2, which replicated in independent datasets (n = 580). These variants included a previously reported AD risk‐reducing allele in rs1582763, which associated with increased CSF sTREM2 (β = 735, P = 1.15e‐15). This variant was found to influence gene expression of a few MS4A family members including MS4A4A in blood and brain tissue. Using cell models, we validated the genetic findings by demonstrating that changes in MS4A4A expression influenced concentration of sTREM2.ConclusionHuman genetic, molecular, and cellular findings strongly suggest that MS4A4A modulates sTREM2. As also reported by our group, CSF sTREM2 is associated with tau‐related neurodegeneration and rate of memory decline in AD. Combined, these findings provide a potential mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that sTREM2 is involved in sporadic AD pathogenesis.
Joint modeling of time‐varying exposure history and health outcomes: Identification of critical windows
Authors: Wagner Maude , Grodstein Francine , Samieri Cécilia , Proust‐Lima Cécile 
Published: December 2020

AbstractBackgroundLife‐long exposures constitute a primary focus of research on the etiology of many chronic diseases. Yet, identifying the critical windows when risk factors mostly impact the risk of disease remains an open statistical question. Some methods have already been proposed to assess the effect of a time‐varying exposure history. However, research mostly focused on a continuously observed error‐free exposure, a binary or time‐to‐event outcome and a concomitant evaluation of exposure and outcome.MethodWe jointly model the trajectory of the exposure over time and its weighted cumulative effect on the subsequent trajectory of the outcome. As we consider separate time‐windows for the exposure and the outcome, inference can be obtained with a two‐stage approach. Subject‐specific predictions of exposure are computed from a flexible mixed model in stage 1, thus handling missing data and error in exposure measurement. In stage 2, weighted time‐dependent effects (modelled by splines) of these predicted exposures are included in the mixed model for the outcome. The method, which was evaluated in simulations, can be easily implemented in standard statistical software (see Figure).ResultWe studied the association between body mass index (BMI) history (collected from midlife) and cognition (evaluated after age 70) in the Nurses’ Health Study cohort. In a sample of 19,415 women, the method identified two major critical windows of association. Long before the first cognitive evaluation (roughly 24 to 12 years), higher levels of BMI were associated with poorer cognition. In contrast, adjusted for the whole history, higher levels of BMI became associated with better cognition in the last years prior to the first cognitive interview, thus reflecting reverse causation (changes in exposure due to underlying disease).ConclusionThe proposed joint modelling approach provides a flexible tool to evaluate the trajectory of effect of a time‐varying exposure on a subsequent longitudinal outcome. It is particularly useful to explore complex dynamic relationships, as illustrated with BMI and cognition, and address for various clinical questions by identifying critical windows of lifelong exposures.
Mechanisms underlying the procognitive effects of intranasal insulin
Authors: Erichsen Jennifer M. , Woodruff Jennifer L. , Burzynski Hannah E. , Grillo Claudia A. , Reagan Lawrence P. , Fadel James R. 
Published: December 2020

AbstractBackgroundIntranasal insulin (INI) represents a potential treatment for age‐related cognitive decline (ARCD), as numerous studies and multi‐center clinical trials have demonstrated that it enhances memory. However, the mechanism underlying these pro‐cognitive changes is unknown. Several methods were implemented to begin to uncover a neurochemical/molecular basis underlying the effects of acute and subchronic INI.MethodNeurochemical and molecular techniques were employed in adult male Sprague‐Dawley rats following acute and/or subchronic INI. The animals received bilateral hippocampal injections of a lentiviral vector containing a selective insulin receptor antisense sequence (LV‐IRAS) or a control virus (LV‐Con). To measure neurotransmitter efflux following INI, probes were inserted into the medial prefrontal cortex (mPFC) and hippocampus for in vivo microdialysis. Levels of acetylcholine and glutamate were measured for three hours following acute INI or IN vehicle. To investigate insulin receptor signaling following acute and subchronic INI, a separate cohort of animals (no virus) were administered INI or IN vehicle for 10 days. The next day they were given another dose of INI to stimulate insulin signaling and euthanized at various time points post‐administration. Olfactory bulb and hippocampal extracts were processed for immunoblot analysis to assess changes in central insulin signaling.ResultBaseline levels of glutamate were significantly decreased in LV‐IRAS animals compared to LV‐Con in the hippocampus but not the mPFC. Additionally, INI administration appeared to increase hippocampal glutamate efflux. Finally, a time‐dependent increase in insulin signaling in response to INI was observed after subchronic INI administration.ConclusionThese results begin to uncover a mechanistic basis for the pro‐cognitive effects of INI. The effects of acute INI may be partially mediated by a neurochemical mechanism, specifically involving glutamate. This study also revealed that molecular changes were dependent on timing and length of dose; therefore a more chronic INI administration may affect neurotransmission differently. More studies are needed to fully understand the mechanistic changes following INI and to determine the most effective clinical dose and dosing regimen. It is important to understand the mechanism of action, as INI could eventually be used in the broader clinical setting to treat ARCD.
Level of plasma tau and depression, anxiety and worry in cognitively normal older adults
Authors: Hall James R , Petersen Melissa , Johnson Leigh Ann , O'Bryant Sid 
Published: December 2020

AbstractBackgroundNeurobehavioral changes in cognitively intact individuals may represent early indicators of underlying pathophysiological processes such as the development of tau related changes in the brain. Research assessing tau pathology with PET has shown a relationship between tau accumulation in the inferior temporal lobes and entorhinal cortex and depression and tau accumulation in the right entorhinal cortex and loneliness. The current research investigated the relationship between levels of plasma tau and measures of depression, anxiety and worry in a community‐based sample of cognitively normal older adults.MethodParticipants were drawn from a community‐based, longitudinal study of cognitive aging in Mexican‐Americans. 415 cognitively normal Mexican Americans (328 females, 87 males) and 134 cognitively normal non‐Hispanic whites (95 females, 39 males) were administered the Geriatric Depression Scale (GDS), the Beck Anxiety Inventory (BAI)and the Penn State Worry Questionnaire PSWQ). Plasma tau was assayed via Single Molecule Array (Simoa) technology. Data were analyzed using t tests and ANOVA.ResultThere was no significant main effect for plasma tau on any of the emotional measures. To assess the possible impact of level of tau, the sample was divided into those in the highest quartile of tau (N=89) and those in the lower three quartiles of tau (N=460). Analyses controlling for age, education and gender revealed that those in the highest quartile scored significantly higher on GDS total score (p= .011), three of the four subscales of the GDS (Dysphoria p=.020; Apathy p=.021; Cognitive Impairment p=.029), the BAI (p=.005) and the PSWQ (.003).ConclusionIn cognitively normal elderly, higher levels of plasma tau were significantly related to measures of emotional functioning with significantly greater endorsement of symptoms of depression, anxiety and worry. The presence of high levels of these symptoms and higher levels of plasma tau may be an indicator of preclinical Alzheimer’s disease. Longitudinal research is needed to assess the strength of these factors in later cognitive decline and may suggest areas for early intervention.
Developing CNS therapeutics for brain insulin resistance in Alzheimer’s disease (AD) and mild cognitive impairment (MCI)
Authors: Talbot Konrad , Wang Hoau‐Yan 
Published: December 2020

AbstractBackgroundBrain insulin resistance is established as an early, common, and profound feature of AD dementia (ADd). This phenomenon can be induced by multiple AD risk factors and by early abnormalities in the disorder. Once induced, brain insulin resistance promotes many other AD‐associated abnormalities. Brain insulin resistance consequently appears to be a nodal abnormality in ADd and thus an efficient target for treating the disorder in general. We accordingly tested antidiabetic incretin receptor agonists (IRAs) shown to relieve AD‐related pathology in animal models of AD on brain insulin resistance in ex vivo hippocampal formation (HF) preparations from ADd and MCI cases.MethodFresh frozen HF tissue was obtained from age‐ and ‐sex matched Caucasians with no history of diabetes and low postmortem intervals (m ± SD = 6.75 ± 2.2 h). They were from non‐cognitively impaired, non‐amnestic MCI, amnestic MCI, and ADd cases (n = 10 per clinical group). Using our ex vivo stimulation protocol (Talbot and Wang et al., JCI 122: 1316‐1338, 2012), the ex vivo tissues were tested for their signaling responses at the level of the insulin receptor, insulin receptor substrate‐1, and Akt to 60 min incubation in 0, 1, or 10 nM insulin with or without 30 min pretreatment with 100 nM of single IRAs such a liraglutide activating just one incretin receptor (i.e., the glucagon‐like peptide‐1 [GLP‐1] receptor) or dual IRAs activating both incretin receptors (i.e., GLP‐1 + gastric inhibitory peptide [GIP] receptors). Statistical significance was defined as p < 0.05.ResultHF responsiveness to 1 and 10 nM insulin was significantly reduced in all the clinical groups at all levels of the insulin signaling pathway tested. Pretreatment with single IRAs, as well as dual IRAs markedly improved insulin responsiveness of HF tissue from MCI cases. All the IRAs tested significantly increased such responsiveness in HF tissue from ADd cases, but the dual IRA was roughly twice as effective as the single IRAs.ConclusionIRAs are thus emerging as high priority candidates for development as AD therapeutics, especially since they have all passed phase II and/or III clinical on type 2 diabetics.
White matter hypertensity burden varies in empirically derived incident MCI subtypes
Authors: Machulda Mary M. , Lundt Emily S. , Albertson Sabrina M. , Graff‐Radford Jonathan , Jack Clifford R. , Mielke Michelle M. , Kremers Walter K. , Knopman David S. , Petersen Ronald C. , Jones David T. , Bondi Mark W. , Vemuri Prashanthi 
Published: December 2020

AbstractBackgroundWhite matter changes and Alzheimer’s disease pathology frequently co‐exist in the population. Recently we empirically derived subtypes of incident mild cognitive impairment (MCI) and found that there was significant heterogeneity not only in cognitive impairment profiles but also gray matter atrophy suggesting that multiple etiologies may contribute to cognitive impairment in these subtypes. The aim of this study was to examine differences in white matter hyperintensity (WMH) volume in these same MCI subtypes and investigate amyloid deposition in a smaller subset.MethodWe analyzed data from 188 participants with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) identified as having one of four MCI subtypes: subtle cognitive impairment (SCI), amnestic, dysnomic, and dysexecutive. All participants completed 3T imaging at the time of the MCI diagnosis. Using WMH volume scaled by TIV and PIB SUVR, we compared each MCI subtype to 344 cognitively impaired (CU) participants (mean age 78; 46% women) and each other.ResultThe amnestic (n = 83; mean age 80; 43% women), dysnomic (n = 30; mean age 84; 47% women) and dysexecutive subtypes (n = 49; mean age 83; 35% women) had significantly higher WMH volumes compared to CU (p < .02) while the SCI subtype (n = 26; mean age 80; 23% women) did not differ from CU (p = .76). Amongst the MCI subtypes, the amnestic (p = .04) and dysexecutive subtypes (p = .01) had significantly higher WMH volumes than the SCI subtype [Figure 1]. In a smaller subset of individuals who also completed PiB‐PET (17/26 SCI; 39/83 amnestic; 10/30 dysnomic, 28/49 dysexecutive), we found evidence for higher amyloid load in all MCI subgroups except the SCI group (p<0.05) in comparison to CU.ConclusionWe found significantly elevated levels of WMH and amyloid burden in amnestic, dysnomic, and dysexecutive subtypes of incident MCI supporting the notion that both vascular changes and amyloid contribute to the development of clinical symptoms. Surprisingly, WMH and amyloid positivity were not high in SCI suggesting that the pathophysiology in this group needs further investigation.
In‐vivo characterization of progressive amnestic syndrome due to suspected neurodegenerative non‐Alzheimer’s disease
Authors: Bailly Laurent , Villain Nicolas , Houot Marion , Hourregue Claire , Paquet Claire , Leroy Melanie , Lebouvier Thibaud , Dubois Bruno , Epelbaum Stéphane 
Published: December 2020

AbstractBackgroundNeuropathological bases of suspected non‐Alzheimer’s disease pathophysiology (SNAP) have recently been identified as frequent causes of progressive isolated amnestic non Alzheimer’s disease (AD) neurodegenerative diseases1,2. Nonetheless, their in‐vivo profiles have so far been only poorly characterized. The goal of this study is to specify their clinical, neuroimaging profile and evolution, compared to patients with amnestic AD and cognitively normal subjects.MethodsWe retrospectively selected patients with progressive amnestic syndrome of hippocampal type3, signs of neurodegeneration (elevated CSF t‐ tau concentration and/or brain hypometabolism and/or atrophy) and normal CSF Amyloid values (Aβ42 concentration ; Aβ40/42 ratio if available) from 3 tertiary memory centers (amnestic SNAP). They were compared to patients with prodromal typical (amnestic) AD (without impairment of instrumental functions, MMSE >20, elevated CSF p‐tau and abnormal CSF Amyloid values) and cognitively normal controls with normal CSF Amyloid values. We compared clinical data and neuropsychological tests between amnestic SNAP and the two other groups.Results25 patients with amnestic SNAP (median age=74.7), 24 amnestic AD (median age=71) and 35 controls (median age=75) were included. At baseline, controls had better global cognitive performances (MMSE=29 vs. 27 vs. 25 respectively, p<0.001) as well as verbal fluency performances than amnestic SNAP and amnestic AD but no significant difference were found between amnestic SNAP and AD (p=0.096). Executive functioning was significantly different between controls, amnestic SNAP and AD (FAB=17, 16 and 14 respectively, p<0.001) and there was a significant difference between amnestic SNAP and AD (p=0.034). We found no other significant difference between amnestic SNAP and AD: neither regarding memory performances (FCSRT) nor other cognitive functions (language, visuo‐spatial abilities).ConclusionPatients with amnestic SNAP show a weaker impairment in executive functions than patients with prodromal amnestic AD, highlighting a specific identifiable baseline neuropsychological pattern. This work will be completed by the analysis of clinical evolution, and the pattern of brain atrophy and brain metabolism that will be available at the time of AAIC. References: 1. Nelson et al. (2019). Brain, 142(6):1503‐1527. 2. Crary et al. (2014). Acta Neuropathol. 2014 Dec;128(6):755‐66. 3. Dubois B. & Albert M (2004). Lancet Neurol, 3 (4), 246‐8.
The sustainability of community interventions for people affected by dementia: A realist review
Authors: Morton Thomas Alexander , Atkinson Teresa , Brooker Dawn , Wong Geoff 
Published: December 2020

AbstractBackgroundCommunity‐based support for people with dementia and their care partners (family/friends), such as regularly‐meeting groups and activities, can play an important part in post‐diagnostic care: from combating isolation and maintaining positive self‐image, to delaying decline and hospitalisation. However, in countries such as the UK these are typically delivered piecemeal by a variety of agencies with inconsistent funding. This has led to fragmented provision with significant gaps and, to add to this, many such interventions are forced to fold after only a short period. The SCI‐Dem review is investigating what can promote, or get in the way of, community interventions for people affected by dementia becoming sustainable over time.MethodThis review is utilising a Realist approach. Key sources of evidence were gathered using formal searches of electronic databases and grey literature, together with informal search methods such as citation tracking and snowballing. Data were interrogated, assessed and organised with the aid of NVivo software, and a Realist logic of analysis was applied to trace context‐mechanism‐outcome configurations as part an overall programme theory, indicating what works for whom, in what circumstances, in what respects and how, with regards to sustaining community interventions. Consultation with stakeholders, involved with a variety of such interventions in various roles, informed this process throughout.ResultDue to complete in September 2020, this review will produce an evidence‐informed programme theory mapping how different contexts can trigger mechanisms (processes in people and organisations) to produce outcomes that help or hinder the sustainability of a community group or activity. Early findings suggest a range of factors affecting four key areas for sustainability: whether a group or activity can get or keep 1) members; 2) appropriate staff and volunteers; 3) necessary resources; 4) necessary funding.ConclusionConclusions will focus upon how best to implement community‐based interventions, with recommendations to those commissioning, planning or running such schemes, based upon our programme theory. Accessible publications and online materials will be produced, aiming to provide an evidence‐informed ‘blueprint’ for other community settings. Recommendations about what could be useful at both regional and national policy and infrastructure levels will also be made.