bluuebunny/crossref_metadata_2025 huggingface dataset:
Single bilateral injection of endothelin‐1 leads to temporary deficits in memory and synaptic dysfunction
Authors: Diwakar Latha , Chithanathan Keerthana , Tomar Deepika Singh , Gowaikar Ruturaj , Ravindranath Vijayalakshmi
Published: December 2020

Background

Cerebral small vessel disease (SVD) has gained prominence worldwide as a major factor for cognitive impairment seen in dementia. Micro infracts causing elusive changes in cognitive function clinically will not get diagnosed are found to be the main risk factor for SVD. We were interested in creating micro infarcts rather than a severe insult to replicate small vessel damage, so we opted for Intra cerebroventricular (ICV) bilateral stereotaxic injection of endothelin‐1 (ET‐1) into lateral ventricles. Sub cortical injections of ET‐1 in brain has been used in many studies to accomplish long lasting vasoconstriction and gradual reperfusion causing lesion. Therefore, we tried to overcome this by injecting into lateral ventricles allowing it to spread through cerebrospinal fluid.

Method

ET‐1 (Endothelin‐ 1) a 21 amino acid vasoconstricting peptide was injected bilaterally into lateral ventricles of C57 mice. Some animals were injected unilaterally to see whether there are any motor deficits. Expression of CD31, a marker of endothelial cells was done by immunohistochemistry to assess vasoconstriction. Contextual fear conditioning, object recognition and Morris water maze task was performed to examine associative learning and spatial memory deficits. Gait and rotarod was performed to examine if there are any motor deficits. Synaptic plasticity was evaluated as activity dependent protein translation was measured in synaptoneurosomes prepared from hippocampus.

Result

The obstruction in cerebral blood flow due to vasoconstriction caused by ET‐1 injection leads to deficits in associative learning and spatial memory after 7 days. There was no change in gait or rotarod performance indicating no effect on motor function. However, the behavioral dysfunction was temporary and reversed after 30 days of ET‐1 treatment once the blood flow was restored. These changes were demonstrated as drop in the activity dependent protein translation after 7 days of ET‐1 injection and raise after 30 days of treatment as it is an indicator for synaptic plasticity.

Conclusion

Bilateral injection of ET‐1 leads to prominent associative and spatial memory deficit and decline in activity dependent protein translation in hippocampus. Still these defects are reversible once the blood flow is restored. Unilateral injection of ET‐1 did not show any motor dysfunction.
BDNF‐Met polymorphism on top of amyloid pathology predisposes for faster cognitive decline in cognitively normal elderly: The SCIENCe Project
Authors: van den Bosch Karlijn Antoinette , Verberk Inge M.W. , Ebenau Jarith , van der Lee Sven J. , Jansen Iris E. , Prins Niels D. , Scheltens Philip , Teunissen Charlotte E. , van Der Flier Wiesje
Published: December 2020

Background

Previous studies showed that in preclinical AD, the Brain‐derived neurotrophic factor (BNDF) Val66Met polymorphism Met was related to faster decline in episodic memory. We aimed to assess the joint associations of BDNF Val66Met polymorphism and amyloid positivity with decline over time in the main cognitive domains, and with risk of incident dementia in cognitively normal adults with subjective cognitive decline (SCD). Additionally, we explored the effect of BDNF plasma levels on cognitive decline.

Method

We included 688 individuals with SCD (59 ± 8y, 39%F, MMSE = 28 ± 2) from the Amsterdam Dementia Cohort (ADC) and the SCIENCe project, with repeated performance on neuropsychological tests available (average follow‐up: 1.6 ± 2.4y, median number of visits 2 ± 2, total datapoints 1660). Participants were grouped by a four‐level variable based on Met‐carrierschip (Met+) and decreased baseline CSF Abeta42 (A+), resulting in n = 39 (6%) Met+A+, n = 206 (30%) M+A‐, n = 76 (11%) Met‐A+, n = 367 (53%) Met‐A‐ (reference group). For a subgroup (n = 198) baseline plasma levels BDNF was measured by Simoa. Linear mixed models (LMM) were used to assess associations with cognitive decline. We evaluated the association with risk of dementia using Cox proportional hazard model. All analyses were adjusted for age, gender and education.

Result

Compared to Met‐A‐, Met‐A+ showed a steeper decline on some tests for memory, attention and executive functioning, while Met+A+ showed steeper decline on almost all cognitive tests, covering global cognition, memory, language, attention and executive functioning (Table 1). Met+A‐ was not associated with steeper decline. Met+A+ (HR = 9.2; 95%CI: 2.9‐29.1) and Met‐A+ (HR = 6.6, 95%CI: 2.2‐19.7) were at increased risk of dementia compared to Met‐A‐ (HR – reference), whereas Met+A‐ (HR 1.3, 95%CI 0.3‐4.8) was not. Plasma levels of BDNF were not associated with cognitive decline.

Conclusion

Among individuals with SCD, Met‐carriership on top of amyloid pathology is associated with faster cognitive decline over time, and associated with higher risk of dementia. These results imply that this group might benefit from more frequent clinical monitoring.
Behavioural characterization of a new Alzheimer′s disease mouse model
Authors: Camargo Luana Cristina , Schöneck Michael , Sangarapillai Nivethini , Honold Dominik , Schemmert Sarah , Langen Karl‐Josef , Kutzsche Janine , Willbold Dieter , Willuweit Antje
Published: December 2020

Background

Besides a large variety of research on Alzheimer’s disease (AD), there are still open questions regarding its pathophysiology. In this context, the development of a new transgenic mouse model TAPS, a genetic combination of heterozygous APP‐PS1dE9 and TBA2.1 mice, was accomplished. The TBA2.1 line expresses truncated amyloid‐β (Q3‐42), which is post‐translationally modified to pyroglutamate amyloid‐β (pE‐Aβ). Since this species of Aβ has been shown to be particularly cytotoxic and induces neurodegeneration in transgenic mice, TAPS mice were developed to mimic the combined human pathology of AD with amyloidosis and neurodegeneration.

Method

In this study, both male and female animals (18‐19 months old) were subjected to four cognitive tests: The Novel Object Recognition test (ORT), the T‐maze spontaneous alternation test, the Contextual and Cued Fear Conditioning test and the Morris Water Maze (MWM). Four groups were evaluated: Wild Type (n = 9), APP‐PS1dE9 (n = 4), TBA2.1 (n = 6) and TAPS (n = 7). Additionally, immunofluorescent staining was performed against amyloid‐β (6E10) and reactive astroglia (GFAP) in animals between 6‐18 months.

Result

In the ORT, wild type mice showed increased exploration of novel objects in comparison to familiar ones. In contrast, TAPS mice explored novel and familiar objects similarly, indicating loss of object recognition memory. In the Cued Fear Conditioning test, TAPS mice showed a significantly lower performance, as well as significantly less alternation than the wild types in the T‐maze. In the MWM, TAPS mice took more time to find the platform than the Wild type on the last day of training, suggesting a spatial memory deficit. Amyloid‐β staining showed progressive plaque formation between 6‐18 months, with an earlier onset in TAPS, in comparison to the parental APP‐PS1dE9 mice. TBA2.1 mice showed only small aggregates in striatum. The plaque‐pattern in TAPS mice combined those of the parental lines, as they showed agreggates in all brain regions including the striatum. Amyloidosis was accompanied by increasing reactive astrogliosis over the same period.

Conclusion

It can be concluded that the TAPS mice have, besides an increased plaque pathology in comparison to the parental lines, cognitive deficits in four different behavioural tests, which underlines their potential as a mouse model for pE‐Aβ dependent amyloidosis.
Deficiency in a fly ortholog of HS‐aging related gene, sulfonylurea receptor/SUR, increased vulnerability to neurodegeneration in drosophila models of Alzheimer’s disease
Authors: Sekiya Michiko , Quan Xiuming , Sakakibara Yasufumi , Chikamatsu Sachie , Iijima Koichi M.
Published: December 2020

Background

Hippocampal sclerosis of aging (HS‐aging) is a common senile dementia characterized by sever neuron loss and gliosis in the hippocampus, and clinically mimics Alzheimer’s disease (AD). Polymorphisms in GRN, TMEM106B and ABCC9 have previously shown the association with HS‐Aging. However, the mechanisms and a molecular link between HS‐aging and AD remain elusive. Sulfonylurea receptors (SURs: ABCC8/SUR1 and ABCC9/SUR2) are the regulatory subunits of ATP‐sensitive potassium channels that coordinate energetic status and intracellular Ca2
+ levels in various cells. Mutations in SURs causes diabetes and cardiovascular diseases, both of which are known AD risks. Interestingly, single nucleotide polymorphism that increases the mRNA levels of ABCC9/SUR2 has been associated with a risk for HS‐aging, suggesting that ABCC9/SUR2 might influence pathogenesis of AD as well as HS‐aging.

Method

Using Drosophila as a model, we asked whether deficiency in Sur, a fly ortholog of SURs, is protective or detrimental to neuronal integrity during aging and under neurodegenerative conditions.

Result

We found that Sur deficiency by itself did not affect age‐associated changes in neuronal function and integrity. In contrast, Sur deficiency significantly worsened behavioral deficits and neurodegeneration by impairing energy metabolism in a fly model of amyloid‐β42 toxicity. We also demonstrated that Sur deficiency significantly exacerbated tau‐mediated neurodegeneration and AD‐related tau phosphorylation.

Conclusion

This study suggests that ABCC9/SUR2 plays neuroprotective roles in the pathogenesis of AD and that increased ABCC9/SUR2 might extend clinical onset of AD.
EEG biomarkers for the early diagnosis of DLB
Authors: Bonanni Laura
Published: December 2020

Background

The early detection and classification of Dementia with Lewy Bodies (DLB) are important clinical support tasks for medical practitioners in customizing patient treatment programs to better manage the development and progression of these diseases. Efforts are being made to diagnose DLB in the early stages. Efforts are being made to diagnose DLB in the early stages. The use of electroencephalogram as a tool for the detection of changes in brain activities and clinical diagnosis is becoming increasingly popular for its capabilities in quantifying changes in brain degeneration in DLB. This talk reports results of a multicenter European study on the role of electroencephalogram as a biomarker based on signal processing to detect DLB in early stages and classify its severity.

Method

EEG was recorded in 144 DLB, 116 AD and 65 controls from 7 Centers of the European DLB Consortium. Spectra, divided into delta, theta, pre‐alpha, alpha frequency bands were described by DF, DF variability (DFV), frequency prevalence (FP).

Result

Quantitative EEG was characterized by specific abnormalities in posterior derivations. These include a pre‐alpha‐dominant frequency, either stable or intermixed with alpha/theta/delta activities in pseudoperiodic patterns, which together have a predictive value >90% for the diagnosis of DLB compared with AD. These specific EEG patterns also correlate positively with the severity of clinically observed cognitive fluctuations and are seen at the MCI stage.

Conclusion

In DLB EEG abnormalities can be considered a biomarker for DLB even at the very early stages of the disease.
Hyperbaric oxygen ameliorates cognitive impairment in patients with Alzheimer’s disease and amnestic mild cognitive impairment
Authors: Le Weidong
Published: December 2020

Background

It is reported that environmental factors such as hypoxia could contribute to the pathogenesis of Alzheimer’s disease (AD). Therapeutics like hyperbaric oxygen treatment which improves tissue oxygen supply and ameliorates hypoxic conditions in the brain may be a strategy for AD and amnestic mild cognitive impairment (aMCI) treatment. The present work aims to investigate the potential therapeutic effect of hyperbaric oxygen treatment in patients with AD and aMCI.

Method

We included 42 AD and 11 aMCI patients in this study. All participants were continuously treated with hyperbaric oxygen treatment once daily for 20 days and assessed by neuropsychiatric assessments before and at 1, 3, and 6 months after the hyperbaric oxygen treatment. We also applied fluorodeoxyglucose positron emission tomography (FDG‐PET) in some of the patients.

Result

Hyperbaric oxygen treatment could improve the global cognitive functions, especially visuospatial and executive functions, language and abstract thinking abilities at 1 month after treatment in AD patients and improved the memory of aMCI patients in 1, 3, and 6 months after treatment. The ADL scores were improved in 1, 3, and 6 months after treatment in AD patients. Hyperbaric oxygen treatment also ameliorated the reduced brain glucose metabolism in AD and aMCI patients.

Conclusion

Based on the previous studies and our recent findings, hyperbaric oxygen treatment may be a potential therapeutic and preventive strategy for AD and aMCI.
Hearing loss and microstructural integrity of the brain in a dementia‐free older population
Authors: Croll Pauline H , Vernooij Meike W , Reid Robert I , Goedegebure André , Power Melinda C , Rigters Stephanie C , Sharrett A Richey , de Jong Robert J Baatenburg , Mosley Thomas H , de Groot Marius , Lin Frank R , Deal Jennifer A
Published: December 2020

Background

Recently, hearing loss has been identified as a promising modifiable risk factor for dementia. Several hypotheses explaining a potential underlying pathway have been proposed, including the sensory deprivation hypothesis, describing a direct causal relationship in which hearing loss leads to neuroplastic changes in the brain. Indeed, hearing loss has been associated with smaller macrostructural brain volumes, which is believed to at least partly explain the association between hearing loss and neurodegenerative disease. However, microstructural changes precede macrostructural changes. Therefore, we aimed to assess the association between hearing loss and microstructural integrity of the brain.

Methods

1,086 dementia‐free older adults from the Atherosclerosis Risk in Communities (ARIC) study (mean age = 75.2 [SD: 4.9], 61.4% female) underwent hearing assessment (2016‐2017) and magnetic resonance imaging (MRI) of the brain (2011‐2013). Hearing was assessed with pure‐tone audiometry. Microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD)) of multiple brain regions was determined with diffusion tensor imaging (DTI). Multivariable linear regression models were used to investigate the association between hearing loss and microstructural integrity of the lobes, temporal lobe gyri, medial temporal lobe structures and white matter (WM) tracts, adjusting for relevant confounders.

Result

Hearing loss was associated with lower WM microstructural integrity in the temporal lobe (difference in SD FA for moderate/severe hearing loss as compared to normal hearing: ‐0.19 [95% CI: ‐0.35, ‐0.03]; and difference in SD MD for moderate/severe hearing loss as compared to normal hearing: 0.15 [95% CI: 0.01, 0.28]). Hearing loss was associated with lower gray matter (GM) microstructure of the hippocampus, but not the amygdala. Moreover, hearing loss was associated with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus (Figure 1).

Conclusion

Our results demonstrate that age‐related hearing loss is associated with lower WM microstructural integrity in the temporal lobe, the limbic tracts and the uncinate fasciculus and lower GM microstructure in the hippocampus. These associations suggest that poorer hearing may affect brain regions that are important for different cognitive processes. However, the results should be interpreted with caution as this study is of a cross‐sectional design.
Biological substrates of cortical atrophy in prodromal AD: A CSF proteomic study
Authors: Ekblad Laura L. , Visser Pieter Jelle , Tijms Betty M.
Published: December 2020

Background

Brain atrophy is a characteristic feature of Alzheimer´s disease (AD). Atrophy typically begins in the medial temporal regions and is closely related to cognitive decline. The biological processes that associate with or possibly lead to regional cerebral atrophy are largely unexplored. We used a cerebrospinal fluid (CSF) proteomic approach to study which biological processes are associated with cortical atrophy in prodromal AD.

Method

Prodromal AD individuals based on abnormal CSF beta‐amyloid were selected from ADNI when they had structural MRI and CSF proteomic data (measured with MRM and RBM). Correlations between 217 CSF proteins and cortical thickness of 34 cortical regions (averaged over the left and right hemispheres) were analyzed with linear models. We used hierarchical clustering to identify clusters of brain regions that showed similar CSF protein correlations. ClueGO enrichment analysis was used to identify biological processes associated with proteins that correlated with atrophy.

Result

We included 104 individuals (37.5% female; mean age 74.5±7.2 years). In total 150 proteins showed associations with cortical thickness in at least one brain region (p<0.05). We identified 4 clusters of brain regions that showed similar proteomic correlations with atrophy (Figure 1). Cluster 1 included the medial temporal, medial orbitofrontal and superior temporal regions. In these regions thinner cortex was associated with lower levels of proteins involved in the beta‐amyloid metabolic process and synaptic plasticity. Cluster 2 included dorsolateral frontal regions and the isthmus cingulate, and lower cortical thickness was associated with higher levels of proteins that reflect inflammatory processes and blood‐brain barrier disruption (Dayon et al. J Proteome Res. 2019;18:1162‐1174). Cluster 3 included the precuneus, superior and caudal middle frontal and superior parietal regions and the paracentral and postcentral gyri. Cortical thinning in Cluster 3 was associated with higher levels of proteins that associated with embryogenic hemopoiesis. Cluster 4 included regions in which thinning was not associated with CSF proteins.

Conclusion

In prodromal AD, regional cortical atrophy is associated with disruptions in distinct biological processes depending on the region involved. This suggests that treatment may need to consider a combination of targets in order to prevent atrophy, and eventually cognitive decline.
Platelet‐derived growth factor receptor‐beta as a potential CSF biomarker for Alzheimer’s disease
Authors: Kuiperij H. Bea , de Kort Anna M. , Kersten Iris , Versleijen Alexandra A.M. , Schreuder Floris H.B.M. , Klijn Catharina J.M. , Claassen Jurgen A.H.R. , Verbeek Marcel M.
Published: December 2020

Background

There is a lack of biomarkers for the early detection of Alzheimer’s disease (AD). Cerebral amyloid angiopathy (CAA), which is characterized by the accumulation of amyloid‐β (Aβ) in the cerebral vasculature, is commonly found in AD. Platelet‐derived growth factor receptor‐β (PDGFRβ) is expressed by pericytes and since blood‐brain barrier (BBB) dysfunction is associated with pericyte degeneration, release of PDGFRβ protein may be a biomarker for BBB dysfunction, that is expected in CAA. Indeed, it has recently been described that PDGFRβ levels are elevated in cerebrospinal fluid (CSF) from patients with mild cognitive impairment (MCI) as compared to controls1. The aim of our study was to investigate the diagnostic and discriminative value of PDGFRβ in CSF in patients at various clinical stages of AD and in patients with CAA.

Method

CSF PDGFRβ, Aβ42, total tau (t‐tau) and phosphorylated tau (p‐tau) levels were quantified by ELISA. Cohorts of controls (n=47), CAA patients (n=27) and AD patients (n=59; 19 patients with MCI (clinical dementia rating (CDR) = 0.5), 28 patients with CDR 1.0 and 12 patients with a CDR of ≥ 2.0) were studied.

Result

CSF PDGFRβ levels were similar in controls, AD and CAA patients. Moreover, PDGFRβ levels were similar in patients at the various clinical stages of AD. PDGFRβ levels also did not correlate with blood‐CSF barrier dysfunction (i.e. elevated albumin ratio). We observed a strong correlation of CSF PDGFRβ levels with t‐tau and p‐tau levels, the degree of which was dependent on the CDR score. Interestingly, CSF PDGFRβ levels were significantly elevated in a selection of MCI/AD patients with an AD‐positive CSF biomarker profile (A+T+) as compared to controls with a completely normal profile of AD biomarkers (A‐T‐N‐).

Conclusion

We could neither confirm previously reported elevated CSF PDGFRβ levels in MCI patients1, nor did we find elevated PDGFRβ levels in CAA patients. Our results suggest that CSF PDGFRβ levels are not useful as marker of BBB integrity, but instead may, as previously reported, be associated with AD (tau) pathology2. References: 1Nation et al., Nat Med. 2019;25(2):270‐276; 2Miners et al., Alzheimers Res Ther. 2019;11(1):81.
Characterization of DNA methylomic signatures in induced pluripotent stem cells during neuronal differentiation
Authors: Imm Jennifer L.
Published: December 2020

Background

In development, inducing pluripotency and differentiation into different cell types results in global epigenetic changes, although the extent this occurs in induced pluripotent stem cell (iPSC)‐based neuronal models has not been extensively characterized.

Method

Human fibroblast cells were reprogrammed using lentiviral transfection. The resulting iPSC colonies were expanded, differentiated and collected at three different time points: day0 (iPSCs), day16 (neuronal progenitor cells), day37 and day58 (mature neurons). DNA methylation was assessed using the Illumina EPIC array. Using WGCNA, trajectory inference modelling and pathway analysis we identified loci undergoing dynamic changes during differentiation and the pathways these loci are associated with.

Result

This study has identified methylomic variation associated with neuronal differentiation and maturation. We identified 5,866 Bonferroni‐significant loci during differentiation using lineage modelling and noted that these loci are involved in pathways associated with head development, transcriptional regulation and cellular signalling. A gene‐gene interaction network analysis identified 50 densely connected genes that are influential in the differentiation of neurons, with STAT3 being the gene with the highest connectivity. Finally, we demonstrated that despite being functionally mature these iPSC‐derived neurons have a fetal epigenome.

Conclusion

We have shown that there are large epigenetic changes occurring throughout neuronal differentiation. These changes are within pathways that are key to neuronal development. Alongside this we have also identified an epigenetic trajectory signature associated with maturation and shown that neurons derived from iPSCs have a fetal epigenome.
Polygenic‐wide analysis to assess the impact of genetic risk profiles on brain morphometry in the ALFA study
Authors: Vilor‐Tejedor Natalia , Guigó Roderic , Operto Greg , Crous‐Bou Marta , Cacciaglia Raffaele , Falcon Carles , Arenaza‐Urquijo Eider M , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Gispert Juan Domingo
Published: December 2020

Background

Neurodegenerative diseases are associated with progressive neuronal vulnerability and loss of function, along with an accelerated brain atrophy, which is partly influenced by multiple genetic factors. Polygenic risk scores (PRSs) are used for both identifying the genetic architecture of complex diseases and predict disease genetic risk (GR), as well as testing its shared genetic architecture. In this study we investigated whether a genetic predisposition to neurodegenerative and related complex diseases were associated with brain morphometry in a sample of cognitively unimpaired individuals of the ALFA cohort.

Method

A total of 479 participants with available genotype and neuroimaging data were included. PRSs were calculated from the most recent genome‐wide association meta‐analyses for neurodegenerative diseases (Alzheimer’s disease (AD), parkinson disease), related complex diseases (stroke, hypertension, hypercholesterolemia, diabetes, depression, cerebrovascular disease (CV)), and susceptibility to AD‐core biomarkers (p‐tau and amyloid Aβ‐42). Association analyses included measures of brain morphometry as outcomes. PRS were standardized for easy interpretation. Associations were estimated using linear regression models. All models were adjusted for age, sex, education, APOE‐ϵ4 status, and total intracranial volume.

Result

Preliminary results suggested increased PRS average of AD, tau and Aβ42 levels, indicating higher genetic risk for ALFA participants [Figure 1]. In addition, we found strong positive correlation patterns between GR of hypertension with diabetes, GR of cholesterol with hypertension and diabetes, and GR of depression with diabetes, hypertension and cholesterol [Figure 2]. Furthermore, the most remarkable results suggested evidence of association between increased risk of cholesterolemia and reduced volumes of left accumbens area, increased risk of CV and reduced volumes of thalamus proper, as well as increased risk of tau and reduced volumes of right thalamus proper and right cerebellum cortex [see Figure 3 for further results].

Conclusion

We identified strong evidence that genetic liability of related cardiovascular diseases and AD‐core biomarkers influences brain morphology in ALFA. In addition, across all diseases, ALFA participants showed increased genetic risk on AD, and AD‐core biomarkers. In further analyses, we will assess the relationship between neuroanatomical differences in the whole brain and PRSs using voxel‐based morphometry analyses.
Contribution of Alzheimer’s disease risk genes in the maintenance of endolysosomal transport regulation
Authors: Bretou Marine , Sannerud Ragna , Vermeire Wendy , Demedts David , Annaert Wim
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common form of dementia of which the incidence increases with age. No cures are available yet, urging to explore new strategies for the identification of pathways that can be targeted therapeutically. Research in AD has been majorly driven by studying familial AD (FAD)‐associated mutations in the APP and PSEN genes, albeit they represent only a minor fraction of all cases. GWAS studies have identified ≈30 late‐onset AD (LOAD) susceptibility loci that, when functionally clustered, are directly or indirectly linked to cellular trafficking routes and functioning. These include genes linked to cholesterol metabolism (e.g. APOE4, ABCA7, INPP5D), endocytic transport regulation (e.g. BIN1, CD2AP, PICALM, SORL1) and lysosomal processes (e.g. GRN, PLD3). The genetic findings concur with the appearance of endolysosomal abnormalities at preclinical stages, before the appearance of senile plaques and tangles.

Method

To investigate the role of LOAD risk factors involved endosomal transport regulation, we generated knock‐out (KO), and their corresponding rescued cell lines for several proteins including PSENs, PICALM and PLD3 and this in fibroblasts and neuronal SHS5Y5Y cells. These are now subjected to a comparative analysis of the endolysosomal pathway and lysosomal function.

Result

PSENdKO cells present with enlarged late endosomes/lysosomes that (i) display an increased co‐localization with early endosomal markers, (ii) accumulate various lipids as shown by lipidome profiling of isolated organelles, and (iii) accumulate various cargoes and adaptors such as the retromer subunit VPS35. These aberrant accumulations could be corrected by the re‐expression of catalytic active and inactive human PSEN1, indicating that a γ‐secretase‐independent role of PSEN1 is partially connected to recycling. Interestingly, activation of recycling could significantly alleviate endolysosomal defects observed in PSEN KO cells. Ongoing analysis of LOAD risk genes shows both similar as well as distinct endolysosomal defects underscoring that a possible common endosomal deregulations may originate from different upstream mechanisms.

Conclusion

Together, these observations are shedding light on the potential of modulating/restoring endosomal transport regulation as a strategy to alleviate observed early endolysosomal dysfunctions at preclinical stages of AD pathogenesis.
Resilience monitor for informal caregivers for people with dementia (REMIND): Digital monitoring of informal caregivers’ well‐being to prevent crises
Authors: Oostra Dorien L. , Nieuwboer Minke S. , Rikkert Marcel G.M. Olde , Perry Marieke
Published: December 2020

Background

The number of people with dementia living at home is likely to increase, resulting in a growing societal dependency on informal care. Informal caregiving causes a considerable burden on caregivers’ wellbeing, both physical and mental. A decrease in caregivers’ wellbeing is often a direct reason for crisis admission of the person with dementia. Close monitoring of wellbeing and resilience of caregivers followed by early intervening by case managers may prevent crisis. Our aim is to develop a user‐friendly digital monitor to assess wellbeing and resilience of caregivers to enable case managers to provide timely support and prevent crises.

Method

A human centered design method was used. To identify wishes and needs, develop ideas for the monitor and test first visual prototypes, focus groups with end users and experts in the field of primary dementia care took place. End users were informal caregivers and professionals from different disciplines. Experts were researchers, clinicians, innovation experts and application designers. The 3‐month pilot study will include caregivers and case managers and consists of monitoring wellbeing and resilience weekly by a set of questions. Intervention delivery and acceptability will be assessed together with changes in number of crisis and caregiver’s perseverance time.

Result

Three focus groups with end user and multiple expert sessions took place. Wishes, needs and functionalities were identified during the first two focus group meetings. To detect deterioration of caregivers’ wellbeing earlier, an application connected to a dashboard with an alert system for case managers is desired. To assess wellbeing, questions were reviewed during the third meeting covering the topics: social support, reciprocity, burden/competence, mood, own activities, small crises, person with dementia. Caregivers indicated they want to fill in approximately seven questions per week. Additionally, concept screens of the application and dashboard were discussed. Preliminary results of the pilot study will include adherence, user satisfaction and usability.

Conclusion

This methodological approach will result in a product that best meets the needs and wishes of caregivers and case managers in order to prevent crises. The pilot study will provide insight into the possible effectiveness and usefulness of this product in practice.
Neurotoxicity and hyperphosphorylation of tau protein induced by the amyloid peptide oligomers involve different glutamate dependent and independent mechanisms
Authors: Henriques Alexandre , Rouvière Laura , Farrugia Clémence , Poindron Philippe , Callizot Noelle
Published: December 2020

Background

Alzheimer’s disease is characterized by the extracellular accumulation of senile plaques composed of amyloid beta and the intracellular deposition of neurofibrillary tangles composed of hyperphosphorylated tau (Tp). Aβ oligomers (AβO) induced sequential damages starting with synapses loss, followed by the neurite network disorganization and finally the neuronal death. In this study, we deeply investigated the role of glutamate and its receptors (mGluR5 and NMDARs) in the AβO neurotoxicity and in the Tp.

Method

Using primary cultures of rat embryonic cortical neurons, the AβO toxicity was investigated in presence or absence of glutamate receptor antagonists (MPEP, Ifenprodil, MK801, memantine...). The AβO effects on the glutamate release and on the Ca2+ flux were studied in presence or absence of BAPTA in the medium. In addition, the AβO effect on the hyperphosphorylation of Tau was studied. Different sites of hyperphosphorylation were investigated (AT100, AT8 and Thr231 involving the DAPK1 and GSK3β).

Result

We showed that 5 min after AβO application, a large release of glutamate was seen in the extracellular medium. This release was immediately followed by a Ca2+ entrance in the neurons. In absence of extracellular Ca2+, the caspase‐3 activation was abolished as well as the neuronal death. Similarly, in presence of NMDAR or mGluR5 antagonists, the neuronal death was abolished, by contrast, Tau hyperphosphorylation and aggregation was still observed.

Conclusion

Altogether, these findings showed the crucial role of glutamate and Ca2+ in the AβO acute neuronal death, and demonstrated that the effects on Tp might not involve the NMDAR and the mGluR5.
Advanced glycation end products, their receptor and the risk of dementia in the general population: A prospective cohort study
Authors: Chen Jinluan , Mooldijk Sanne S. , Licher Silvan , Waqaz Komal , Ikram M. Kamran , Uitterlinden André G. , Zillikens M. Carola
Published: December 2020

Background

Advanced glycation end products (AGEs) and their receptor (RAGE) are implicated in the pathophysiology of dementia and potentially underlie the relation between diabetes and neurodegeneration. We determined the link between two proteins involved in the AGE‐RAGE system, namely Extracellular Newly identified RAGE binding protein (EN‐RAGE) and the soluble form of RAGE (sRAGE), and dementia prevalence and incidence. Additionally, we assessed the association between skin auto fluorescence (SAF), a proxy for AGEs tissue accumulation, and cognition.

Method

Within the prospective Rotterdam Study, plasma EN‐RAGE and sRAGE were measured in 1208 participants (mean age 74.1 (standard deviation (SD) 7.7); 57.5% women). Participants were categorized into tertiles, to compare participants with high, intermediate and low concentrations, with the lowest tertile as the reference. Associations of SAF, measured in 3009 participants (mean age 72.3 (SD 9.4); 56.4% women), and cognition were assessed using linear models. We adjusted for age, sex, diabetes, APOE ε4 carrier status and other potential confounders, including cardiovascular risk factors, and additionally stratified by sex and APOE ε4 status.

Result

Participants with higher EN‐RAGE and lower sRAGE levels were more likely to have dementia (adjusted odds ratio (OR); 3.64 [95% confidence interval 1.56‐8.50] and OR 0.39 [0.17‐0.83], for high level compared to low level). During follow‐up (median 12.4 years), 161 participants developed dementia, of whom 130 Alzheimer’s disease (AD). Higher EN‐RAGE was non‐significantly associated with higher risk of dementia during the first years of follow‐up (adjusted hazard ratio (HR); 1.48 [0.52‐4.25] after 4 years of follow‐up), while a lower risk was found over the entire follow‐up duration (HR 0.65 [0.42‐1.01]) (Figure 1). Higher SAF was associated with lower global cognitive function (adjusted difference in z score per SAF standard deviation (SD); 0.07 [0.04‐0.11]). This effect was stronger for carriers of the APOE ε4 allele (0.15 [0.07‐0.22]).

Conclusion

Our results indicate involvement of the AGE‐RAGE system in the pathophysiology of dementia, independent of the history of diabetes, showing involvement of EN‐RAGE and sRAGE, and of SAF in cognitive functioning. These associations were stronger for APOE ε4 carriers, suggesting a combined role of AGEs and APOE in neurodegeneration.
The influence of antipsychotics and antidepressants on people with dementia in Northern Ireland: A retrospective analysis
Authors: McMichael Alan J , Zafeiridi Evi , Passmore Anthony Peter , McGuinness Bernadette
Published: December 2020

Background

Dementia is a term used to describe a broad group of conditions that affect the brain and causes a progressive cognitive decline in the ability to think, learn and remember. People with dementia may be prescribed medications such as antipsychotics and antidepressants to help deal with their symptoms. Little is known about the rate of which these drugs are prescribed in Northern Ireland and whether such drugs influence mortality rates among people with dementia.

Method

Using data from the Honest Broker Service, which holds information on approximately 13,000 people with dementia in Northern Ireland we aim to assess the number of people with dementia who are currently being prescribed antidepressants and antipsychotics and determine whether or not such medications influence mortality rates. In addition we also aim to explore what demographic characteristics influence the liklihood of whether a person with dementia will be prescribed antipsychotics and / or antidepressants. Data will be ready for analysis in February 2020.

Result

By conducting a retrospective analysis on national datasets, we aim to determine whether antipsychotics and antidepressants influence mortality rates in people with dementia and investigate what demographic parameters in

Conclusion

Given the questionable benefits of antipsychotics in particular for treating people with dementia, these results have the potential to provide valuable information to clinicians and the carers of people with dementia.
The association between low social support and risk of cognitive impairment is partially mediated by neuroanatomic biomarkers of Alzheimer’s disease
Authors: Petkus Andrew J , Gruenewald Tara L , Wang Xinhui , Younan Diana , Espeland Mark A , Widaman Keith F , Gatz Margaret , Rapp Stephen R , Shadyab Aladdin H , Lockhart Samuel N , Flores Melissa , Kroenke Candyce H , Tindle Hilary , Masaki Kamal , Chen Jiu‐Chiuan
Published: December 2020

Background

Social relationships with less support are linked to greater risk of developing Alzheimer’s disease (AD) and other dementias. Despite growing evidence of this link, to our knowledge, no studies have examined neuropathological processes through which low social support may affect risk of cognitive impairment. We used data from the Women’s Health Initiative Memory Study (WHIMS)‐MRI Study to examine whether neuroanatomical characteristics indicative of AD risk and cerebrovascular diseases underlie the greater risk of cognitive impairment or dementia over time in those with less supportive social relationships.

Method

Participants included 989 women (aged 73‐87 years) from the WHIMS‐MRI study who completed the Medical Outcomes Study Social Support Scale, assessing perceived emotional, tangible, and affectionate support, in 2004‐05. Structural brain scans were performed in 2005‐06 to assess small‐vessel ischemic disease (SVID) volume and determine AD pattern similarity scores (AD‐PS), a brain‐MRI measured neuroanatomical biomarker reflecting diffuse gray matter atrophy in brain regions vulnerable to AD neuropathologies, developed by supervised machine learning and validated with AD Neuroimaging Initiative data. Annual WHIMS follow‐ups included extensive neuropsychological assessments to ascertain centrally‐adjudicated incident cases of mild cognitive impairment (MCI) or all‐cause dementia. Structural equation models were used to assess the association between social support and risk of MCI/dementia (diagnosis data available through June 2018), and whether the association was mediated by global SVID volumes or AD‐PS scores. Models were adjusted for depressive symptoms, demographic, lifestyle, and clinical covariates.

Result

Low social support was associated with higher MCI/dementia risk (hazard ratio= 1.23 per 1‐SD; 95% CI: 1.07, 1.44) and also with higher AD‐PS scores (β=.067; 95% CI: .01, .12), but not SVID volume. Higher AD‐PS score accounted for 18.6% (95% CI: 4%, 43%) of the total effect of low social support on risk of MCI/dementia (Figure 1). Higher SVID only accounted for 1.9% (95% CI: ‐1.5%, 8.8%) of the total effect.

Conclusion

Our study illustrates an association between low social support and higher MCI/dementia risk among older women, which was partly mediated by gray matter atrophy indicative of higher AD risk. Findings also suggest less of a role of cerebrovascular disease in mediating these associations.
Implementation of a targeted screening program for Alzheimer's disease risk in a primary care setting
Authors: Korthauer Laura E , Denby Charles , Molina David , Wanjiku Janet , Daiello Lori A , Drake Jonathan D , Grill Josh D , Ott Brian R
Published: December 2020

Background

Primary care providers (PCPs) are well‐positioned to promote early detection of cognitive impairment, yet the value of comprehensive screening of Alzheimer’s disease (AD) risk factors has received limited attention. The goal of this pilot study was to evaluate the feasibility of implementing a population health approach to screening for cognitive and genetic risk for AD in a primary care setting.

Method

PCPs (N=6) referred patients with a family history of AD or memory complaints (N=94) to the Rhode Island Alzheimer’s Disease Prevention Registry for apolipoprotein E (ApoE) genotyping and a telephone‐based cognitive screen (Minnesota Cognitive Acuity Screen). PCPs informed patients of testing results (ApoE status, cognitive screening diagnosis) and counseled them about risk factor modification. The impact on patients’ understanding of their AD risk and providers’ care management was subsequently assessed via surveys.

Result

Twenty‐three participants (31%) had probable mild cognitive impairment; 30 participants (35%) had one or two ε4 alleles. More cognitively normal (93%) than MCI patients (50%) correctly recalled their cognitive screening results (p=.003). Compared to cognitively normal patients, MCI patients correctly reported a higher likelihood of developing AD (p<.001). More ApoE non‐ε4 carriers (100%) than ε4 carriers (80%) correctly recalled their genetic test results (p<.001); both groups correctly reported that the ε4 allele confers greater AD risk. PCPs reported recommending lifestyle changes (e.g., diet, exercise, cognitive stimulation) to 99% of patients, but only 27% of patients reported that this recommendation was made. However, patients who recalled being given a lifestyle recommendation were significantly more likely to have enacted a lifestyle change (OR=7.2; p=.01) than those who did not recall this recommendation. Each PCP reported that the program was a valuable addition to their practice and benefitted their care management. Psychological distress was reported in <5% of participants (1 MCI‐positive, 3 ε4‐positive individuals).

Conclusion

Given the increasing focus on cognitive health in aging, population health initiatives delivered in primary care are needed to offer guidance to at‐risk patients. Implementing a cognitive and genetic screening program for AD risk in a primary care setting is feasible and may provide added value to PCPs in advising patients about risk factor modification.
The role of sleep apnea in APOE‐Alzheimer's disease pathway
Authors: Hegde Krupa N , Ding Xiuhua , Gardner Marylin
Published: December 2020

Background

Previous studies have shown contradictory findings on if the APOE gene is associated with sleep apnea. Thus, the goal of this study is to examine the relationship between the APOE gene and sleep apnea and investigate whether levels of amyloid beta in cerebrospinal fluid (CSF) depend on sleep apnea and/or APOE gene.

Method

Data was obtained from the National Alzheimer’s Coordinating Center (NACC). We restricted participants to those who were enrolled at or after 2015 due to availabilities of sleep apnea measurements and with normal cognition status at enrollment. CSF sample data for a subset of these participants were merged to initial visit data by subject ID and year of visit. Logistic regression was used to investigate the association between sleep apnea and APOE and backward elimination was used to identify a final model. T‐tests were used to compare the mean levels of CSF amyloid beta between APOE gene groups and between sleep apnea groups, respectively.

Result

Of a total of 1630 subjects identified to meet criteria, 3.83% participants had sleep apnea and are APOE ε4 carriers, 26.87% did not have sleep apnea and are APOE ε4 carriers, 9.88% had sleep apnea and are APOE ε4 non‐carriers, 59.45% did not have sleep apnea and are APOE ε4 non‐carriers. Logistic regression showed that sleep apnea was not significantly associated with APOE gene after adjusting age, gender and BMI. The mean levels of CSF amyloid beta among APOE ε4 carriers (mean± SD: 414.7±241.7) were lower than APOE ε4 non‐carriers (mean± SD: 500.9±150.5), and the mean levels of CSF amyloid beta among sleep apnea subjects (mean± SD: 434.6±90.1) were lower than subjects without sleep apnea (mean± SD: 504.9±194.3). However, the differences were not statistically significant.

Conclusion

In this study, sleep apnea was not significantly associated with APOE in the NACC sample and the mean levels of CSF amyloid beta did not depend on sleep apnea or APOE gene in cognitively normal subjects.
Alzheimer’s disease‐related sex differences in insulin sensitivity, glucose metabolism, and spatial memory
Authors: Findley Caleigh A. , Sime Lindsey N. , McFadden Samuel , Hascup Kevin N. , Bartke Andrzej , Hascup Erin R.
Published: December 2020

Background

Women are at higher risk for developing Alzheimer’s disease (AD), comprising two‐thirds of AD patients. In this study, we aimed to characterize AD‐related sex differences in insulin sensitivity, glucose tolerance, and spatial learning and memory in male and female APPNL‐F/NL‐F mice, a model of AD, and normal aging C57BL/6 mice.

Method

Male and female C57BL/6J and APPNL‐F/NL‐F mice underwent data collection at 6 months of age. Insulin and glucose tolerance testing (ITT, GTT) were performed to examine metabolic function, followed by Morris water maze (MWM) to determine cognitive ability.

Result

Preliminary ITT data (area under the curve for percent change from baseline) indicate that male APPNL‐F/NL‐F mice (n=9; 10,260 ± 679) tended to be less insulin sensitive than genotype‐matched females (n=5; 7,900 ± 494). There were no sex differences observed for C57BL/6 mice and no genotype differences. GTT results support a trend of female C57BL/6 mice (n=7; 9975 ± 1,517) having impaired glucose metabolism compared to genotype‐matched males (n=5; 7,083 ± 584). No sex differences were observed for APPNL‐F/NL‐F mice. Of note, APPNL‐F/NL‐F (n=9; 9,211 ± 1,391) males tended to have impaired glucose metabolism compared to C57BL/6 males. For MWM, female mice tended to have impaired long‐term memory recall as supported by cumulative distance measures (C57BL/6J n=7, 15.24 ± 1.73; APPNL‐F/NL‐F n= 5, 15.61 ± 2.38) and annulus 40 entries normalized for distance swam (C57BL/6J n=7, 0.4833 ± 0.0485; APPNL‐F/NL‐F n=5, 0.4542 ± 0.1174) compared to genotype‐matched males (C57BL/6 n=5, 12.11 ± 1.20; APPNL‐F/NL‐F n=9, 12.03 ± 1.86) (C57BL/6J n=5, 0.6732 ± 0.1128; APPNL‐F/NL‐F n=9, 0.6534 ± 0.1150).

Conclusion

Preliminary results support insulin insensitivity in male APPNL‐F/NL‐F mice compared to genotype‐matched females and impaired glucose metabolism compared to C57BL/6 males, a potential early indication of AD pathology. Female mice from both genotypes had impaired long‐term memory retrieval compared to genotype‐matched males, possibly providing an insight into female AD pathology. Collectively, these preliminary findings support potential sex differences for insulin sensitivity and long‐term spatial memory in AD pathology. Studies to further elucidate sex differences in AD disease progression are ongoing. This research was supported by the NIH and SIUSOM.