bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between mild behavioral impairment and hippocampal structural covariance in amnestic mild cognitive impairment
Authors: Yoon Eun Jin , Lee Jun‐Young , Kim Heejung , Kim Yu Kyeong
Published: December 2023

Background

Our previous work reported that mild cognitive impairment (MCI) patients with multiple mild behavioral impairment (MBI) domain symptoms (complex group) revealed a higher risk of developing Alzheimer’s disease (AD) compared with those with no MBI symptoms (asymptomatic group) and cortical thinning in the parietal and frontal areas. However, MCI patients with only affective dysregulation (affective dysregulation group) were not associated with the risk of AD and revealed relative cortical thickening (Yoon EJ, Front Aging Neurosci 2023). To clarify relationships of cortical thickness changes and risk of progression to AD in MCI patients, we compared structural covariance patterns between hippocampal volume and cortical thickness among the MBI subgroups.

Method

A total 201 older adults with amnestic MCI were classified based on profiles of MBI domain symptoms into asymptomatic, affective dysregulation, and complex groups. The FreeSurfer was used to estimate cortical thickness and volumes of hippocampal subfields (Fig 1). A vertex‐wise general linear interaction model was used to compare group map of covariance between volumes of hippocampus subfields and thickness at each of vertices. Correlations between the thickness in regions showing significant group differences and mini‐mental state examination (MMSE) scores were also assessed.

Result

In the affective dysregulation group, the structural covariance of left CA1, CA4/DG and molecular layer were increased in the left superior and inferior parietal cortex (Fig 2a), and the thickness of this region showed positive correlation with MMSE (spearman’s rho = 0.302, p‐value = 0.046). The structural covariance of left hippocampal tail for the affective dysregulation group was increased in left lateral occipital cortex, and those for the complex group was increased in left inferior parietal and lateral occipital cortex compared with the asymptomatic group (Fig 2b). Also, the complex group revealed decreased structural covariance of right subiculum with left rostral middle frontal cortex (Fig 2c).

Conclusion

Our findings suggest that the lateral parietal area might have an important role in compensatory mechanisms in the affective dysregulation group. On the other hand, the complex group may be associated with more advanced stages of disease in which the patterns of increased covariance of hippocampal subfields were disappeared or inversed.
Subclinical mesial temporal lobe activity in Alzheimer’s Disease
Authors: Devulder Astrid , Testelmans Dries , Bossche Maarten Van Den , Cleeren Evy , Theys Tom , Van Paesschen Wim ,   Laboratory for Epilepsy Research, KU Leuven
Published: December 2023

Background

Animal and human studies of Alzheimer’s disease (AD) demonstrated that aberrant network activity with neuronal hyperexcitability plays a role in disease pathogenesis and cognitive functioning. Suppressing network hyperexcitability with levetiracetam improved cognitive functioning in familial AD mice and executive functioning in patients with AD and epileptiform activity. Manifestations of network hyperexcitability are unsensitive biomarkers since they are mostly subclinical and not visible on scalp EEG. (Lam et al. 2019, Vossel et al. 2021, Sanchez et al. 2012).

Our purpose was to identify subclinical epileptiform activity in two patients with mild cognitive impairment (MCI) and one patient with moderate AD, with a suspicion of network hyperexcitability based on either spikes on 24‐h scalp EEG or a history suspect for seizures without epileptiform discharges on scalp EEG.

Method

Three patients were implanted with bilateral foramen ovale (FO) electrodes to obtain more direct measures of mesial temporal lobe epileptiform activity. Scalp EEG according to the 10‐20 system and polysomnography were simultaneously recorded in all subjects for three to five consecutive days. Polysomnography was scored according to the AASM scoring rules. Persyst 14 software was used for automatic spike detection.

Result

Invasive recordings showed interictal epileptic activity in all three patients, which was occasional during wakefulness and abundant during sleep. In one patient two nocturnal unilateral mesiotemporal seizures, characterized by arousal, were recorded during N1 sleep, while at the same time no epileptiform activity was visible on scalp EEG.

Conclusion

In patients with AD subclinical mesial temporal epileptiform activity can be present with a normal scalp EEG. Epileptic activity is predominantly found during sleep. Our findings suggest an important role for network hyperexcitability in AD disease pathogenesis.
The impact of co‐morbid LATE‐NC pathology in Alzheimer’s Disease.
Authors: Tomé Sandra O. , Tsaka Grigoria , Ronisz Alicja , Ospitalieri Simona , Gawor Klara , von Arnim Christina , Otto Markus , Vandenberghe Rik , Schymkowitz Joost , Rousseau Frederic , Thal Dietmar Rudolf ,   Neuropathology
Published: December 2023

Background

TDP‐43 is known to co‐accumulate in the brains of most Alzheimer’s Disease (AD) cases, in addition to amyloid‐β plaques and tau tangles, and it has been recently defined as limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC). TDP‐43 pathology is thought to worsen cognitive decline and neurodegeneration, but it is not yet understood whether TDP‐43 expression impacts AD pathogenesis, specifically tau pathology.

Method

We performed a histological evaluation of 85 human cases including controls, symptomatic AD cases with (ADNC+LATENC) and without (ADNC) LATE‐NC using paraffin‐embedded post‐mortem tissue. We quantitatively assessed pTau load and neuronal density. Additionally, we measured brain levels of p‐tauT181 and total TDP‐43 (1‐300aa.) through ELISA using fresh frozen tissue of controls, ADNC, ADNC+LATENC and FTLD‐TDP cases. Moreover, we tested the seeding potential of ADNC+LATENC and AD seeds in vivo, using a TDP‐43A315T transgenic mouse model as well as in vitro, using a tau biosensor cell line (HEK293T cells transfected with a tau PS301S mutation).

Result

We observed that ADNC+LATENC cases presented increased neuronal loss (p = 0.0231) and hippocampal tau pathology (p<0.0001) compared to ADNC and controls. Moreover, the ADNC+LATENC group showed increased levels of the p‐tauT181 in frontal (p = 0.0212) and entorhinal cortex (p = 0.0003) compared to the ADNC group. Total TDP‐43 levels were decreased in ADNC+LATENC and FTLD‐TDP cases compared to controls in entorhinal (p = 0.0151 and p = 0.0041, respectively) but not frontal cortex. Moreover, we observed that TDP‐43A315T mice injected with ADNC+LATENC seeds exhibited significantly increased p‐tau seeding compared to ADNC (p = 0.0163) and control‐injected animals (p = 0.0007). In line with these findings, ADNC+LATENC seeds also triggered increased p‐tau cell seeding in tau biosensor cells compared to ADNC seeds (p = 0.0048).

Conclusion

These results highlight the synergy between TDP‐43 and tau proteins in the context of AD pathogenesis. Specifically, our data suggest that the presence of comorbid LATE‐NC in AD aggravates tau pathology, increasing its aggregation and seeding. Moreover, a decrease in total TDP‐43 in ADNC+LATENC and FTLD‐TDP groups points to a loss of function of this protein. We highlight the importance of considering comorbid co‐pathologies in the context of clinical diagnosis and patient stratification.
Nicotinic ACh receptor activation induces BACE1 transcription via MEK⁄ERK‐SP1 signaling pathway
Authors: Nakano Masaki , Mitsuishi Yachiyo , Saito Takashi , Saido Takaomi C. , Nishimura Masaki
Published: December 2023

Background

Epidemiological studies showed that cigarette smoking increases a risk of Alzheimer disease. In contrast, nicotine treatment reportedly reduces brain Aβ deposition of APP‐transgenic mice. These findings seem inconsistent. Previously, we reported that nicotine perfusion using reverse microdialysis increased Aβ levels of the cerebral cortex of APP‐knockin mice (J Alzheimers Dis, 2021). In this study, we further examined nicotine effects on Aβ metabolism and the underlying mechanisms.

Method

Using AppNL‐G‐F mice and SH‐SY5Y neuronal cells, we analyzed nicotine effects on cellular and brain Aβ metabolism. (1)AppNL‐G‐F mice were exposed ad libitum to drinking water containing nicotine for 2 months and then brain Aβ of these mice was quantitatively evaluated by ELISA and immunostaining. (2) Effects of nAChR activation on Aβ production were examined using SH‐SY5Y cells. (3) We also evaluated nicotine effects on Aβ aggregation using an in vitro assay.

Result

Chronic treatment of AppNL‐G‐F
mice with nicotine resulted in increased contents of brain Aβ but had no obvious effect on aggregated Aβ deposition. We found that nAChR activation increased Aβ production of SH‐SY5Y cells, which was associated with induction of BACE1 transcription and activation of MEK/ERK‐SP1 signaling pathway. Further analysesindicated that nAChR stimulation upregulated SP1 transcription factor to induce BACE1 transcription, and that nicotine inhibited Aβ42 aggregation in vitro.

Conclusion

Our study revealed that nicotine has two major effects on Aβ metabolism; an increase in Aβ production and an inhibition of Aβ aggregation. Thus, nicotine could have opposite effects on brain Aβ deposition, which may explain inconsistency of previous studies on nicotine and Alzheimer disease.
Role of miR‐802 in brain insulin signaling and its impact on Down syndrome
Authors: Tramutola Antonella , Barone Eugenio , Pagnotta Sara , Domenico Fabio Di , Perluigi Marzia
Published: December 2023

Background

Down syndrome (DS) individuals are characterized by a variety of pathological phenotypes that manifest with wide variability in the different tissues. At the level of the central nervous system, the accelerated aging phenotype is associated with the risk to develop Alzheimer‐like dementia. A central aspect of neurodegeneration is the close association between metabolic disorders and cognitive decline. Multiple studies have suggested a link between metabolic disorder and microRNAs (miR), small non‐coding RNAs acting as post‐transcriptional regulators of a plethora of genes. Among triplicated miRNAs on chromosome 21, we focus on miR‐802 because recent studies demonstrated its association with development on insulin resistance in obesity and diabetes. Considering these findings and based on the “gene dosage hypothesis” of DS, the goal of the study is to decipher how miR‐802 may contribute to aberrant insulin signaling (IS) and, in parallel to the risk to develop dementia early in life in DS.

Method

The miR‐802 expression, protein levels and activation state of main components of the IS were evaluated (i) in the brain of autoptic cases from DS, DSAD and age‐matched controls and (ii) in the brain of euploid and Ts65Dn mice (a model of DS). Further, using bioinformatic tools we identified miR‐802 predicted target genes that are involved in the IS (PTEN and GSK‐3β).

Result

The IS alterations worsen in the transition from DS to DS/AD and similar findings were collected inTs65Dn mice where IS dysregulation persists with aging where neurodegeneration becomes significant. Intriguingly, these latter changes were driven by the over‐expression of miR‐802, which negatively regulates PTEN and GSK‐3β mRNA in the brain.

Conclusion

In this picture, the identification of specific targets modulated by miR‐802 and involved in IS pathway, will provide molecular basis to develop novel therapeutic strategies to prevent/delay the onset of brain insulin resistance in DS.
Trajectories of cognition and functional ability in people with dementia: Two‐year longitudinal results from the IDEAL programme
Authors: Martyr Anthony , Ravi Madhumathi , Gamble Laura D , Morris Robin G. , Pentecost Claire , Matthews Fiona E , Clare Linda
Published: December 2023

Background

Impairment in both cognition and instrumental activities of daily living (iADL) are key diagnostic features of dementia. Few studies have compared trajectories of cognition and iADL. By comparing trajectories of cognitive decline with both self‐rated and informant rated iADL, the study determines whether these aspects are related or decline in parallel and where there is a difference between perceptions of change.

Method

Data from the Improving the experience of Dementia and Enhancing Active Life (IDEAL) study were used. The study comprises 1537, 1183, and 851 people with dementia, and 1277, 977, and 749 carers at baseline (T1), 12 months later (Time 2, T2), and 24 months later (Time 3, T3), respectively. Cognition was assessed with the Addenbrooke’s Cognitive Examination‐III (ACE‐III), higher scores indicate fewer cognitive difficulties. iADL was assessed using the Functional Activities Questionnaire (FAQ), higher scores indicate more iADL difficulties. Both self‐ratings (FAQ‐S) and informant ratings (FAQ‐I) were collected. Because of the differences in the scale and distribution of FAQ and ACE‐III, scores were converted to ranks to enable comparison of trajectories between the two measures; deciles were calculated at T1 and imposed on T2 and T3 scores.

Result

As ACE‐III decreased both FAQ‐S and FAQ‐I increased suggesting that people with dementia with more cognitive difficulties were rated as having greater iADL difficulties by both people with dementia themselves and their carers. FAQ‐S declined on average by ‐0.10 (‐0.26, 0.06) decile points per timepoint more than ACE‐III. As confidence intervals overlapped zero this suggests that FAQ‐S and ACE‐III ratings declined at a similar rate. FAQ‐I declined on average by ‐0.31 (‐0.43, ‐0.19) decile points per timepoint more than ACE‐III. The trajectory over the two years suggests that FAQ‐I ratings declined at a significantly greater rate than ACE‐III scores.

Conclusion

Both cognition and iADL, whether self‐ or informant‐rated declined over two years. Trajectory analysis suggests that self‐rated iADL was generally concordant with cognitive decline, whereas informant‐rated iADL reflected more perceived decline than cognition. Therefore, either cognition and perceived iADL decline at different rates or informants overestimate increasing iADL difficulties compared to both cognition and self‐ratings.
Misalignment in circadian‐regulated glymphatic clearance as a driver of neurodegeneration
Authors: Fagiani Francesca , Ciampi Clara , Pittaluga Anna Maria , Trabace Luigia , Raso Giuseppina Mattace , Meli Rosaria , Ghelardini Carla , Govoni Stefano , Mannelli Lorenzo Di Cesare , Lanni Cristina
Published: December 2023

Background

Glymphatic system (GS) is a glial‐dependent perivascular network that under circadian regulation (Hablitz et al, 2020) controls the clearance of waste products in the central nervous system during the sleep (Xie et al, 2013) and its function is suppressed in several neurodegenerative diseases. Our aim is to investigate whether alteration in the circadian‐controlled dynamics of the GS may be the linker between the periphery and the brain. Our hypothesis is that the disruption of the gut‐brain dialogue, due to peripheral colonic inflammation, alters the circadian clockwork both in periphery and CNS, thereby impacting on the circadian‐regulated GS flux in the brain.

Method

The peripheral inflammation was obtained using an acute dextran sulfate sodium (DSS) mouse model of colitis. Alterations in GS dynamics and in the relative concentrations of selected metabolites in the brain have been evaluated by MRI and MRS, respectively. Aquaporin‐4, α‐syntropin, Connexin‐43 as well as clock genes expression have been assessed in colon, and in different brain areas, by real‐time PCR. AQP4 mis‐location has been evaluated by transmission electron microscopy.

Result

Our data demonstrate that, in DSS‐driven acute colitis model, the inflammatory hit strongly impacts on the circadian clockwork both at peripheric and central level, by altering the expression of the core clock components. Such alteration in the clock components expression pattern correlates with changes in GS dynamics in the brain. In particular, colonic inflammation impacts on the expression of astrocyte aquaporin‐4, as well as of α‐syntropin and Connexin‐43, in both cerebellum and cortex, thus suggesting a potential molecular derangement in the regulation of glymphatic influx. Alterations in GS dynamics have also been detected in the relative concentrations of specific metabolites in selective brain areas by MRS. As a consequence of brain changes in GS dynamics, we observed an increased phospho‐tau deposition in the hippocampus of DSS mice.

Conclusion

The characterization of the cascade of events and the relationship among gut inflammation, glymphatic influx alteration and brain waste product deposition has a novel significance since it will allow understanding how a persistent peripheral enteric hit may disorganize a central hierarchy thus triggering a self‐sustaining process prodromal of neurodegeneration.
Amyloid‐β immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer’s Disease mice
Authors: Taylor Xavier , Clark Isaiah , Oluoch Herold , Fitzgerald Griffin , Hole Justin T. , DeMattos Ronald B. , Wang Yaming , Pan Feng
Published: December 2023

Background

Amyloid‐related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events caused by pathological changes in the cerebral vasculature during several recent anti‐amyloid‐b (Aß) immunotherapy trials. However, the cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)‐mediated alterations of vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, additional studies are required to understand how perivascular macrophages play a role in enhancing CAA‐related vascular permeability and microhemorrhages associated with amyloid immunotherapy.

Methods

We study immune responses induced by amyloid targeting antibodies and CAA‐mediated microhemorrhages using histology and gene expression analyses in AD mouse models and primary culture settings.

Results

In the present study, we show that anti‐Aβ (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169+ perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aβ immunotherapy.

Conclusions

In summary, our findings demonstrate that Aß antibodies engaged at CAA deposits are associated with the activation of perivascular macrophages and the upregulation of vascular permeability related genes. Whether this leads to increased susceptibility to microhemorrhages remains to be seen. Additional studies need to be performed to establish the role of CD169+ perivascular macrophages in enhancing CAA‐mediated vascular permeability, plasma protein extravasation, and infiltration of monocytes associated with microhemorrhages.
Vitamin C is protective against a microglial inflammatory phenotype following LPS exposure
Authors: Marino Amanda L , Wilcox Jordyn M , Harrison Fiona E.
Published: December 2023

Background

Neuroinflammation is considered a key pathogenic feature of Alzheimer’s disease (AD) progression. Presence of reactive oxygen species is a driving factor in neuroinflammatory processes and deficiency of antioxidants in the brain can contribute to AD pathogenesis via this mechanism. However, more specifically depletion of ascorbic acid (ASC, vitamin C) may directly impact microglial function. Like neurons, microglia express the sodium‐dependent vitamin C transporter (SVCT2) and can store ASC at high concentrations. Nevertheless, specific roles for ASC and SVCT2 in the inflammatory response are not well understood. This present study investigated a protective role for vitamin C (ASC) following LPS administration to microglial cells.

Method

HMC3 cells (P8‐12) were cultured in 6‐well plates in DMEM (10% FBS, 1% Pen/Strep) treated with ASC (0 or 200 mM) LPS (0, 1mg/mL or 10mg/mL) for 24 hours. After 24 hours, cells were collected to identify intracellular and extracellular (media levels) of ASC by high pressure liquid chromatography. Expression of a number of inflammatory and apoptosis linked genes was assessed by qPCR with reference to two housekeeping genes [GAPDH, ACTB]. Immunofluorescent staining of SVCT2 was performed in fixed cells that were co‐stained with Iba‐1.

Result

Intracellular ASC was increased by ASC treatment and was not significantly changed due to LPS treatment. 1mg/mL LPS significantly induces inflammatory phenotype in HMC3 microglia including upregulation of mRNA levels of inflammatory cytokines including [IL‐1B, IL‐6, NF‐kB] and this effect was attenuated by ASC treatment. 10mg/mL induced cell death in HMC3 microglial cells and this effect was also at least partially mitigated by concurrent treatment with ASC.

Conclusion

uroinflammation is a critical component of AD neuropathology and ASC decreased inflammatory cytokine signaling and an inflammatory phenotype following LPS treatment in HMC3 microglia. These data suggest that maintaining adequate cellular ASC levels may preserve microglial function in the presence of inflammatory stimuli such as beta‐amyloid or delay neuroinflammation‐linked facets of Alzheimer’s disease pathology.
PRX005, a novel anti‐MTBR tau monoclonal antibody: results from a first‐in‐human double‐blind, placebo‐controlled, single ascending dose phase 1 study
Authors: Martenyi Ferenc , Campbell Brian , Kinney Gene G. , Lee Jun , Jin Yuying , Zago Wagner M. , Garren Hideki
Published: December 2023

Background

Multiple lines of evidence indicate that tau protein spreads throughout the brain via synaptically connected pathways and that this propagation could be mediated by tau “seeds” containing the microtubule binding region (MTBR) of tau. In addition, cerebrospinal fluid (CSF) MTBR‐tau levels correlate with tau tangles and clinical stages of Alzheimer’s disease. To block the spread of tau pathology, we developed PRX005, a humanized monoclonal tri‐epitopic antibody that binds with high affinity to the R1, R2, and R3 repeats in the MTBR region of tau, and targets both 3R and 4R tau isoforms.

Method

Healthy volunteers were randomly assigned to three dose cohorts and randomized in a 3:1 manner to receive either PRX005 or placebo. Primary endpoint was safety and tolerability with up to 2 months of follow‐up. Secondary endpoints included PRX005 pharmacokinetic parameters in plasma and CSF penetrance.

Result

A total of 19 healthy volunteer participants received study drug or placebo. PRX005 was well tolerated and had a pharmacokinetic profile typical of IgG1 antibodies, with dose‐proportional increase in plasma concentration and central nervous system (CNS) penetrance. No persistent drug‐induced anti‐drug antibodies were observed following treatment with PRX005. Additional results from this Phase 1 will be presented.

Conclusion

In this first‐in‐human, single ascending dose study, PRX005 was well tolerated and achieved CNS concentrations for pharmacological targeting of MTBR‐tau. Our results support the progression of the clinical development of PRX005 in an ongoing, multiple ascending dose study in patients with Alzheimer’s disease.
Plasma melatonin night‐time peak levels and 24‐hour area under the curve profile seem higher in AD patients with epileptiform activity than in those without
Authors: Nous Amber , Seynaeve Laura , Feys Odile , Wens Vincent , De Ti Xavier , Smolders Ilse , Engelborghs Sebastiaan
Published: December 2023

Background

Plasma melatonin levels drop in elderly, which might become more pronounced in Alzheimer’s disease (AD) as compared to controls.(1) Melatonin can serve as a potential biomarker for AD, given the inverse correlation between cerebrospinal fluid (CSF) melatonin levels and severity of neuropathology (Braak stages).(2) Due to suggested antiepileptic effects(6), melatonin can potentially slow down disease progression as epileptiform activity may contribute to AD disease progression.(3‐5). We here present a preliminary interim analysis of an ongoing study.

Aims

1. To evaluate melatonin’s potential as biomarker for AD by comparing blood melatonin levels between patients with mild cognitive impairment (MCI) and dementia due to AD and preclinical AD subjects.

2. To study the link between melatonin levels and epileptiform activity in AD.

Methods

All subjects underwent a neuropsychological examination, and lumbar puncture for analysis of core AD CSF biomarkers or amyloid brain PET. Subjects belonging to the AD continuum (dementia [n = 7]; MCI [n = 4]; preclinical AD [n = 1]) were diagnosed according to the NIA‐AA research criteria. A subset of subjects (n = 6) underwent 50‐minute magnetoencephalography to detect epileptiform activity. Blood samples were taken multiple times during a 24‐hour period, in in‐hospital controlled circumstances, and were analysed by use of liquid chromatography‐mass spectrometry.

Results

AD patients with epileptiform activity (n = 2) tended to have a higher melatonin 24‐hour area under the curve (AUC) and peak concentration (AUC 517.9pg/ml.h [+/‐140.1pg/ml.h] versus 204.5pg/ml.h [+/‐115.5pg/ml.h]; peak 65.4pg/ml [+/‐14.6pg/ml] versus 25.8pg/ml [+/‐17.5pg/ml]) than AD patients without (n = 4) (p = 0.064 for both; MWU test). There was no statistical difference regarding the melatonin 24‐hour plasma AUC or peak levels between patients with dementia, MCI, preclinical AD subjects (p = 0.760 for both; Kruskall‐Wallis test). We have to interpret these data with caution since sample sizes are still small and more patients are being recruited.

Conclusion

On the basis of very preliminary data, 24‐hour plasma melatonin profile and peak plasma melatonin concentration tended to be higher in AD patients with epileptiform activity than in those without. Whether this could be a potential compensatory mechanism against epileptiform activity in AD or whether melatonin could rather have pro‐epileptic effects, remains to be elucidated in future research.
Day‐to‐day Sleep Variability in Val66Met BDNF Carriers: A Potential Biological Pathway Between BDNF Activity and Alzheimer’s Disease Pathology?
Authors: Baril Andree‐Ann , Picard Cynthia , Labonte Anne , Sanchez Erlan , Mohammediyan Bery , Duclos Catherine , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: December 2023

Background

We previously showed that day‐to‐day sleep variability was associated with biomarkers of Alzheimer’s disease (AD) pathology. Given that brain‐derived neurotrophic factor (BDNF) activity has been involved in both AD and cognitive impacts of lifestyle risk factors, we sought to evaluate day‐to‐day sleep variability in those carrying the Met allele of the Val66Met BDNF polymorphism, which affects BDNF release. Additionally, we explored whether BDNF polymorphism modified the association between CSF AD pathology and day‐to‐day sleep variability.

Method

The PREVENT‐AD cohort enrolls dementia‐free persons with a parental history of sporadic AD. We characterized 203 dementia‐free participants from this cohort at the polymorphic BDNF locus, identifying 136 persons with genotype Val/Val (age 68.2±5.3y, 75%women), 67 Met heterozygotes/homozygotes (68.4±5.6y, 73% women, including six Met/Met homozygotes). After a week of actigraphy, we calculated these participants’ standard deviation of day‐to‐day sleep characteristics. We used t‐tests to compare day‐to‐day sleep variability in sleep characteristics between Val homozygotes and Met carriers. In a subsample of 101 participants, we assayed CSF Aβ42, t‐tau and p‐tau181, and used age‐ and sex‐adjusted linear regressions with an interaction term to test for moderation by BDNF genotype (36 Met carriers vs. 65 Val homozygotes) between sleep variability and CSF biomarker results.

Result

As compared to Val homozygotes, sleep was disturbed and unstable in BDNF Met carriers (heterozygotes/homozygotes). They had higher day‐to‐day variability in sleep fragmentation (activity counts, wake after sleep onset, fragmentation index), sleep onset latency, and sleep duration, resulting in weekly sleep patterns that were more fragmented and less efficient. Further, BDNF genotype moderated the association between CSF t‐tau and p‐tau181 with day‐to‐day sleep duration variability, such that only Met carriers showed an association between elevated tau concentration and sleep duration variability.

Conclusion

BDNF Met carriers had disturbed and unstable daily sleep patterns. Because the Met allele is known to decrease plasticity of neural mechanisms, the ability to achieve healthy and stable sleep may depend on such mechanisms. Thus, poorer sleep in Met carriers might be a biological mechanism by which altered BDNF activity affects tau pathology or, alternatively, accumulated AD pathology in Met carriers may disrupt sleep‐wake patterns.
Correction of mTORC1‐mediated brain protein synthesis rescues memory in mouse models of Alzheimer’s disease
Authors: Cozachenco Danielle , Ribeiro Felipe C. , Argyrousi Elentina K. , Staniszewski Agnieszka , De Felice Fernanda G. , Lourenco Mychael V. , Arancio Ottavio , Aguilar‐Valles Argel , Sonenberg Nahum , Ferreira Sergio T.
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by synapse failure and cognitive decline. Brain mRNA translation is central to synaptic plasticity and cognition, and converging evidence indicates it is impaired in AD. The mammalian target of rapamycin complex 1 (mTORC1) pathway plays a key role in regulating protein synthesis, and mTORC1 signaling has received considerable attention in AD research. In this current work, we investigated whether stimulating mTORC1‐mediated protein synthesis can alleviate the impairments in synaptic plasticity and memory in AD mice.

Method

To address this question, we used two different approaches: 1. genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)‐binding protein 2 (4E‐BP2); and 2. pharmacological treatment with (2R,6R)‐hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine that stimulates mTORC1 signaling.

Result

Our results showed that genetic reduction of FMRP and 4E‐BP2 prevented the inhibition of hippocampal protein synthesis and memory impairment induced by amyloid‐β oligomers (AβOs) in mice. Reduction of 4E‐BP2 further rescued memory deficits in the APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Moreover, HNK treatment prevented deficits in long‐term potentiation (LTP) and fear memory in AbO‐infused and APP/PS1 mice.

Conclusion

Taken together, our findings indicate that strategies targeting mRNA translation correct hippocampal protein synthesis, synaptic plasticity and memory deficits in AD models, and raise the prospect that HNK could emerge as a therapeutic approach in AD.
HDAC3 inhibition increases the expression levels of the Amyloid Precursor Protein
Authors: Sastre Magdalena , Palmisano Ilaria , Taylor Ben , Davis Nicola
Published: December 2023

Background

Epigenetic‐based interventions have recently garnered attention as potential therapies for Alzheimer’s disease (AD). Histone deacetylases (HDACs) represent an interesting target for neurodegenerative diseases therapies, since HDAC inhibitors have been shown to have the ability to reinstate memory even after neuronal loss. Particularly, HDAC3 inhibition has been shown to enhance long‐term memory and reduce amyloid‐β in AD models, although the molecular mechanisms behind these effects are unclear. The aim of this study was to characterise the effects of HDAC3 inhibition on the mechanisms of generation and degradation of Aβ using in vitro and in ex vivo models of AD

Method

N2a mouse neuroblastoma cells overexpressing the Swedish mutation (N2asw) as well as organotypic brain cultures (OBCs) of 5XFAD mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1‐10 μM) for 24h.

Result

Treatment with HDAC3 inhibitor RGFP966, led to a 4% increase on Aβ42 levels in N2a cells, associated with elevated levels carboxy‐terminus fragments (CTFs) and APP protein expressions as well as APP mRNA levels. In vitro chromatin immunoprecipitation (ChIP) analysis in N2a cells, revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCs from 5XFAD mice incubated with 1 μM RGFP966, without significant changes in Aβ secretion. In addition, mRNA sequencing in OBCs revealed that HDAC3 inhibition affects neuronal regenerative pathways, in particular linked to neurogenesis, neuronal differentiation, axonogenesis, resulting in an increase in dendritic spine density.

Conclusion

These results suggest that the HDAC3 therapeutic role in AD involves the regulation of APP expression and regenerative pathways, leading to increased synaptic connectivity.
Evaluating dynamic autophagic responses to tau inclusions
Authors: Vontobel Davi , Rowe Lyla A , Goodwin Marshall S , Ryu Daniel H , McHutchon Andrew , Golde Todd E , Croft Cara L
Published: December 2023

Background

Alzheimer’s disease and other tauopathies are characterised by the accumulation of misfolded microtubule‐associated protein tau in intracellular inclusions. We recently showed that newly formed tau inclusions are dynamic structures with a slower, but constant turnover of aggregated tau in murine organotypic brain slice cultures (BSCs) (Croft et al., 2021). Clearance by autophagy or the proteasomal machinery are indicated to be the key mechanisms involved in pathogenic protein clearance. However, the current tools to measure these processes have received mixed review, and in particular struggle to capture these processes in a continuous manner.

Methods

To dynamically assess autophagy in the presence of tau inclusions we have repurposed the autophagic flux sensor (GFP‐LC3‐RFP∆G‐LC3) to be delivered by rAAV to specific central nervous system (CNS) cell types in BSCs. This probe delivers a cytosolic internal control so autophagic flux can be estimated by calculating the GFP/RFP ratio. When utilized in conjunction with live imaging, the rate of autophagic flux can be measured over time in the same CNS cells expressing pathological or physiological tau. The rate of autophagic flux can also be measured in response to established/novel compounds or genetic manipulation.

Results

We have successfully developed and characterized the use of rAAV‐GFP‐LC3‐RFP∆G‐LC3 specifically in neurons and astrocytes in BSCs and are expanding its use to other CNS cell types. We have validated its use to sense autophagic flux whilst pharmacologically enhancing and inhibiting autophagy in BSCs. We are now using this sensor to determine dynamic autophagic processes in the presence of soluble tau and aggregated tau and its response to other manipulations.

Conclusions

Methods to understand autophagic processes have traditionally only provided snapshots over time. With this tool we can now dynamically assess autophagy in ex vivo BSCs and characterize changes in response to tau and other pathologies. Overall, understanding the mechanisms that enable tau turnover may guide therapies for Alzheimer’s disease and other neurodegenerative conditions where tau plays a role. Importantly, we will also begin to understand whether enhancing tau inclusion clearance may be beneficial or detrimental to cell health.
In vivo neuronal deficits and microglia structural dynamics in the course of tau pathology and during antibody treatment
Authors: Martin‐Avila Alejandro , Sigurdsson Einar M.
Published: December 2023

Background

We crossed mouse models Thy‐1GCaMP6, Cx3cr1CreER:tdTomatoflox and Cx3cr1GFP with PS19 P301S tauopathy mice to visualize neuronal calcium and microglia structural dynamics in vivo during the progression of tau pathology and after tau immunotherapy.

Method

By using two‐photon live imaging in head‐restrained mice attached to a custom‐made, free‐floating treadmill, we examined calcium activity in L2/3 pyramidal neurons and microglia structural dynamics in the motor cortex during tau pathology progression and after two intravenous antibody injections targeting the truncated Asp421 epitope of tau.

Result

L2/3 pyramidal neurons from young Thy‐1GCaMP6:wild‐type mice (1‐6 months old) increased their somatic activity during running periods as expected, but their littermate Thy‐1GCaMP6:PS19+/− mice did not. Importantly, acute tau immunotherapy restored neuronal function after two intravenous antibody injections (100 µg each) in Thy‐1GCaMP6:PS19+/− mice (5‐6 months old), whereas control antibody had no effect. Although tau pathology is evident in the cortex and hippocampus in 2‐3 months old Cx3cr1GFP/+:PS19+/− mice and Cx3cr1CreER/+:tdTomatoflox:PS19+/− mice, their microglia morphology did not differ from control littermate Cx3cr1GFP/+:wild‐type mice.

Conclusion

Our current findings indicate that functional deficits in cortical neurons associated with tau pathology start early in PS19 mice and can be alleviated by two acute tau antibody injections. Also, those neuronal functional impairments can be detected without accompanying structural changes in microglia, which suggests that neuronal deficits linked to tau accumulation precede microglial activation. Studies on the potential influence of tau antibody treatment on microglia morphology in vivo are underway.
Functional connectivity moderates the impact of synaptic loss on behaviour in frontotemporal lobar degeneration syndromes
Authors: Whiteside David J , Holland Negin , Tsvetanov Kamen A , Malpetti Maura , Savulich George , Jones P Simon , Naessens Michelle , Fryer Tim D , Hong Young T , Aigbirhio Franklin I , Mulroy Eoin , Bhatia Kailash , Rittman Timothy , O'Brien John T , Rowe James B.
Published: December 2023

Background

There is growing evidence for early and extensive synaptic loss in frontotemporal lobar degeneration syndromes from in vivo and post‐mortem studies. We proposed that synaptic loss would affect behaviour, in relation to changes in functional connectivity.

Method

We recruited 29 participants with progressive supranuclear palsy, 16 participants with amyloid‐negative corticobasal syndrome, 8 participants with behavioural variant frontotemporal dementia and 24 similarly‐aged healthy volunteers. All participants underwent resting‐state functional 3T MRI and positron emission tomography with [11C]UCB‐J, that binds synaptic vesicle 2A. We compared the connectivity metrics of nodal weighted degree and voxelwise regional homogeneity with [11C]UCB‐J non‐displaceable binding potential (BPND), in associative and commonality analyses. We then used independent component analysis to extract [11C]UCB‐J BPND signal variance across participants, followed by derivation of participant‐specific scores of functional spatial covariance with the [11C]UCB‐J components. We applied model selection to assess whether connectivity scores would improve prediction of and moderate the effect of synaptic loss on clinical severity.

Result

Reduced [11C]UCB‐J BPND was associated with reduced connectivity, with synaptic density predicting both measures of connectivity over and above grey matter volume (Figure 1). The anatomical distribution of synaptic loss partially overlapped in PSP, bvFTD and CBS, but there were also disease‐specific effects (Figure 2). The effect of synaptic loss on functional connectivity was expressed local to the regions of severe synaptic loss, and in remote regions. Moreover, functional connectivity explained additional variance and moderated the relationship between synaptic density and clinical severity (Figure 3).

Conclusion

In vivo synaptic loss is associated with reduced connectivity, and changes in behaviour, with implications for modelling disease pathogenesis and translational studies.
A Culturally Competent Approach to the Lived Experience of Dementia
Authors: Michael Mary Chi
Published: December 2023

Background

In 2021, the Global Council on Alzheimer’s Disease (GCAD) conducted research of the lived experience and care partner journey. In 2022 and 2023, GCAD expanded this research to focus on the experiences of individuals from historically underrepresented populations, specifically the LGBTQ+, Black, Latinx, and Asian communities.

"A Culturally Competent Approach to the Lived Experience of Dementia” seeks to explore the key differentiating factors in the journey for each population, how and when behavioral symptoms are identified and managed, and how the burden of care shifts among each community.

Method

To understand the experiences of each community living with dementia, we undertook qualitative primary research, complemented by secondary research. Primary research consisted of dozens of one‐on‐one interviews with people living with dementia and their care partners. Secondary research consisted of a review of existing literature on each community’s experiences with dementia.

Result

Results account for the journey that each community experiences. It maps not only the challenges they face, but also the resources the community has built, and how they manage care along the disease progression.

Conclusion

The research identifies several key differences in the dementia experience among each community. For instance, medical inequity includes a history of exploitation, discrimination, and distrust, which impacts how care is managed. Additionally we found that there is potential for a lack of a traditional family care structure, stigma surrounding dementia, and lack of resources and tools for living well with dementia.

This research also highlights the ways in which the communities are responding to those challenges. For instance, advocating for fair treatment within medical systems, raising awareness around dementia within their community, and creating systems of support and practices of care

Finally, it provides calls to action for how the broader dementia community can better support those from the underrepresented communities living with dementia. Addressing bias, discrimination, and inequity in healthcare settings, and creating resources that account for the specific needs and challenges of Black, LGBTQ+, Latinx, and Asian people living with dementia.
Can an online battery match in‐person cognitive testing in predicting age‐related cortical changes
Authors: Thienel Renate , Borne Léonie , Faucher Caroline , Robinson Gail , Fripp Jurgen , Giorgio Joseph , Martin Nicholas G , Breakspear Michael , Lupton Michelle K
Published: December 2023

Background

Studies into cognitive changes typically employ detailed in person cognitive testing, which is not always feasible. Therefore, we compared the relationship between brain morphology (sulcal width) and cognitive functioning, using an online and an in‐person modality and disentangled the influence of age, sex, β‐Amyloid (Aβ) and APOE‐status.

Method

141 healthy participants (mean age 60, range 46‐71 years, 75% female) assessed with structural MRI; cognitive batteries both, face‐to‐face and online (Cambridge Brain Systems), Aβ status (Fluorine‐18 florbetaben‐PET scan) and APOE genotype (Lupton et al., 2021); Canonical Partial Least Square method to compare cognitive modalities and Sulcal width (SW; Morphologist pipeline‐BrainVISA toolbox; Borne et al., 2020). Age effects tested with two‐sided Wald Test. Analysis of covariance to test age and sex‐interactions, amyloid and APOE status, sex‐effects (controlling for age), Aβ, and APOE (controlling for age and sex).

Result

The single robust mode for brain (SW) ‐ behaviour (cognition) covariation loaded most strongly onto memory and executive functions for both the onsite (1st mode, p = 0.013, cov = 3.55, z‐cov = 2.93, R2 = 0.18, z‐R2 = 0.95; 2nd mode, p>0.99), and the online battery (1st mode, p<0.001, cov = 2.76, z‐cov = 4.71, R2 = 0.14, z‐R2 = 1.15; 2nd mode, p = 0.99) (Fig. 1).

Cognition‐related SW showed a regional pattern similar for online and in person cognitive appraisal. Significant effect of sex on SW projections in both the online and onsite conditions with larger sulcal width for men (p<0.001) and a similar effect on onsite cognitive projections with lower performance for men (p<0.001) (Fig. 2a). Cognitive performance ‐ both online (p = 0.03) and in‐person (p<0.01) – showed a significantly steeper decline with age for Aβ‐positive participants (Fig. 2b). Variance explained for the online cognitive assay (R2 = 0.15) was only slightly less than for the in‐person testing (R2 = 0.18). Brain‐behaviour z‐transformed covariance was likewise comparable across modalities.

Conclusion

Similar sulcal width brain projections for both cognitive modalities, with memory and executive domains showing the strongest loadings. Aβ‐aggregation associated with a steeper cognitive projection slope for both batteries, suggesting that in our preclinical sample the early stages of Aβ accumulation accelerate cognitive ageing potentially before translation into structural brain changes. Adequate sensitivity of online cognitive tests for studying age‐related neurobiology of cognition is suggested.
Amyloid‐β and monocytes in Alzheimer’s disease
Authors: Huang Xin , Fowler Christopher J , Li Qiao‐Xin , Perez Keyla , Lim Yen Ying , Drysdale Candace , Rumble Rebecca , Villemagne Victor L , Rowe Christopher C , Martins Ralph N , Maruff Paul , Doecke James D , Lin Yong , Barnham Kevin J , Masters Colin L , Gu Ben J ,   Aibl Research Group
Published: December 2023

Background

Compelling evidence suggests that failure of Aβ clearance is a major mechanism of late‐onset Alzheimer’s disease (LOAD). The molecular basis remains unclear, but genome‐wide association studies (GWAS) strongly point to altered phagocytosis/endocytosis in the CNS and peripheral. Previously, we have demonstrated perturbation of monocyte basal and stimulated innate phagocytosis in LOAD.

Method

Flow cytometry immunophenotyping (FCIP) is used to investigate the relationship between peripheral blood leukocyte transport Aβ and disease stage in AD patients.

Results

In this study, we identified a subset of circulating intermediate monocytes (CD14+CD16+) that carry high amounts of Aβ dimers and co‐express the cell migration receptors CX3CR1 and CCR2. We then performed a quantitative study involving 165 AIBL participants and found that the number of monocytes carrying Aβ was decreased by 26% in AD and was inversely correlated with the subjects’ brain Aβ load and accumulation rate. Curiously, our further investigations revealed that the predominant type of infiltrating monocytes in human CSF are intermediate monocytes (CD45+CD14+CD16+).

Conclusion

The passage of those cells across blood‐brain barrier and their physiological significance are unknown. But it suggests a possible mechanism for the transport of brain Aβ to the periphery by monocytes.