bluuebunny/crossref_metadata_2025 huggingface dataset:
Volumetric, shape and microstructural alterations of the hippocampal subfields in healthy aging
Authors: Bussy Aurelie , Plitman Eric , Patel Raihaan , Salaciak Alyssa , Farzin Sarah , Bedford Saashi , Béland Marie‐Lise , Tullo Stephanie , Devenyi Gabriel A. , Chakravarty Mallar
Published: December 2020

Background

Although several volumetric studies have attempted to examine the relationship between hippocampal subfields and age, their findings are heterogenous. Here, in addition to typical volumetric measures, we investigated age‐related alterations of hippocampal subfield shape and microstructure.

Method

The present work included 161 healthy participants (ages 18‐81) recruited as part of two local datasets. Standard T1‐weighted (T1w; MPRAGE sequence, 1 mm3 voxels) and high‐resolution T2‐weighted (T2w, 0.64 mm3 voxels) magnetic resonance images were acquired. The minc‐bpipe‐library pipeline (https://github.com/CobraLab/minc‐bpipe‐library) was used to preprocess images. The MAGeT‐Brain algorithm (Pipitone et al., 2014) was utilized for segmentation of the hippocampal subfields (Amaral et al., 2016). The volume and shape (i.e. surface area [SA] and displacement) of the grey matter (GM) subfields (i.e. Cornus Ammonis [CA]1, CA2CA3, CA4 and dentate gyrus [CA4DG], stratum radiatum/lacunosum/moleculare and subiculum) and the volume of associated white matter (WM) regions (i.e. fimbria, fornix, alveus and mammillary bodies [MB]) were estimated using T1w images. Mean T1w/T2w signal intensity ratio (Glasser & Van Essen, 2011) of each subfield was calculated to examine microstructural alterations sensitive to myelin. Linear‐mixed effects models and Akaike information criterion were used to select the most appropriate age relationships from multiple fits (i.e. linear, quadratic, and cubic) for each structure of interest. Sex and ipsilateral hippocampal GM or WM volume were included as covariates. Statistical analyses were performed in R 3.5.0; comparisons surviving p<0.05 (Bonferroni‐corrected) were reported.

Result

Right CA1 and alveus volumes were positively cubically related to age and bilateral CA4DG volumes were negatively linearly related to age. T1w/T2w intensity linearly decreased with age for all subregions except for bilateral fornix and MB, which expressed quadratic evolution with age (Figures 1‐2). Age was also inversely related to bilateral SA reduction in the head and medial‐posterior hippocampus, and lateral outward and medial inward displacement (Figure 3).

Conclusion

The current work suggests that certain subfields of the hippocampus are more (e.g. CA1) or less (e.g. CA4DG) preserved in healthy aging. These differences do not appear to be explained by microstructural variation.
HCMV infection induces AD pathology in astrocytes in vitro
Authors: Barbian Hannah J. , Lurain Nell S. , Bennett David A. , Al‐Harthi Lena
Published: December 2020

Background

Infectious agents have long been suspected to be risk factors for Alzheimer’s disease (AD). Some studies have identified a link between neurotropic viruses and AD. While these studies demonstrated an association between AD and neuroviruses, most do not establish a causal link. However, many AD pathological hallmarks, including beta amyloid plaques (Aβ), astrogliosis, neuroinflammation, and neuronal damage, overlap with pathologies caused by neuroviruses. Approximately 80% of adults are seropositive for human cytomegalovirus (HCMV), a virus that is neuroinvasive, productively infects brain cells, and is immune‐dominant in aging populations. Using post‐mortem tissues from the Rush Alzheimer’s Disease Center we previously reported that HCMV infection is associated with AD clinical markers. In the present study, we assessed the ability of HCMV infection to induce two AD pathological hallmarks in astrocytes: Aβ production and astrocyte reactivity.

Method

To determine the impact of HCMV infection on astrocytes, we generated low‐passage clinical HCMV isolates for infection of human fetal astrocytes (HFA) and astroglioma (U251) cells. To assess the ability of HCMV to produce Aβ, we infected HFAs and U251s with HCMV for 3‐9 days then immunostained for Aβ and HCMV proteins. To test whether HCMV infection results in astrocyte reactivity, we infected HFAs with HCMV for 5 days then quantified levels of reactivity‐associated transcripts via quantitative PCR.

Result

HFA and U251 infected cells showed HCMV cytopathic effects characteristic of permissive cells, including enlargement and plaque formation. HCMV infection of HFA and U251 cells induced the expression of Aβ as observed by co‐staining of Aβ and HCMV proteins. Aβ production was observed within 3 days and persisted until at least 9 days post‐infection. To assess the amyloidogenicity of HCMV, we employed the Waltz algorithm, which predicted two amyloidogenic sequences within immunodominant HCMV proteins pp65 and IE1 (average score: 98.3). Further, HCMV infection of HFAs mediated a 2‐ to 4‐ fold induction in CXCL10, CD44, and IRGM, reactivity‐associated genes also involved in immune and inflammatory pathways.

Conclusion

Our data demonstrate that HCMV infection can contribute to AD pathology in cultured astrocytes. These findings could ultimately inform the use of antiviral therapy to prevent and/or reduce AD severity.
Comparison of brain atrophy and cognitive performance in individuals with low and high cardiovascular risk: Data from the Diabetes and Dementia (D2) Study
Authors: Restrepo Carolina , Werden Emilio , Singleton Rebecca , Khlif Mohamed Salah , Bird Laura J. , Ekinci Elif , MacIsaac Richard , Srivastava Piyush , Patel Sheila , Burrell Louise , Brodtmann Amy
Published: December 2020

Background

Growing evidence suggests that increased cardiovascular risk might accelerate brain atrophy and cognitive decline. The aim of this analysis was to investigate associations between the Framingham Risk Score (FRS), brain volume and cognitive function in individuals with type 2 diabetes (T2DM) participating in the Diabetes‐and‐Dementia (D2) study.

Method

Ninety cognitively‐normal participants with T2DM completed neuropsychological assessments, health‐and‐lifestyle questionnaires, 24‐hour ambulatory blood pressure monitoring and a 3T‐MRI scan. FreeSurfer (version 6.0) was used to estimate total brain volume (TBV), mean cortical thickness and subcortical volumes, including the thalami and caudate nuclei. TBV was expressed as a percentage of intracranial volume. Averages between left and right volumes were calculated for subcortical structures. The sample was divided into low (n=45) and high (n=45) FRS groups based on the median score (X=39.7). Differences in volumes were compared between groups. Four cognitive domains, including visuospatial skills, verbal memory, language, and executive functions & speed of processing information, were derived using a factor analysis. These domains were used to compare cognitive performance between individuals with low and high FRS.

Result

Participants in the high FRS group were significantly older and had a lower percentage of women: age (F (1, 89)=26.6; p<0.000); sex (x2=10.07, p=0.01). The high FRS group, after correcting for age and sex, had significantly smaller TBV (F (1, 86)=60.6; p=0.023) and reduced cortical thickness (F (1, 82)=9.93; p=0.002). No difference was found in other subcortical structures. Multivariate analysis revealed a statistically significant difference in cognition between individuals with low and high FRS (F (1, 85)=4.46, p=0.003). Univariate analyses showed statistically significant differences in executive function & processing speed (F (1, 81) = 5.69; p=0.019), with the low FRS group outperforming the high FRS group.

Conclusion

High cardiovascular risk in T2DM is associated with accelerated structural brain aging, manifesting as cerebral atrophy and poorer cognitive function, particularly in processing speed and executive function.
Potential epigenetic pathways linking high mental work demands to dementia risk
Authors: Rodriguez Francisca S. , Leber Markus , Riedel‐Heller Steffi G. , Ramirez Alfredo
Published: December 2020

Background

Mental demands at work are associated with dementia risk. Recent rodent studies with enriched environments suggest that epigenetic alterations moderate such an effect. Aim of the study was to investigate in whether high mental demands at work – as a form of enriched environment – are associated with epigenetic alterations on the GRIN 2B and DNMT 3B and whether this that could explain dementia risk.

Method

A case‐control sample (n = 289) was randomly selected from the longitudinal population‐based AgeCoDe study of individuals age 75+. Associations between mental demands at work of the participants’ entire occupational history and methylation of GRIN 2B and DNMT 3B sites and dementia were analyzed using generalized linear regression and logistic regression models adjusted for age, gender, education, depression, diabetes, and smoking.

Result

Results suggested associations between the mental work demands ‘Language & Knowledge’ and ‘Information processing’ and the methylation of six GRIN 2B sites and nine DNMT 3B sites. Results indicate that dementia risk is associated with high levels in the mental work demand ‘Language & Knowledge’ together with high methylation of the sites GRIN 2B cg05885720 (OR 0.38, p = 0.011), DNMT 3B cg13681935 (OR 0.26, p = 0.001), DNMT 3B cg13636640 (OR 0.39, p = 0.013), DNMT 3B cg22605822 (OR 0.46, p = 0.049), and a low methylation of DNMT 3B cg09835408 (OR 0.38, p = 0.017). Dementia risk was also associated with high levels in the mental work demand ‘Information Processing’ together with high methylation of the sites GRIN 2B cg05885720 (OR 0.37, p = 0.012), GRIN 2B cg14409083 (OR 0.33, p = 0.006), GRIN 2B cg03777288 (OR 0.39, p = 0.020), DNMT 3B cg22605822 (OR 0.35, p = 0.012), DNMT 3B cg13636640 (OR 0.43, p = 0.029), DNMT 3B cg08240466 (OR 0.39, p = 0.017) and low methylation of DNMT 3B cg09835408 (OR 0.36, p = 0.013).

Conclusion

If what the findings suggest is true, then the protective effect of high mental demands at work against dementia is dependent on epigenetic alterations. However, our study is a first attempt to identify potential effect sizes between mental demands at work and DNA methylation on dementia risk long after retirement. Further studies with larger sample sizes need to be designed to gain a better understanding of the underlying associations.
Risk for disorientation: Longitudinal evidence from three old‐age cohorts in Germany (AgeDifferent.de)
Authors: Rodriguez Francisca S , Pabst Alexander , Heser Kathrin , Kleineidam Luca , Hajek Andre , Eisele Marion , Roehr Susanne , Loebner Margrit , Wiese Birgitt , Angermeyer Matthias C. , Maier Wolfgang , Scherer Martin , Wagner Michael , König Hans‐Helmut , Riedel‐Heller Steffi G.
Published: December 2020

Background

Only little evidence is available on disorientation, one of the most challenging symptoms of Alzheimer’s disease and related dementias (ADRD). Aim of this study was to investigate the occurrence of disorientation in association with the level of cognitive functioning, personal characteristics, and specific life events.

Method

Three population‐based longitudinal cohort studies on cognitive health of elderly adults in Germany were harmonized (AgeDifferent.de platform: LEILA 75+, AgeCoDe/AgeQualiDe, AgeMooDe). Data on cognition, personal characteristics, and life events were collected in standardized interviews and questionnaires with the participant, a proxy informant, and the participant’s general practitioner. Participants who completed the cognitive assessments at follow‐up and who did not have stroke, Parkinson’s, atherosclerosis, kidney infection/disease, and/or alcoholism were included in the analysis (n=2135).

Result

Older age, a lower MMSE score (without the disorientation items), impairments in walking and being divorced or widowed came with a greater likelihood of having disorientation. Incident disorientation over the study period was predicted by older age, a lower MMSE score (without the disorientation items) and living in a nursing home. Of the life events that we investigated, only the event ‘moving’ was significantly associated with a greater likelihood of incident disorientation. Subgroub analyses for dementia patients emphasize the relevance of certain cognitive deficits.

Conclusion

Clinicians and health care workers should be aware that elderly people with decreased cognitive functioning who have difficulties walking, disrupted family relationships, and are in the process of moving to a new home are more likely to experience disorientation. More research is needed to identify specific situations that trigger disorientation at certain stages of dementia.
‘No, I don't know where that is. All I know is my room.’: Topographical disorientation and user‐centred requirements for in‐hospital navigation aids of people with dementia and their caregivers
Authors: Kowe Antonia , Goerss Doreen , Teipel Stefan J.
Published: December 2020

Background

Hospitals are complex buildings in which the risk of disorientation is high with negative consequences on financial and staff resources due to missed appointments and increased need of support. Existing indoor navigation aids, such as accompanying services, spatial design or technical assistance, often miss the intended users’ needs. Based on the value sensitive design approach, this study asked people with dementia (PwD) and their caregivers about the requirements in‐hospital navigation aids should fulfil for them to be considered useful.

Method

We conducted semi‐structured interviews with two stakeholder groups of stationary dementia care: PwD (n = 10, agemean = 83,9 years) and informal caregivers (n = 5, agemean = 73,8 years). In the interviews, we asked for previous experiences including barriers for the use of existing navigation aids. We analysed underlying values and requirements for improved technologies. The interviews were evaluated using qualitative content analysis according to Mayring.

Result

Accompanying services by hospital staff or relatives were considered by respondents to be the most helpful support for in‐hospital orientation. Barriers for the use of existing in‐hospital navigation aids are their low visibility and lacking need of usage due to restricted mobility of in‐patients with dementia. Interestingly, some PwD are willing to use technical assistance for navigation support although their digital competencies are considered to be very low by caregivers. For both stakeholder groups, trust is an important value in technical devices for navigation. PwD highlighted independence as further important value while caregivers prioritized safety. Both respondents groups wanted a device that could be worn on the body and that gave simple instructions for finding rooms via visual or acoustic signals.

Conclusion

PwD and caregivers can specify needs for in‐hospital navigation aids and their requirements differ only slightly due to varying values. User‐centred design potentially helps to improve emerging technologies for patient‐centred stationary care.
Alzheimer's disease phenotypes misdiagnosed with frontotemporal lobar degeneration: A retrospective neuropathologic study
Authors: Lecerf Simon , Leroy Melanie , Lebouvier Thibaud , Lebert Florence , Deramecourt Vincent , Maurage Claude Alain , Pasquier Florence
Published: December 2020

Background

Alzheimer's disease (AD) is a heterogeneous illness, with a common clinical presentation of progressive amnesia and less common « atypical » presentations which may be misdiagnosed with a pathology of the frontotemporal lobar degeneration (FTLD) spectrum. This study sought to characterize which phenotypes of AD are difficult to distinguish from FTLD.

Method

Among the patients followed in the Lille Memory Clinic (France) between 1993 and 2018 and having a neuropathologic diagnosis of AD, the clinical phenotypes of those for whom there was a diagnostic hesitation between AD and FTLD (« doubt group », n = 13) were compared with the clinical phenotypes of those for whom there was no hesitation in diagnosing AD (« no doubt group », n = 40).

Result

A primary progressive aphasia (PPA) phenotype and a corticobasal syndrome (CBS) phenotype are most likely to be found in the « doubt group » (PPA n = 8/13, 62,5% ; CBS n = 2/13, 15,4%) than in the « no doubt group » (PPA n = 1/40, 2,5% ; CBS n = 0/40, 0%). In this study, no patient with confirmed AD fulfilled precociously the Rascovsky criteria for possible behavioural variant of frontotemporal dementia (bvFTD).

Conclusion

As reported, PPA and CBS phenotypes are syndromes that can be observed in AD as in FTLD. Frontal variant of AD seems very uncommon.
EEG: A valuable tool to screen for neurodegeneration in preclinical Alzheimer’s disease
Authors: Gaubert Sinead , Raimondo Federico , Houot Marion , Corsi Marie‐Constance , Naccache Lionel , Sitt Jacobo Diego , Hermann Bertrand , Oudiette Delphine , Gagliardi Geoffroy Pierre , Habert Marie‐Odile , Dubois Bruno , Fallani Fabrizio De Vico , Bakardjian Hovagim , Epelbaum Stéphane ,   the Alzheimer’s Disease Neuroimaging Initiative, the MEMENTO study group and the INSIGHT‐preAD study group
Published: December 2020

Background

Early biomarkers are needed to identify individuals at high risk of preclinical Alzheimer’s disease (AD) (Jack et al., 2018). Electroencephalography (EEG) is a non‐invasive and cheap technique that would be an interesting screening tool for the preclinical stage of AD.

Method

We included participants from the INSIGHT‐preAD cohort, which is an ongoing single‐center multimodal observational study designed to identify risk factors and markers of progression to clinical AD in 318 cognitively normal individuals aged 70–85 years with a subjective memory complaint (Dubois et al., 2018). We divided the subjects into four groups, according to their amyloid status (on 18F‐florbetapir PET) and neurodegeneration status (on ¹⁸F‐fluorodeoxyglucose PET). We analysed 314 baseline 256‐channel high‐density eyes‐closed 1‐minute resting‐state EEG recordings. We extracted 10 quantitative EEG biomarkers, including spectral measures, algorithmic complexity and functional connectivity metrics. We evaluated three different classifiers (random forest, decision tree and logistic regression) to predict amyloid and neurodegeneration status from multimodal data, combining EEG, ApoE4 genotype, demographic, neuropsychological and MRI data. We divided the dataset into a training set (n=258) and validation set (n=46). We used a 5‐fold cross‐validation on the training set to identify the optimal combination of features.

Result

As recently published (Gaubert et al., 2019), the most prominent effects of neurodegeneration on EEG metrics were localized in fronto‐central regions with an increase in high‐frequency oscillations (higher beta and gamma power) and a decrease in low‐frequency oscillations (lower delta power), higher spectral entropy, higher complexity and increased functional connectivity measured by weighted Symbolic Mutual Information in theta band. In the machine learning analysis, among the different features, EEG was the most strongly predictive of neurodegeneration. Similar predictive performance was obtained when reducing the number of electrodes from 256 to 8. EEG biomarkers combined with hippocampal volumetry had a high negative predictive value (91%) and high sensitivity (82%) to predict neurodegeneration. The combination of ApoE4 genotype with demographic data was most strongly predictive of amyloid status.

Conclusion

EEG could be a valuable tool to screen for or rule out neurodegeneration in elderly memory complainers. This procedure has been patented under the following PCT number: PCT/EP2019/086629.
Interaction of neuropsychiatric symptoms with APOE e4 and conversion to dementia in MCI patients in a memory clinic
Authors: Valero Sergi , Marquie Marta , Rojas Itziar , Moreno Sonia , Espinosa Ana , Orellana Adelina , Montrreal Laura , Hernandez Isabel , Mauleon Ana , Rosende‐Roca Maitee , Alegret Montserrat , Pérez‐Cordón Alba , Ortega Gemma , Roberto Natalia , Sanabria Angela , Abdelnour Carla , Gil Silvia , Tartari Juan Pablo , Vargas Liliana , Antonio Ester Esteban‐De , Benaque Alba , Tarraga Lluis , Boada Mercè , Ruiz Agustín
Published: December 2020

Background

To the date, scarce studies have been focused in the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE e4 on conversion to dementia in Mild Cognitive Impaired patients (MCI). None of them taking into account clinical settings of MCI patients. The objective was to determine the predictive value of additive and multiplicative interactions of NPS and APOE e4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic.

Method

1512 patients (aged 60 and older) with prevalent MCI have been followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated, and several clinical variables were used as an adjusting factors, including the memory impairment condition, the attributed etiological pattern, and the antidepressant and anxiolytic medication used.

Result

Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, increasing significantly the hazard ratios of incident dementia (HR range 1.3 – 2.03).

Conclusion

Synergistic interactions between NPS and APOE e4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.
Uncovering superficial white matter changes in young‐onset Alzheimer’s disease
Authors: Veale Thomas , Malone Ian B , Poole Teresa , Parker Thomas D , Slattery Catherine F , Schott Jonathan M , Zhang Hui , Fox Nick C , Cash David M
Published: December 2020

Background

Superficial white matter (SWM), subjacent to the cortex, has unique vulnerabilities to Alzheimer’s disease (AD) but is understudied. The organisational complexity of SWM means conventional diffusion tensor imaging (DTI) has difficulty characterising both the degeneration and dispersion of fibres. We used both DTI and Neurite Orientation Dispersion and Density Imaging (NODDI) to assess AD‐related SWM changes while accounting for fibre density and dispersion.

Method

51 participants were included: 22 healthy controls (mean age 61 (+/‐6) years) and 29 individuals with young onset AD (YOAD: mean age 62 (+/‐5) years; 18 with typical AD, 11 posterior cortical atrophy). We used single‐shell (b=1000) and multi‐shell (b=300; b=700; b=2000) diffusion MRI (dMRI) data. Preprocessing involved correcting for eddy currents, motion and susceptibility artefacts followed by fitting DTI and NODDI models. DTI and NODDI metrics were sampled across the GM/WM FreeSurfer surface in 15 cortical regions of interest (ROI) (Figure 1). Linear mixed effect models of fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI) and orientation dispersion index (ODI) were fit for each ROI while controlling for cortical thickness (correcting for multiple comparisons using False Discovery Rate of 0.05). Average Marginal Effects (AMEs) representing the change in YOAD versus controls, while holding other fixed effects constant, were calculated.

Result

In the GM, widespread significant differences were observed in both DTI and NODDI metrics (pFDR < 0.05) (Figure 2). In the SWM, YOAD patients had lower FA and/or changes in MD in five ROIs (pFDR < 0.05) (including parahippocampal gyrus and superior temporal cortex). NODDI metrics showed more widespread differences in the SWM, as the YOAD group had lower NDI and/or higher ODI across ten ROIs (pFDR < 0.05) (including parahippocampal gyrus and inferior parietal cortex).

Conclusion

Diffusion imaging can detect microstructural changes occurring within the SWM of YOAD individuals in regions associated with AD‐pathology. These changes in SWM not only persist, but are more prominent, when independently accounting for the density and dispersion of fibres using NODDI. These novel NODDI SWM measures may uncover previously under‐recognised degeneration and organisational WM alterations in AD.
A randomized controlled trial to evaluate the effectiveness and cost‐effectiveness of the FindMyApps intervention for improving self‐management and social participation of community‐dwelling people with dementia, compared to normal tablet use
Authors: Neal David Peter , Kerkhof Yvonne JF , Ettema Teake P , Muller Majon , Bosmans Judith , Finnema Evelyn , Graff Maud , Tanja‐Dijkstra Karin , Stek Max L , Droes Rose‐Marie
Published: December 2020

Background

For the rising number of people living with dementia, cost‐effective community‐based interventions to support psychosocial care are needed. The FindMyApps program helps people with dementia and their caregivers learn to use tablet computers and find user‐friendly apps that facilitate self‐management and engagement in meaningful activities. This definitive trial builds on previous feasibility pilot trials of FindMyApps and further evaluates cost‐effectiveness.

Method

This is a protocol for a non‐blinded randomized controlled trial (RCT) with two arms (intervention and usual care). 150 dyads (person with dementia and their carer) will be recruited. Participants must be resident in the community, with a diagnosis of Mild Cognitive Impairment or mild dementia (Mini Mental‐State Examination 17‐26, or Global Deterioration Scale 3‐4. Dyads will be randomly assigned in equal proportions to receive either the FindMyApps intervention (experimental arm) or usual care (control arm). Primary outcomes measured at 3 months will be: self‐management and social participation of the person with dementia; caregiver sense of competence. Data will be collected through questionnaires, filled in by the researcher or participants themselves. In addition to a main effect analysis, a cost‐effectiveness analysis will take place. In line with Medical Research Council (MRC) guidance for the evaluation of complex interventions, a process analysis will be undertaken, to identify factors that may influence trial outcomes. Semi‐structured interviews and remotely collected data regarding use of the FindMyApps app will support the process analysis.

Result

Results of this study are expected in 2022. The study will be adequately powered to detect at least a moderate effect size of the intervention with respect to the primary outcomes.

Conclusion

This study will investigate the effectiveness and cost‐effectiveness of the FindMyApps intervention. The results of the study will provide strong evidence to support or oppose scaling up implementation of the intervention. This is also an example of how the MRC framework for the evaluation of complex interventions can be implemented in practice. In a field which is often criticized for a lack of high quality evidence, randomized controlled trials should be applied more frequently designed for the robust and transparent evaluation of digital tools and technologies.
Highly palatable diet changes brain glucose metabolism in mice
Authors: Gehres Sarah Wehle , da Rocha Andreia Silva , Rodrigues Yuri Elias , Peixoto Guilherme G Schu , Carvalho Afonso Kopczynski , Carteri Randhall K , Venturin Gianina Teribele , Greggio Samuel , Costa daCosta Jaderson , Leonardi Bianca F , Zimmer Aline R , Souza Diogo O , Portela Luis V , Zimmer Eduardo R
Published: December 2020

Background

Obesity has become a global public health issue and is knowingly associated with several pathological conditions. Epidemiological data indicate it is an important risk factor for the development of neurodegenerative diseases, such as Alzheimer’s Disease (AD). However, the pathological mechanisms connecting these two conditions are still elusive. Current evidence points toward glucose metabolism dysregulation, as well as defective insulin signaling and low grade inflammation. Objective: Our main goal was to investigate the effects of a highly palatable diet (HPD) on brain glucose metabolism. Hypothesis: We hypothesized that the obesity induced by the HPD could lead to alterations in brain glucose metabolism similar to those found in AD.

Methods

Male C57BL/6J mice (45 days old) were fed with HPD (rich in simple sugars and fat) for four months. They were then examined in vivo via microPET [18F]FDG. Data from images were used to assemble [18F]FDG‐derived brain metabolic networks. A glucose tolerance test (GTT) was also performed to assess peripheral insulin response. Post‐mortem, the brain tissue was used in a high resolution respirometry test to evaluate mitochondrial activity.

Results

HPD animals presented increased body weight (HPD= 37.17±4.38g; control= 28.72±1.23g; P<0.0001) and abnormal peripheral tolerance to glucose (peak blood glucose: HPD=421.93±47.13mg/dL; control=323.60±43.83mg/dL P<0.0001). HPD also induced [18F]FDG hypermetabolism in the prefrontal cortex and a hypersynchronicity in the metabolic network, where the hypothalamus appears to be more connected to the hippocampus, thalamus, prefrontal cortex, and striatum. Brain post mortem analysis indicated a less efficient mitochondrial oxidative phosphorylation in the hypothalamus of HPD fed animals as measured by the Respiratory Chain Ratio (HPD=0.640±0.022; control= 0.810±0.012 P<0.001).

Conclusion

These preliminary results show that HPD causes peripheral and central disturbances in glucose metabolism, also altering brain mitochondrial activity. Interestingly, in vivo imaging indicates that the prefrontal cortex is highly active and the hypothalamus is unusually connected to other brain regions in these animals.
Decrease in olfactory cortex volume and alterations in caspase expression in the olfactory bulb in the pathogenesis of Alzheimer’s disease
Authors: Alotaibi Majed , Lessard‐Beaudoin Mélissa , Loudghi Amel , Chouinard‐Watkins Raphaël , Plourde Melanie , Calon Frederic , Castellano Christian‐Alexandre , Cunnane Stephen , Gaudreau Pierrette , Graham Rona
Published: December 2020

Background

Alzheimer disease (AD) is a chronic disorder that affects millions of individuals worldwide. Symptoms include memory dysfunction, and also alterations in attention, planning, language and overall cognitive function. Olfactory dysfunction is a common symptom of several neurological disorders including AD. Studying the mechanisms underlying the olfactory dysfunction may therefore lead to the discovery of potential biomarkers and/or treatments for neurodegenerative diseases.

Method

For the human study, quantitative olfactory tests (UPSIT and OMT) have been done on 93 subjects from the Quebec Longitudinal Study on Nutrition and Successful Aging cohort accepting to participate in the ORCA secondary study. The telephone Modified Mini Mental State examination (t‐MMSE) was used to assess cognition levels, and an olfactory self‐report was also collected. In a separate cohort, olfactory cortical volume was calculated using MRI results from healthy old adults (n=25) and patients with AD (n=14) using the AAL single‐subject atlas and performed with the PNEURO tool.

Result

Human Study: Based on the self‐report, 81% of the participants claimed to not suffer from any problem with olfaction. However, based on the UPSIT, 94% of those subjects showed a poor olfactory performance and different forms of microsmia. Moreover, our results confirm that olfactory function declines with age. We also detected a significant decrease in olfactory cortical volume in AD individuals compared to controls. Murine study: Preliminary data demonstrate there is a significant decrease in expression levels of the proform of caspase‐3 and the caspase substrate STK3, in the olfactory bulb of mice expressing human APOE4 compared with controls. The data also suggest that Iba‐1 immunostaining is increased in the olfactory bulb of APOE4 mice compared to wild type mice.

Conclusion

The activation of caspase‐3 may be the cause of the decreased levels of STK3 through caspase cleavage and may play a role in the inflammation observed. In the clinical study, our results suggest that seniors are unaware of their olfactory function status and therefore it is not sufficient to measure olfaction using the self‐report in the elderly. Studying olfactory function in the aging population will help to discover biomarkers in the early stage of the AD.
The impact of green care farms and other innovative nursing home models on BPSD symptoms in everyday life for people with dementia
Authors: Verbeek Hilde , De Boer Bram , Zwakhalen Sandra , Hamers Jan
Published: December 2020

Background

Many countries are introducing small‐scale, home‐like care facilities that represent a radically new approach to nursing home care for people with dementia. These facilities emphasize person‐centered care, focus on remaining strengths and value autonomy. Originated outside of the healthcare sector, green care farms (GCFs) are a new type of nursing home in the Netherlands. GCFs provide care in small‐scale, homelike environment, in which agricultural activities are combined with care and support services for a variety of client groups, including people with dementia. This study investigated effect of GCFs on residents, in particular on behavioral and psychological symptoms.

Method

In total, 115 residents with a formal diagnosis of dementia were included, living at GCFs (n=34), regular small‐scale living facilities (n=52) and traditional nursing homes (n=29). Residents were matched regarding cognitive status (S‐MMSE). Ecological momentary assessments (n=16,860) were conducted using the Maastricht Electronic Daily Life Observation Tool, assessing activity engagement, social interaction and emotional well‐being. Furthermore, neuropsychiatric symptoms (NPI‐NH), agitation (CMAI), depressive symptoms (CSDD), quality of life (Qol‐AD and QUALIDEM) and social engagement (RISE) were measured.

Result

The daily life of residents living at GCFs was significantly different compared with traditional nursing homes. Residents were significantly more active (p<0.05, SE=0.9) and socially engaged (p<0.05) at GCFs compared with traditional nursing home wards. Furthermore, residents living at GCFs scored significantly higher on the Qol‐AD (p<0.05, ES=0.8) and on three domains of the Qualidem: positive affect, social relations and having something to do (p<0.05, ES>0.7) compared with traditional nursing homes. No significant differences were found regarding neuropsychiatric symptoms (mean NPI‐NH score 15.4), agitation (mean CMAI score 41.9) and depressive symptoms (mean CSDD score 5.4).

Conclusion

This study showed that GCFs provide an attractive, homelike environment and activities that positively influence engagement and social interaction. GCFs appear to be a valuable alternative to existing nursing homes. This is important as people with dementia are a heterogeneous group with varying needs. In order to provide tailored care there also is a need for a variety of living environments.
Continuous palliative sedation in nursing home residents with dementia suffering from extreme refractory BPSD symptoms: A qualitative study
Authors: Koopmans Raymond , Veldwijk‐Rouwenhorst Annelies , Smalbrugge Martin , Zuidema Sytse U , Hanssen Suzan , Gerritsen Debby L
Published: December 2020

Background

BPSD are highly prevalent in nursing home (NH) residents with dementia. Sometimes these BPSD are very severe or even extreme resulting in the application of continuous palliative sedation (CPS) CPS is defined as “the deliberate lowering of a patient’s level of consciousness in the last stages of life”. The aim of this study was to explore the trajectory leading to CPS and its application NH‐residents with dementia and case of so called ‘refractory BPSD’.

Method

A qualitative interview study on dementia special care units of three NHs in the Netherlands was performed in 2017. Relatives, elderly care physicians and other staff members involved with three NH‐residents with dementia and extreme refractory NPS who received CPS. We used consecutive sampling to select participants. Medical files were studied. Semi‐structured interviews were conducted. Transcriptions were analyzed with thematic analysis, including directed content analysis.

Result

Nine in‐depth interviews with fourteen participants were held. Analysis resulted in five main themes with several subthemes reflecting phases of the trajectory leading to CPS and the CPS application itself, a sixth main theme concerned evaluations thereof. According to the first theme (run‐up), the suffering of the NH‐resident was described as unbearable/an inner struggle. Participants still had hope for improvement. Concerning the second theme (turning point), hope was lost, participants were convinced they had tried everything and experienced feelings of powerlessness and failure. Regarding theme three (considering CPS), intermittent sedation was applied in all three cases and peer consultation was employed. Honoring the wish of the NH‐resident and therapeutic uncertainties, among others, were important subthemes. According to theme four (decision to start CPS), in each case one specific aspect was a decisive trigger for administering CPS. Concerning theme five (applying CPS) feelings of relief were experienced after starting with CPS.

Conclusion

The trajectory leading up to CPS in NH‐residents with dementia and extreme refractory BPSD was complex and burdensome, but the application led to relief and contentment of all those involved. We recommend to include external consultation in the decision process and to apply intermittent sedation as a preceding step when CPS is considered.
Effectiveness of Reducing Disability in Alzheimer’s Disease among dementia patients and their family caregiver
Authors: Perales Jaime , Barton Kelli , Ptomey Lauren , Niedens Michelle , Vidoni Eric D
Published: December 2020

Background

Dementia impacts the mental health of individual‐caregiver dyads. Interventions such as Reducing Disability in Alzheimer’s Disease (RDAD) improve dyad mental health, but to implement it locally community agencies in Kansas City suggested three changes: 1) reduced reliance on licensed social workers, 2) centralized exercise interventionists and 3) more flexible delivery. We aimed to assess the effectiveness of the Kansas City RDAD implementation (RDAD‐KC), which addressed these three gaps. We hypothesized that dyads’ mental health would improve from baseline to the end of the intervention.

Method

This is a secondary‐analysis of an in‐home dementia support services quality improvement project amongst a collaborative of nine community agencies in the Kansas City region. Agencies administered RDAD‐KC to a non‐probabilistic sample of dyads they recruited in their service areas. Eligibility criteria included living in the community, having moderate dementia, with enough home space to exercise, ability to walk across the room with or without assistive devices and no physical activity restrictions. The original RDAD is a 12‐module dyad home‐based multicomponent intervention that focuses on exercise for people with dementia and coping with behavioral symptoms for caregivers. RDAD‐KC 1) allowed non‐licensed interventionists, 2) included exercise videos and contact of a centralized exercise team and 3) allowed fitting the intervention delivery to the dyads’ situation, needs, and time available. Data analyses included paired samples t‐tests. Final data analysis included those who had a family caregiver, no intellectual disability and completed nine of the 12 modules.

Result

Among the 157 screened dyads, 66 completed ≥9 modules. People with dementia were 77.4 years in average, 72.9% identified as White, 19.7% as Black, 17.0% rural and 71.2% had their partners as caregivers. All outcomes improved statistically (p<0.01) from pre to post‐intervention: Behavioral symptom severity (range 0‐36) decreased from 11.3 to 8.6, caregiver unmet needs (range 0‐34) decreased from 10.6 to 5.6, caregiver behavioral symptom distress (0‐60) decreased from 15.5 to 10.4 and caregiver strain (0‐26) decreased from 11.1 to 9.7.

Conclusion

A more flexible implementation of RDAD leads to clinically meaningful improvement of mental health outcomes among dyads. RDAD‐KC might inform the scaling‐up of RDAD in the region.
Higher TREM2 levels and microglia activation associated with slower rates of amyloid PET increase in humans and a transgenic mouse model of beta‐amyloid
Authors: Ewers Michael , Franzmeier Nicolai , Brendel Matthias , Suarez‐Calvet Mark , Biechele Gloria , Sacher Christian , Blume Tanja , Haass Christian ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Loss‐of‐function mutations in the TREM2 gene, a key receptor molecule on microglia, are associated with a 2 – 3 fold increase in the risk of Alzheimer’s disease (AD). Biomarker‐levels of soluble TREM2 (sTREM2) are increased in AD and associated with slower cognitive decline, suggesting a protective role of sTREM2‐related microglia activity (Suarez Calvet et al. Science Trans Med, 2016; Ewers et al. Science Trans Med., 2019). However, whether microglia activity reduces the future accumulation of core AD‐pathology remains unclear. Here we 1) tested in elderly subjects whether higher cerebrospinal fluid (CSF) levels of sTREM2 are associated with slower longitudinal rates of global amyloid‐PET accumulation, and 2) in a transgenic mouse model of Ab, whether higher baseline microglia‐PET is associated with slower rates of amyloid‐PET accumulation.

Method

206 Ab‐positive participants (global 18F‐AV‐45‐PET SUVR > 0.79, Landau et al. 2015) comprising 55 cognitively normal, 136 amnestic mild cognitive impairment and 15 AD dementia participants, and in addition, 94 Ab‐negative CN were included from ADNI. CSF sTREM2 and 18F‐AV‐45 PET were measured at baseline, and 18F ‐AV‐45 PET was repeated during follow‐up (mean = 2 years, range = 1.71‐6.1 years). 15 APPNL‐G‐F transgenic mice and 43 age‐ and gender matched C57BL/6 control mice were assessed with 18F‐GE180 TSPO‐PET at age 5 months and 18F‐AV‐45 PET at ages 5 and 10 months.

Result

In linear mixed effects analysis across all participants, the rate of change in amyloid PET showed a quadratic curve as a function of baseline amyloid‐PET levels, peaking at SUVR = 0.95 (Fig. 1A). Baseline levels of CSF sTREM2 modulated the rate of change in amyloid‐PET, such that at higher CSF sTREM2, the rate of subsequent increase in amyloid‐PET was reduced, controlled for demographics, diagnosis, CSF p‐tau181, and ApoE e4 (Figure 1B). In the AppNL‐G‐F
mice, higher microglia‐PET at baseline was associated with slower rate of increase in global amyloid‐PET increase, controlled for baseline amyloid‐PET (Figure 2).

Conclusion

Across humans and mice, higher microglia activation as measured by CSF sTREM2 or microglia PET showed protective effects on subsequent amyloid accumulation, supporting the critical role of microglia activation in the development of AD.
Innate immune activation of the NLRP3 inflammasome pathway drives tau pathology
Authors: Ising Christina , Venegas Carmen , Zhang Shuangshuang , Scheiblich Hannah , Schmidt Susanne V. , Vieira‐Saecker Ana , Schwartz Stephanie , Albasset Shadi , McManus Roisin M. , Tejera Dario , Griep Angelika , Santarelli Francesco , Brosseron Frederic , Opitz Sabine , Stunden James , Kayed Rakez , Golenbock Douglas T. , Blum David , Latz Eicke , Buee Luc , Heneka Michael T.
Published: December 2020

Background

Alzheimer’s disease is characterized by the extracellular accumulation of amyloid beta (Aß), intraneuronal formation of neurofibrillary tangles made of hyperphosphorylated tau and activated microglial cells, the innate immune cells of the brain. Activation of microglia by Aß or other DAMPs results in the assembly of the NLRP3 inflammasome consisting of NLRP3, ASC and Caspase‐1. This leads to subsequent production and secretion of inflammatory mediators including IL‐1β and ASC specks. Here, we investigate a contribution of the NLRP3 inflammasome to the development and progression of tau pathology.

Method

Tau22 transgenic mice, that express human 4‐repeat tau mutated at sites G272V and P301S under a Thy1.2‐promotor, were crossed into either NLRP3 inflammasome knockout or ASC knockout mice and analyzed before development of tau pathology (3 month of age) and when robust tau pathology is present (11 month of age). Animals underwent behavioral phenotyping, analysis of pathology as well as assessement of microglial activation. Additionally, Tau22/NLRP3‐knockout and Tau22/ASC‐knockout mice received an injection of Aß‐containing APP/PS1 mouse brain derived lysates to study Aß‐induced spreading of tau pathology. For in vitro studies, primary mouse microglia were treated with different forms of tau and analyzed for NLRP3 inflammasome activation.

Result

NLRP3 inflammasome activation was increased in fronto‐temporal dementia patients as well as in Tau22 mice. Knockout of ASC or NLRP3 in Tau22 mice decreased levels of active tau kinases while increasing activity of phosphatase PP2A in the hippocampus. This strongly protected from accumulation of hyperphosphorylated, misfolded tau in ASC knockout and more robustly in NLRP3 knockout mice while attenuating behavioral deficits. Furthermore, loss of NLRP3 inflammasome function ameliorated Aß‐induced tau pathology. In vitro, treatment of microglia with tau‐containing mouse brain homogenates or recombinant tau monomers and oligomers resulted in IL‐1β release in a NLRP3‐dependet manner, most likely mediated via TLR4. However, the same concentration of recombinant tau fibrils did not evoke this response.

Conclusion

These findings are in line with the hypothesis that innate immune activation represents an important pathogenic factor for tau pathology. In Alzheimer’s disease, early Aß deposition may cause subsequent tau pathology and neuronal demise through NLRP3‐mediated innate immune pathways.