bluuebunny/crossref_metadata_2025 huggingface dataset:
A qualitative study of the experiences of male and female spousal and adult children caregivers across the caregiving trajectory
Authors: Kokorelias Kristina Marie , Gignac Monique AM , Naglie Gary , Rittenberg Nira , Cameron Jill I
Published: December 2020

Background

Caregiving is not static and changes across the illness trajectory. Our first research objective was to determine phases of caregiving throughout the Alzheimer’s disease trajectory. Our second objective was to explore the similarities and differences in the experiences of male and female adult children and spousal caregivers to persons with Alzheimer’s disease over time.

Method

We applied a constructivist grounded theory approach to data collection and analysis. Forty spousal (10 husbands+ 10 wives) and adult children (10 sons+ 10 daughters) caregivers to persons with Alzheimer’s disease were recruited and interviewed using a semi‐structured interview guide.

Result

We identified 5 phases reflecting caregiving roles related to: 1) monitoring initial symptoms, 2) navigating diagnosis, 3) assisting with instrumental activities of daily living, 4) assisting with basic activities of daily living, and 5) preparing for the future. We were not able to identify any differences by gender or relationship in the caregiving phases. However, our results suggest that when looking at the experiences of caregiving from a gender‐and‐relationship lens experiences across the phases become complex and variable. For instance, spousal caregivers approach a dementia diagnosis with denial, with wives being optimistic for a slow progression of the disease for long periods of time. Adult children caregivers are concerned about the ways the caregiving role will impact their personal and career obligations and seek ways to mitigate the changes to their daily lives. Male caregivers largely utilize home and community health services to assist with personal care tasks whereas female caregivers utilize the same services to allow them to complete other caregiving tasks.

Conclusion

We identified five distinct phases of caregiving and revealed that gender and relationship influence caregiving experiences across the Alzheimer’s disease trajectory. Recognition of the differential impact of gender and relationship on caregiving can inform future intervention efforts by suggesting ways to tailor interventions based upon gender and/or relationship to best support caregivers.
APOE genotype, sex, and ovariectomy influence anxiety‐like behaviors in an EFAD mouse model of Alzheimer’s disease
Authors: Philippi Sarah M , Taxier Lisa R , York Jason , LaDu Mary Jo , Frick Karyn M
Published: December 2020

Background

Behavioral changes accompanying the cognitive decline associated with Alzheimer’s disease (AD) are a growing concern. Symptoms of anxiety occur in 50‐75% of AD patients and increase throughout disease progression (Gustavson and Cummings, 2004; de Toledo et al., 2004). APOE4 genotype, the leading genetic risk factor for AD, may influence symptoms of anxiety in AD patients. Women APOE4 carriers are at greatest risk of developing AD, perhaps due in part to estrogen loss after menopause. However, contributions of APOE4 genotype, sex, and estrogen loss to anxiety in AD remain unclear.

Method

Effects of APOE status, sex, and ovariectomy (OVX) on anxiety‐like behaviors in an open field were measured. First, effects of sex and APOE genotype were examined in gonadally‐intact transgenic male and female mice expressing 5 familial AD mutations (5xFAD+/‐) and human APOE3
+/+ (E3FAD) or APOE4
+/+ (E4FAD). We next examined effects of APOE genotype and OVX in female EFADs. Mice were trained in object recognition (OR) and object placement (OP) tasks. Anxiety‐like behaviors were measured using open field (OF) data collected during the first habituation trial of OR or OP testing, during which mice had 5 minutes to explore an empty box (60 cm x 60 cm x 47 cm). Total distance traveled, average speed, and time spent in the center of the apparatus were measured.

Result

Sex influenced total distance and average speed, such that females traveled further at faster speeds than males. Only APOE genotype affected the time spent in the center of the OF apparatus, with E3FADs spending more time in the center than E4FADs, regardless of sex. OVXed E3FADs exhibited similar anxiety‐like behaviors as both intact and ovariectomized E4FADs.

Conclusion

E3FADs spent more time in the center of an OF than E4FADs of both sexes, suggesting an association between APOE4 and increased anxiety‐like behavior. OVX increased anxiety‐like behaviors in E3FADs to similar levels observed in intact and OVXed E4FADs, suggesting that the loss of estrogens in E3FAD females heightens anxiety‐like behaviors. These findings suggest significant interactions among APOE genotype, sex, and estrogens that may influence the incidence of anxiety in women with AD.
Blood pressure is associated with tau pathology independent of beta‐amyloid
Authors: Rizvi Batool , Lao Patrick J , Brickman Adam M
Published: December 2020

Background

High blood pressure is a risk factor of Alzheimer’s disease (AD) but it is unclear whether it plays a direct role in disease pathogenesis. Recent animal work indicates that induced ischemic disease promotes tau hyperphosphorylation, suggesting that vascular risk factors may directly contribute to AD via neurofibrillary tangle pathology. We examined the relationship between blood pressure indicators and tau pathology, measured with Flortaucipir PET, in early Braak regions among older adults with mild cognitive impairment (MCI) or no cognitive impairment (NC) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Method

A total of 141 ADNI 2 participants (75.6 + 6.72 years old, 53.2% women, 92% White, 33.3% MCI) who underwent Florbetapir (AV‐45) amyloid and Flortaucipir (AV‐1451) tau PET imaging were included in the analyses. Diastolic (DBP) and systolic blood (SBP) pressure measurements from screening visits were considered. We derived mean arterial pressure (MAP; SBP+2(DBP)), pulse pressure (SBP–DBP), and characterized participants as Stage 2 hypertensive (systolic BP > 140 and/or diastolic BP > 90). We examined the association of each blood pressure indicator with tau standardized uptake value ratios (SUVR) in the entorhinal cortex (EC), adjusting for age, sex/gender, MCI diagnosis, time interval between the screening visit and PET visit (4.5 + 1.17 SD years prior to the PET scan), and a cortical amyloid summary measure. We tested interactions between MCI diagnosis and blood pressure.

Result

Independent of amyloid pathology, higher systolic pressure (β=0.217, p=0.009), higher MAP (β=0.186, p=0.021), and hypertension (β=0.165, p=0.044) were associated with increased tau deposition in the entorhinal cortex. Of the covariates, amyloid SUVR (βs=0.301‐0.303, p<0.001), and MCI diagnosis (βs=0.165‐0.189, p=0.031–0.049) were also associated with entorhinal cortex tau. The association between MAP and entorhinal cortex tau was stronger in MCI relative to controls (MCI: β=0.330, p=0.037, NC: β=0.086, p=0.321).

Conclusion

High blood pressure is associated with future neurofibrillary tangle pathology in early Braak regions, independently of amyloid. Our results are consistent with reports of earlier life hypertension as risk for later life AD. Together with results from recent animal studies, they highlight a potential pathway in which vascular factors promote AD pathogenesis via tau.
Peripheral inflammatory biomarkers and risk factors of dementia in the Chilean GERO cohort
Authors: Orellana Paulina , Duran‐Aniotz Claudia , Baez Pablo , Gomez Rodrigo , Lillo Patricia , Villagra Roque , Thumala Daniela , Toledo Carolina , Cabello Victoria , Henriquez Fernando , Parrao Teresa , Gonzalez Christian , Slachevsky Andrea
Published: December 2020

Background

Dementia is one of the mean causes of disability in elderly. Peripheral inflammatory biomarkers and ApoE‐ε4 allele have been described as important biological risk factors of dementia in Caucasian population. Currently, there is scarce information about the specific age‐related and predisposition factors to develop dementia in Latino populations. The aim of this study is to investigate these biological risks factors in Chilean elderly with healthy and pathological brain ageing.

Method

We evaluated and quantified plasma samples obtained from the GERO cohort (114 elderly subjects, >70 years, classified in 51 subjects with subjective cognitive complaint (SCC) and 63 with mild cognitive impairment (MCI)), in addition to 36 healthy brain controls (HBC) and 31 subjects with Alzheimer’s disease dementia (ADD). Genotyping of ApoE gene was analyzed by qPCR. We analyzed inflammatory biomarkers using Luminex technique including IL‐2, IL‐6, IL‐10, TNF‐α, CRP and SAP proteins. All subjects receive a clinical and neuropsychological assessment.

Result

CRP protein was found significant decrease expression in SCC and ADD groups compared to MCI and HBC (p=0.048). In SAP protein was found a significant decrease in expression in the SSC (p=0.04) and MCI (p=0.0178) groups compared to HBC. It was observed a positive correlation in the SCC, MCI and ADD groups with the IL‐6 and TNFα, and, SAP and CRP. A negative correlation between IL‐2, IL‐6 and IL‐10 cytokines was found with Direct Span Digit test, which assess attentional capacity. Also was identified a negative correlation between SAP protein and the Free and Cued Selective Reminding Test (FCSRT), which assess verbal episodic memory, and IL‐10 cytokine and Montreal Cognitive Assessment (MoCA), which assess global cognition. Finally, a positive correlation was found in CRP protein with Pfeffer Functional Activity Questionnaire. Frequency of the ApoE‐ε4 allele, was significantly higher in ADD (52%) and SCC (27%) patients than controls and MCI (p=1x10‐4).

Conclusion

The results shown correlations between the different inflammatory proteins and performance in neuropsychological test suggesting that inflammatory biomarkers are associated with pathological brain ageing. The correlations in SCC and MCI are not being reported previously. Additionally, the frequency of ApoE‐ε4 allele in ADD group is higher than worldwide populations.
Longitudinal grey matter changes in the healthy aging brain as measured by voxel‐based morphometry
Authors: Neufeld Nicole M , Parker Ashleigh F , Gawryluk Jodie
Published: December 2020

Background

In order to understand the changes that occur in the brain over the course of neurodegenerative disorders, it is imperative to establish how the brain changes over time under healthy conditions (Mattson & Arumugam, 2018). Older adulthood is associated with normal age‐related declines in cognitive functioning (Klimova et al., 2017). However, there are inconsistencies in the literature regarding associated changes in grey matter, with some reporting atrophy across the whole brain and others reporting focal atrophy, localized in the frontal and temporal regions (Pergher et al., 2019; Squarzoni et al., 2018). The current study took a longitudinal approach to investigate changes in grey matter over four years in healthy aging.

Methods

3T T1 anatomical magnetic resonance images (MRI) were obtained from 16 healthy older adults (7 male, 9 female; mean age 74.38 ± 4.52 years at baseline) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database at two time points, four years apart. Voxel‐based morphometry (VBM) analyses were carried out using FMRIB’s Software Library to examine within‐subject changes in grey matter over time.

Results

Figure 1 depicts regions where there was significant atrophy (p<0.05, corrected for multiple comparisons) in grey matter at four‐year follow‐up compared to baseline. Specifically, VBM results indicated atrophy in distributed areas including bilateral frontal and temporal regions as well as in the hippocampi, bilaterally. However, there were no significant changes in cognitive performance over these four years.

Conclusions

The current findings reveal atrophy in multiple regions, including the temporal lobes despite normal cognitive performance over the course of four years in healthy aging. Similar regions are known to be affected in Alzheimer’s disease and associated with cognitive decline (Minkova et al., 2017). Follow up work will aim to replicate the current findings in a larger sample and to examine the relationship between cognitive performance and grey matter volume. Developing an understanding of changes in brain structure and function that occur over time in healthy aging will allow for improved interpretation of changes in neurodegenerative conditions, such as Alzheimer’s disease.
Asparagine residue 368 is involved in Alzheimer’s disease tau strain‐specific aggregation
Authors: Shimonaka Shotaro , Elahi Montasir , Matsumoto Shin‐Ei , Ishiguro Koichi , Hasegawa Masato , Hattori Nobutaka , Motoi Yumiko
Published: December 2020

Background

In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed ‘tau strains’) and acts as an aggregation “seed” promoting the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the carboxy‐terminal region (243–406) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited in comparison to normal tau via templated aggregation are still unknown. Here, we sought to identify the key sequences of seed‐dependent aggregation.

Method

To identify sequences for which deletion reduces tau aggregation, SH‐SY5Y cells expressing a series of 10 partial deletion (Del 1–10, covering 244–400 aa) mutants of tau‐CTF24 (243–441 aa) were treated with tau seeds prepared from a different tauopathy patient’s brain [Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)] or recombinant tau and then, seed‐dependent tau aggregation was assessed biochemically. Furthermore, we systematically repeated cellular tau aggregation assays for the delineation of shorter deletion sites to identify the minimum sequence responsible for tau aggregation.

Result

We found that the Del 8 mutant lacking 353–368 aa showed significantly decreased aggregation in both cellular and in vitro models. Mutagenesis studies revealed that Asn368 mutation suppressed tau aggregation triggered by an AD‐tau seed, but not using other tauopathies seeds, including PSP and CBD. Similar effects were also observed with Ala replacement of the Ser320 residue, which was arranged facing inwards toward Asn368, in the AD‐tau core structure that was determined recently by means of cryo‐electron microscopy.

Conclusion

Our study suggested that 353–368 aa is a novel aggregation‐responsible sequence other than PHF6 and PHF6*, and within this sequence, the Asn368 residue plays a role in strain‐specific tau aggregation in different tauopathies, possibly along with Ser320.
Effect of mindfulness intervention on salivary Aβ‐42 levels in community‐dwelling older adults with mild cognitive impairment: A randomized controlled trial
Authors: Ng Ted Kheng Siang , Tan Crystal Tze Ying , Nur Fadzillah , Wee Sin Tho , Goh Lee Gan , Kua Ee‐Heok , Larbi Anis , Mahendran Rathi , Slowey Paul
Published: December 2020

Background

Few randomized controlled trials investigated the effects of mindfulness intervention on older adults diagnosed with mild cognitive impairment (MCI). Specifically, there has been a scarcity of literature on the potential benefit of a mindfulness intervention on biomarker for AD hallmark. Thus, we conducted a secondary analysis on bio‐banked salivary samples of a pilot randomized controlled trial, examining whether Mindful Awareness Practice (MAP) improved salivary Aβ‐42 levels in older adults with MCI.

Method

55 community‐dwelling older adults diagnosed with MCI were randomized into either the treatment arm, MAP, or the active control arm, health education program (HEP). Interventions were carried out for 9 months. Field and laboratory investigators who were blinded to the treatment allocations collected saliva samples at baseline, 3‐month, and 9‐month follow‐ups. Salivary Aβ‐42 levels were quantified using a newly validated commercial assay. Linear‐mixed models were used to examine the effect of MAP on salivary Aβ‐42 levels.

Result

Compared to the control arm, MAP participants had no significantly changed Aβ‐42 levels throughout the 9‐month intervention period. Exploratory subgroup analyses by either sex or MCI‐subtypes (amnestic and non‐amnestic) also did not show significantly changed Aβ‐42 levels.

Conclusion

MAP did not improve salivary Aβ‐42 levels in community‐dwelling older adults with MCI. Although our previous findings showed the potential of MAP in improving biomarkers of systemic inflammation and synaptic functions, the current findings suggest that mindfulness intervention may not be effective in ameliorating AD hallmark. A more specific/targeted psychosocial intervention may be needed to improve AD pathology in patients with MCI.
Art and dementia education in times of COVID‐19
Authors: Mateus‐Berr Ruth , Al‐Mousli Luna , Carli Christina May Yan , Faißt Verena , Gharashir Nargol , Girotto Lara , Greisberger Eva , Gruber Vanessa Lea , Guserl Stefanie , Hausner Ida Johanna , Muzler Susa , Ngo Nha , Sanglhuber Anna , Schaitl Jasmin , Scharler‐Plotnik Pia Moana , Schroll Alexandra , Schober Michaela
Published: December 2020

Background

Around the world, there will be one new case of dementia every 3 seconds. 152 million people are worldwide living with dementia in 2050, by then 2 billion people will be over 60 years of age. There are negative attitudes towards elderly people and ageism is extremely common. Young people often know somebody in their families with dementia and most of the time do not know how to handle it. This project designs the first arts‐based schooling strategy for empathy for people with dementia, creates a dementia friendly generation, age‐friendly environments, supports young people to understand dementia. Objective of the project is to develop artistic strategies to strengthen empathic abilities with arts‐based methods & interdisciplinary collaboration between people with & without dementia. Stress is a daily challenge faced by family caregivers working with people with dementia, isolation became another demanding situation. Isolation has an impact on health, therefore workshops were designed for caregivers and students in quarantine to engage in the questions ‘How can art‐based research affect intergenerational well‐being of people with dementia and students? And ‘How can these means encourage the handling of the topic dementia?’

Method

Art and design‐based online‐workshops enable family caregivers and students in isolation to take salutogenetic perspectives. Methods of embodied & experiential learning were applied, an interdisciplinary approach as new methodology of teaching awareness about dementia by innovative arts‐based pedagogies. The workshops on Body & Senses engage in body awareness, trigger senses and exploring movement and touch. The workshop Storytelling collects and rewrites memories from different perspectives and narratives. Other workshops create images in innovative ways, through investigating one’s environment, explore documentary material and designing tangible visualization.

Result

Workshops resulted in positive feedback and knowledge about dementia by all participants. 281 people, aged between 13‐65 participated at these workshops. Most of them were students, others engaged in family care in isolation.

Conclusion

Art‐based research facilitated creative approach, self‐awareness about one's own resources and empathy and knowledge growth on dementia.

Highlights: art‐based research methods contributed to well‐being in isolation; creative workshops involved participants to experience resources; awareness growth on dementia.
The role of cardiometabolic risk in the association between accumulation of affective symptoms across adulthood and midlife cognitive function
Authors: John Amber , Desai Roopal , Richards Marcus , Gaysina Darya , Stott Joshua
Published: December 2020

Background

Affective symptoms, such as depression and anxiety, are associated with cognition in midlife and later life. However, the role of cardiometabolic risk in this association has not been examined. The aim of this research was to investigate how cardiometabolic risk contributes to associations between affective symptoms and midlife cognition.

Method

Data were used from the National Child Development Study (NCDS), a sample of people born in Britain during one week in 1958. Affective symptoms were assessed at ages 23, 33, and 42 and a measure of accumulation derived. A cardiometabolic risk score was calculated from nine cardiometabolic biomarkers at age 44. Measures of memory, verbal fluency, and information processing were available at age 50.

Result

Fully adjusted path models indicated significant indirect associations between affective symptoms and midlife immediate memory (β=‐0.002, SE=0.001, p=.009), delayed memory (β=‐0.002, SE=0.001, p=.02) and verbal fluency (β=‐0.002, SE=0.001, p=.045) through cardiometabolic risk. Cardiometabolic risk did not predict subsequent affective symptoms or cognition at age 50.

Conclusion

These findings suggest that cardiometabolic risk may play an important indirect role in the association between affective symptoms and cognitive function (memory and verbal fluency). Results contribute to understanding of biological mechanisms underlying associations between affective symptoms and cognitive ageing, which can have implications for early detection of, and intervention for, those at risk of poorer cognitive outcomes.
Cellular dependency analysis identifies genes implicated in Alzheimer’s disease (AD) as potential treatment targets
Authors: Jaladanki Suraj K , Malave Gabriel Santos , Huang Kuan‐lin
Published: December 2020

Background

Genes involved in the progression of Alzheimer’s disease (AD) have been identified, but these genes have not been studied in the context of CRISPR knockouts and RNAi screens to reveal cell‐specific vulnerabilities.

Method

A list of 105 AD‐associated genes, found through genome‐wide association studies (GWAS) and gene expression network analyses, was compiled. Expression and knock‐down/out dependency data for over 700 cell lines was obtained through the Cancer Dependency Map (DepMap). The expression‐associated dependencies were specifically examined in three tissue types that may be relevant to AD etiology: hematopoietic and lymphoid tissue, central nervous system, and autonomic ganglia.

Result

SPI1, MEF2C, GAB2, and ABCC11 in hematopoietic and lymphoid tissue cell lines were established as genes of interest since their genetic knockouts specifically affected cells showing high expression of these genes. Other genes exhibiting expression‐associated dependencies include ACTG1 in autonomic ganglia and GLS in central nervous system cell lines. Investigating these genes for expression and dependency patterns in their respective AD tissue of interest highlighted cell lines that had the most significant decrease in cell survival and growth after CRISPR knockout or RNAi screen.

Conclusion

SPI1, MEF2C, GAB2, and ABCC11 demonstrated expression‐associated dependencies in cell lines of AD‐associated tissues, and present as potential targets for AD.
Loss of synaptogyrin‐3 rescues tau‐induced memory defects and synaptic loss in the presence of microglial activation
Authors: Largo‐Barrientos Pablo , de Strooper Bart , Spires‐Jones Tara , de Wit Joris , Uytterhoeven Valerie , Verstreken Patrik
Published: December 2020

Background

We previously identified synaptic vesicle protein Synaptogyrin‐3 as a physical interactor of Tau. Upon mutations and/or hyperphosrylation, Tau accumulates at synapses, binds to Synaptogyrin‐3 and clusters synaptic vesicles, reducing vesicle mobility and neurotransmitter release (McInnes et al., Neuron 2018).

Method

We generated a synaptogyrin‐3 knockout mouse usign CRISPR/Cas9. We crossed synaptogyrin‐3 knockout mice with mice expressing human P301S mice (PS19 mouse line) to generate Tau P301S; synaptogyrin‐3
+/‐ mice. We assessed several aspects of mutant Tau‐induced pathology using biochemistry, electrophysiology, histology and behavior experiments.

Result

We show that loss of Synaptogyrin‐3 is benign in mice, but strongly rescues mutant Tau‐induced defects in long‐term synaptic plasticity and working memory. It also significantly rescues the synaptic loss caused by mutant Tau. However, Tau‐induced neuroinflammation remains clearly upregulated when we remove synaptogyrin‐3.

Conclusion

Interaction of Tau and Synaptogyrin‐3 leads to pre‐synaptic dysfunction, and pre‐synaptic defects caused by mutant Tau are enough to drive defects in cognitive tasks. On the other hand, neuroinflammation is not sufficient to induce synaptic loss and these processes are separately induced in response to mutant Tau.
Investigating the pathological mechanisms linking depression and Alzheimer’s disease
Authors: Dunnett Sophie Louise , Cheung Kylie KY , Chang Raymond Chuen‐Chung
Published: December 2020

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by the presence of tau tangles, amyloid beta plaques and neuroinflammation. Although the mechanisms underlying AD are not fully understand, several key risk factors for developing AD have been identified, such as depression. Previous work from our group, using a corticosterone‐induced model of depression in rats, has found that depression leads to tau phosphorylation and its displacement from microtubules, mislocalization and aggregation within neurons. The aims of my project are to continue investigating whether depression leads to other pathological tau alterations, such as acetylation, and to investigate the relationship between tau and neuroinflammation in the context of depression, focusing on the complement and toll‐like receptor (TLR) signaling pathways.

Method

In this project, we are using a corticosterone‐induced model of depression. Corticosterone is administered daily to Sprague‐Dawley (SD) rats for 21 days. Afterwards, a series of behavioral tests are performed including the Open Field test, the Novel Object Recognition task and the Forced Swim Test to assess their anxiety, memory and depressive behaviors, respectively. Afterwards, brain samples are collected from the animals to conduct immunohistochemical analysis, qPCR and western blot.

Result

Following 21 days of corticosterone administration, subjects display decreased adrenal and bodyweight, and anxiety‐like behaviors. Thus far, qPCR data demonstrates that there are increases in TLR4, as well as downstream elements in its signaling pathway, in the hippocampus.

Conclusion

In depression, alterations to the TLR4 signaling pathway are observed in the hippocampus. We will further investigate this pathway, its interplay with the complement system, and how these alterations impact tau pathology.
MEG spectral patterns in the progression from MCI to AD
Authors: Cuesta Pablo , García María Eugenia López , Pusil Sandra Angelica , Bajo Ricardo , Maestú Fernando , Fernandez Alberto
Published: December 2020

Background

Alzheimer's disease (AD) is the most prevalent type of dementia. The relevance of the symptomatic pre‐dementia or mild cognitive impairment (MCI) is central to stablishing a prognosis of the disease. Considering the scarcity of studies within this field and its potential clinical relevance, we conducted a longitudinal magnetoencephalography (MEG) study in two groups: stable (sMCI) and progressive (pMCI) MCIs during a 4‐years followed‐ up.

Method

We compared the power spectra in source space measured by MEG during 5 minutes of resting state eyes‐closed from 49 MCIs (24 pMCI and 25 sMCI) within three frequency bands: delta (1,5‐4Hz), theta (4‐8Hz) and alpha (8‐12Hz). The procedure for statistical comparisons relied on the cluster‐based permutation test (CBPT) and was carried out independently for each frequency band. As both groups did differ in age and educational level, both factors were included as covariates in the statistical tests. Finally, we performed Spearman correlation analyses between the significant power differences and the neuropsychological scores and hippocampal volumes.

Result

pMCI patients showed a significant power increase within theta range (4‐8Hz), compared with the sMCI group (CBPT p <0.05). The significant cluster within this frequency band mainly involved right medial temporal regions, including inferior temporal gyrus, fusiform gyrus, parahippocampal gyrus, hippocampus and amygdala. Besides, the pMCI group exhibited a power shift to lower frequencies than the sMCI group. The correlation analysis carried out with all participants showed a direct association between power results and general cognitive status (Mini‐mental state examination; rho= ‐0.344; p= 0.021), working memory (inverse digit span test; rho= ‐0.285; p= 0.049) and episodic memory (immediate recall; rho= ‐0.405; p= 0.004; and delayed recall; rho= ‐0.358; p= 0.016).

Conclusion

Our results are aligned with previous reports with (EEG)/MEG spectral analysis performed in those MCI that finally progressed to AD. The Progression to AD involved the electrophysiological disruption of the medial temporal lobe structures. Besides, we found that this slowness pattern was related with worse performance in several cognitive measures, such as global cognitive status, episodic and working memory, entitle this MEG profile to be considered as AD‐progression biomarker.
A multivariate model of time to conversion from mild cognitive impairment to Alzheimer’s disease
Authors: García María Eugenia López , Turrero Agustín , Cuesta Pablo , Rojo Inmaculada Concepción Rodríguez , Barabash Ana , Dolado Alberto Marcos , Maestú Fernando , Fernandez Alberto
Published: December 2020

Background

Alzheimer's disease (AD) is a neurodegenerative disorder, clinically defined by a progressive loss of memory and other cognitive and functional abilities. One of the most studied phases in the prognosis of AD is the Mild cognitive impairment (MCI) since it entails a higher risk of developing this type of dementia. The majority longitudinal studies from MCI to AD utilize both a reduce number of potential prediction markers and a shorten length of follow‐up. Therefore, the present study was aimed at determining which combination of demographic, genetic, cognitive, neurophysiological (i.e. magnetoencephalography, MEG), and neuroanatomical (i.e. magnetic resonance imaging (MRI) volumetry) factors may predict differences in time to progression from MCI to AD during an extended follow‐up.

Method

To this end, a sample of 121 MCIs was followed‐up during a 5‐years period. According to their clinical outcome, MCIs were divided into two subgroups: (i) the “progressive” MCI (pMCI; n= 46); and (ii) the “stable” MCI group (sMCI; n= 75). Kaplan‐Meier survival analyses were applied to explore each variable’s relationship with the progression to AD. Once potential predictors were detected, Cox regression analyses were utilized to calculate a parsimonious model that may allow the estimation of differences in time to progression.

Result

Results indicated that the final model included three variables (in order of relevance): Left parahippocampal volume (corrected by intracranial volume, LP_ ICV), Delayed recall (DR), and Left Inferior Occipital lobe individual alpha peak frequency (LIOL_IAF). Those MCIs with LP_ ICV volume, DR score and LIOL_IAPF value lower than the defined cutoff had 6‐times, 5.5‐times and 3‐times higher risk of progression to AD, respectively. Besides, when the categories of the three variables were “unfavourable” (i.e. values below the cutoff), a 100% of cases progressed to AD at the end of follow‐ up, while a combination of “favourable” categories yielded a 94.7% of stable cases at the end of follow‐up.

Conclusion

Our results highlighted the relevance of neurophysiological markers as predictors of conversion, and the importance of multivariate models that combine markers of different nature to predict time to progression from MCI to dementia.
Cerebrospinal fluid fatty acid binding protein 3: A screening biomarker for preclinical Alzheimer’s disease
Authors: Dhiman Kunal , Martins Ralph N , Gupta Veer Bala
Published: December 2020

Background

Preclinical Alzheimer’s disease (AD) is a silent, asymptomatic stage of AD, classified into three sub‐stages based on amyloid positivity, neuronal injury and presence of subtle cognitive decline. Pathophysiological biomarkers are needed to effectively screen cases of preclinical AD based on the specific stage. Fatty acid binding protein 3 (FABP3) is a biomarker of neuronal membrane disruption, associated with lipid dyshomeostasis. The current study evaluated the potential of cerebrospinal fluid (CSF) FAPB3, as a stage‐specific screening biomarker of preclinical AD.

Method

The levels of FABP3 were quantified in CSF samples of healthy participants (n = 159) from the Australian Imaging, Biomarkers and Lifestyle studying of ageing (AIBL), on the Meso Scale Discovery platform using Human FABP3 Kit (Meso Scale Diagnostics, USA). A sub‐set of participants, (n = 142) had undergone positron emission tomography (PET) brain amyloid imaging. These participants were dichotomised into PET amyloid positive (n = 49) and negative (n = 93) based on the PET derived standardized uptake value ratio (SUVR) cut‐off of 1.4. Diagnostic differences in CSF FABP3 levels were assessed among amyloid positive and negative participants. Cox proportional hazards model was used to identify individuals likely to progress to an early stage of cognitive impairment, by assessing the risk of conversion from clinical dementia rating (CDR) of 0 to CDR ≥ 0.5. CDR assessments were done over 4.5 years; participants who had at least two follow‐up assessments were included in the analysis.

Result

CSF FABP3 levels were significantly higher in PET amyloid positive healthy participants as compared to negatives (p = 0.001). CSF FABP3 levels were significantly higher in healthy participants who converted from CDR 0 to CDR ≥ 0.5, over 4.5 years, against non‐converters (p = 0.039). In an unadjusted analyses, CSF levels of FABP3 significantly predicted the risk of conversion from CDR 0 to CDR ≥ 0.5, with a hazard ratio (HR) of 1.58 (CI 1.03‐2.43, p = 0.035).

Conclusion

FABP3 is a biomarker of early neurodegenerative changes, which can be used to screen cases of preclinical AD with asymptomatic amyloidosis, as well as identify individuals likely to progress to a clinical stage of AD.
Effects of early surgical menopause on sleep, memory, and medial temporal lobe structure at midlife
Authors: Gervais Nicole J , Lauzon Claire , Brown Alana , Gravelsins Laura , Nicoll Gina , Baker‐Sullivan Elizabeth , Almey Anne , Reuben Rebekah B , Duchesne Annie , Mendoza Leanne , Perovic Mateja , Kannampuzha Courtney , Grady Cheryl , Olsen Rosanna , Einstein Gillian
Published: December 2020

Background

Women bear the greatest burden of Alzheimer’s disease (AD) with menopause‐associated estrogen (E) loss becoming increasingly implicated. Surgical menopause <45 years of age (via bilateral salpingo‐oophorectomy, BSO) is thought to further increase the risk (Rocca et al., 2007). Neurodegeneration and atrophy in medial temporal lobe (MTL) structures including the perirhinal (PRC) and entorhinal (ERC) cortices occur in the very early stages of AD (e.g. Khan et al., 2013; Wolk et al., 2017). Further, sleep disturbance is also implicated in AD progression (Lim et al., 2013). Unknown is whether BSO‐associated sleep disturbance contributes to reduced memory performance and MTL atrophy via sleep disturbance, and whether E2 supplementation influences this relation. Our study aimed to determine the effect of early hormone deprivation (via BSO) on MTL volume, visual recognition memory, and whether this is correlated with sleep disturbance.

Method

Demographic and cognitive measures were administered to women with an oophorectomy <45 years who were either taking estradiol‐based hormone therapy (BSO+E2: n=19), or not taking E2 (BSO no E2: n=15). Data was also collected from age‐matched premenopausal women (AMC: n=27). High‐resolution T2‐weighted scans were acquired using a Siemens 3T Prisma scanner, and hippocampal subfields, PRC, ERC, and parhippocampal cortex were manually segmented (Olsen et al., 2017) in FSLView. The interference match‐to‐sample (IMTS) task was used to asses and recognition memory (Watson et al., 2013). Sleep was assessed using an at‐home polysomnography device (Vitaport‐5/REMbo‐234, Temec Technologies).

Result

Relative to AMCs, the BSO no E2 group had smaller volumes in the dentate gyrus, CA2, and CA3 (DGCA23) (p<.05, d=1.03). Relative to BSO+E2 women with BSO no E2 had reduced recognition memory performance (p<.05; d=1.36) and their sleep was more disrupted, indicated by increased sleep latency (p<.05, d=.71), and cortical arousals ( p<.05, d=.87]. DGCA23 volume and nighttime arousals were correlated negatively (r=‐.503, p<.05).

Conclusion

Our findings demonstrate that HPC, recognition memory, and sleep are sensitive to E2 loss and suggest that reduced HPC volume relates to disrupted sleep. Taken together these findings begin to explicate the path from early menopause to late‐life dementia and the importance of E2 for women’s brain health.
Novel proteomic molecular signatures of brain endothelial cells and microglia in the aging mouse brain
Authors: Rayaprolu Sruti , Duong Duc , Xiao Hailian , Carter Emma Kathleen , Cheng Lihong , Levey Allan I , Seyfried Nicholas T , Rangaraju Srikant
Published: December 2020

Background

Immune and vascular mechanisms of aging and Alzheimer’s disease (AD) are mediated by microglia and endothelial cells, respectively. Transcriptomic studies of endothelial cells and microglia have revealed distinct and overlapping molecular features between these cell types while brain endothelial proteomic signatures remain unknown. Using concurrent isolation of microglia and endothelial cells from adult mouse brain along with multiplex quantitative proteomics, we contrast the proteomic profiles of these cell‐types and define their unique age‐related proteomic characteristics, for the first time.

Method

The study cohort consisted of 3 and 7‐month‐old C57BL/6J mice (N = 6/age, 3M and 3F). Endothelial cells and microglia were concurrently isolated from fresh, whole mouse brain using fluorescence‐activated cell sorting (FACS). On average, 14,000 endothelial cells and 20,000 microglia were sorted directly into 8M urea and digested. Peptides from each sample were randomized into four batches and labeled using 16‐plex tandem‐mass‐tag (TMT) kits. After high pH fractionation, peptides were analyzed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) with synchronous precursor selection MS3 based quantification (SPS‐MS3). Raw files were processed using Proteome Discoverer. The spectra were searched against UniProt mouse proteome database. Differential expression analysis and Gene Ontology analysis (GO) was performed.

Result

Quantitative proteomics of endothelial cells and microglia from adult mice identified 512 proteins. Of these, 199 proteins differentiated microglia from endothelial cells (Fig.1A) of which 20 proteins had >4‐fold higher expression in microglia (e.g., Rgs10) and 60 proteins had >4‐fold higher expression in endothelial cells (e.g., Hspa12b). 51 proteins demonstrated age‐dependent changes in microglia (Fig. 1B; 18 increased and 33 decreased). 35 proteins demonstrated age‐dependent changes in endothelial cells (Fig.1B; 15 increased and 20 decreased). GO analysis showed age‐dependent increase in structural, morphogenesis, and intermediate filament proteins and decrease in cell motility and macromolecular biosynthetic proteins in microglia. Age‐dependent changes in endothelial cells included increased gene transcription, splicing, and subcellular transport and decrease in chromatin organization and cytokine production proteins.

Conclusion

In this direct comparison of proteomic profiles of adult mouse microglia and endothelial cells, we report proteomic signatures that differentiate microglia and endothelial cells and identify unique age‐dependent changes in microglia and endothelial cells.
Entry of extracellular tau to human neurons is functionally analogous to virus infection
Authors: Evans Lewis D , Livesey Rick
Published: December 2020

Background

In tauopathies, including Alzheimer’s disease, the disease progresses through the brain in a defined spatial and temporal pattern, with the deposition of protein aggregates in brain regions mirroring the clinical symptoms of disease. Progression of tauopathies through the CNS is thought to be mediated by intercellular transfer of disease‐associated forms of the microtubule‐associated protein tau between diseased and healthy neurons. We report here the use of whole genome CRISPR screens to understand the cell biology of entry and processing of extracellular monomeric and aggregated tau by human neurons.

Methods

Whole genome, loss of function CRISPR screens in human iPSC‐derived excitatory neurons were performed to identify genes that regulate uptake and intracellular processing of extracellular monomeric and aggregated tau (MAPT P301S), using a lentiviral library of 100,000 gRNAs targeting 20,000 protein‐coding genes. Neurons that took up transferrin were FACS purified into populations with either low or normal levels of internalised tau and gRNA libraries sequenced from each population to identify genes required for tau uptake, using the MAGeCK data analysis algorithm.

Results

For both monomeric and aggregated tau, multiple genes involved in endosomal sorting and those regulating receptor recycling are required for tau uptake. Aggregated tau uptake is dependent on several other intracellular vesicular trafficking systems, including trafficking between organelles and surface protein glycosylation. In addition, monomeric tau uptake requires the newly identified low‐density lipoprotein receptor LRP1 and the endocytosis regulator LRRK2, mutations in which are causal for monogenic PD. Comparison of the protein networks involved in tau uptake demonstrates a striking similarity to genes identified as host factors required for viral infection, particularly for viruses that enter cells via receptor‐mediated endocytosis.

Conclusions

Monomeric and aggregated tau enter human neurons via overlapping but distinct pathways, dependent on specific surface receptors, the endolysosomal‐autophagy system, the Golgi network and other vesicle trafficking pathways. The similarity of the cell biology of extracellular tau uptake and processing by neurons with that of viral entry suggests that tauopathy spreading is a quasi‐infectious process, analogous to viral infection, suggesting potential therapeutic strategies to prevent disease progression.
APOE genotype and sex influence memory and dendritic spine density in an EFAD mouse model of Alzheimer’s disease
Authors: Taxier Lisa R , Philippi Sarah M , York Jason , LaDu Mary Jo , Frick Karyn M
Published: December 2020

Background

Women carriers of the APOE4 genotype, which is the leading genetic risk factor for late‐onset Alzheimer’s disease (AD), are more likely than women carriers of other APOE genotypes and men of any APOE genotype to develop AD. However, factors underlying the interaction between APOE genotype and sex are not well characterized. The goal of this study was to examine the effects of sex and APOE genotype on memory function and dendritic spine density in a mouse model of AD.

Methods

Six month‐old gonadally‐intact male and female transgenic (Tg) mice expressing 5 familial AD mutations (5xFAD+/‐) and human APOE3
+/+ (E3FAD) or APOE4
+/+ (E4FAD) were trained on object recognition (OR) and object placement (OP) tasks designed to test object recognition and spatial memory formation. Memory for previously seen objects or locations was tested 24 or 4 hours later, respectively. Two weeks after the conclusion of behavioral testing, mice were retrained with novel objects, and brains were collected for Golgi staining. Following staining, apical and basal dendritic spines in the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) were counted and classified by morphological type.

Results

Male E3FAD mice exhibited intact memory for previously seen objects or locations, whereas male E4FADs and female E3FAD or E4FAD mice did not. The density of total, mushroom, and stubby spines on basal CA1 and mPFC dendrites was lower for E4FAD mice of both sexes compared to E3FAD mice. Preliminary data suggest a similar pattern for mPFC apical spine density.

Conclusions

These data suggest that APOE genotype and sex influence object recognition and spatial memory formation, and that APOE4 genotype is associated with reduced density of mature and immature spines in CA1 and the mPFC.
Network analysis of the brain proteome of GRN knockout mice reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations
Authors: Kukar Thomas , Huang Meixiang , Modeste Erica S , Dammer Eric B , Holler Christopher J , Deng Qiudong , Taylor Georgia L , Merino Paola , Seyfried Nicholas T
Published: December 2020

Background

Mutations in the GRN gene, encoding the progranulin (PGRN) protein, are a common cause of Frontotemporal dementia (FTD) and induce haploinsufficiency of PGRN. PGRN is composed of 7.5 repeating domains called granulins (GRNs 1‐7). PGRN is processed into GRNs within the lysosome, where we hypothesize they are critical for lysosome homeostasis and function. However, it is unclear how decreased levels of lysosomal PGRN/GRNs cause FTD, Alzheimer’s disease, and related neurodegenerative disorders.

Methods

We performed quantitative proteomic analysis of whole‐brain tissue from wild‐type (Grn
+/+) and PGRN knockout (Grn
‐/‐) mice at 3‐ and 19‐months of age using 10‐plex Tandem Mass Tag (TMT) isobaric labeling mass spectrometry. Protein changes were validated using immunobloting, immunohistochemistry, and ELISAs.

Results

Deep proteome analysis of mouse brains detected 8,695 proteins. Weighted correlation network analysis (WGCNA) of the brain proteome of Grn
‐/‐ compared to Grn
+/+ mice identified 29 modules of highly co‐expressed proteins. In particular, 3 modules strongly correlated to Grn deficiency, increased with age, and were enriched with lysosomal proteins (Gpnmb, Ctsd, Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44). Immunohistochemistry revealed age‐dependent increases in multiple lysosomal proteins and inflammation throughout the Grn
‐/‐ brain, particularly in the thalamus. Importantly, we discovered similar changes in the brain and cerebrospinal fluid (CSF) of individuals with GRN mutations that cause FTD (FTD‐GRN). GPNMB and galectin‐3 (LGALS3) were significantly elevated in the lysates of FTD‐GRN brain. Further, GPNMB levels were significantly increased in human FTD‐GRN CSF compared to controls and other genetic forms of FTD (MAPT and C9orf72).

Conclusions

These data suggest that common pathogenic pathways are dysregulated in human FTD cases with GRN haploinsufficiency and Grn
‐/‐ mice. Moreover, GPNMB is a novel, potential biomarker for FTD. Our findings support the idea that insufficiency of PGRN and GRNs in humans cause FTD, AD, and related neurodegenerative diseases through lysosomal dysfunction and neuroinflammation and suggest novel therapeutic approaches.