bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneity in longitudinal deterioration of white matter microstructural integrity in the population and its implications for cognitive aging
Authors: Poulakis Konstantinos , Reid Robert I. , Przybelski Scott A. , Knopman David S. , Graff‐Radford Jonathan , Lowe Val J. , Mielke Michelle M. , Machulda Mary M. , Jack Clifford R. , Petersen Ronald C. , Westman Eric , Vemuri Prashanthi
Published: December 2020

Background

White matter (WM) changes are widely seen in the elderly due to aging and pathological processes and have significant impact on cognitive aging. It is critical to understand the heterogeneity and drivers (causes) of the longitudinal deterioration of WM microstructural integrity, especially in a population‐based sample, to provide mechanistic insights into cognitive and brain aging.

Method

Leveraging longitudinal diffusion tensor imaging (DTI) data from Mayo Clinic Study of Aging, we assessed whether individuals clustered based on distinct longitudinal fractional anisotropy (FA) trajectories. A total of 533 subjects (487 cognitively unimpaired, 62 with mild cognitive impairment and 4 with dementia diagnosis) aged ≥ 60 years and with at least two DTI scans (125 subjects had at least 3 scans) were included. To identify clusters of individuals with common FA profiles over time, we applied an in‐house longitudinal Bayesian mixed‐effects clustering analysis framework to the imaging data. Age at MRI accounted for the longitudinal component of the model, while sex and APOE4 carrier status were used as fixed effects.

Result

We identified four distinct clusters (Figure 1). We found that most WM tracts decline with age across all clusters but brainstem and association fibers were least likely to decline with aging. APOE4 carriership and amyloid deposition did not differ between the clusters. We found a resilient cluster of individuals (34%) (cluster 1) with better baseline WM and systemic vascular health who had a slower rate of cognitive and WM integrity decline over time. These individuals had highest baseline commissural and association fibers. The resilient group was in contrast to an “at risk” cluster of individuals (16%) (cluster 2) who had lower baseline WM integrity and systemic health and declined the fastest in both WM health and cognition over time

Conclusion

Longitudinal clustering of WM tracts provided insights into the differential aging of WM in the population which may be unrelated to Alzheimer’s disease pathophysiology. Measuring overall WM health and vulnerable tracts in the elderly can be useful as biomarkers and aid in the identification of “at risk” groups for prevention of future cognitive decline.
APOE‐ε4 and hippocampal volume in the cognitively healthy elderly: Longitudinal analysis reveals origins of apparent cross‐sectional differences
Authors: Zhang Linda , Duenas Eva , Long Christopher , Navas Susana , Calero Miguel , Medina Miguel , Strange Bryan A
Published: December 2020

Background

The Apolipoprotein Ε (APOE) ε4 allele is associated with increased susceptibility to Alzheimer’s disease (AD), but its effects on cognition and brain morphology in cognitively normal (CN) elderly are unclear. Using cross‐sectional and longitudinal data, this study aims to determine whether CN elderly adults with the APOE ε3/ε4 genotype show any differences in cognitive performance and neuroimaging measures.

Method

788 CN elderly men and women (aged 69‐86) were selected from the baseline visit of the Vallecas Project cohort based on genotype (APOE ε3/ε3 (n=648), ε3/ε4 (n=140)). Of these 788 subjects, 230 (aged 69‐75 at baseline; APOE ε3/ε3 (n=192), ε3/ε4 (n=38)) stayed in the project for at least 5 years, and were selected for longitudinal analysis. All participants underwent detailed neuropsychological and neurological evaluation, and MRI scanning at 3T. Neuropsychological test scores and neuroimaging measures (grey matter density, white matter diffusivity, global brain and hippocampal volumes (HV)) were analysed.

Result

From the cross‐sectional analyses, there was a significant genotype‐by‐age interaction in right HV (F (1, 781)=6.06, p=0.014), with ε3/ε3 homozygotes displaying significantly larger volumes before age 75, but similar sized volumes to ε3/ε4 genotypes after age 75 (Fig. 1). However, for the longitudinal subgroup, neither baseline right HV nor its rate of atrophy over 5 years was significantly different between the two genotypes (Fig. 2). A significant genotype‐by‐number of visits interaction (F (1, 433)=6.18, p=0.013) in baseline right HV was found (Fig. 3). Comparison of neuropsychological test scores and other neuroimaging measures did not reveal any significant effects.

Conclusion

We conclude that elderly subjects with APOE ε3/ε4 genotype who stay cognitively normal throughout a 5‐year study duration are not cognitively nor morphologically distinct from those with APOE ε3/ε3 genotype, most likely due to a survival effect.
Computerized decision support to select memory clinic patients for amyloid PET: Which patient to test?
Authors: Rhodius‐Meester Hanneke FM , van Maurik Ingrid S. , Koikkalainen Juha , Tolonen Antti , Frederiksen Kristian Steen , Hasselbalch Steen Gregers , Soininen Hilkka , Herukka Sanna‐Kaisa , Remes Anne , Barkhof Frederik , Van Berckel Bart N.M. , Scheltens Philip , Lötjönen Jyrki , van Der Flier Wiesje ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

The current diagnostic criteria allow the use of amyloid biomarkers (either CSF or PET) to provide pathophysiological support for the diagnosis of AD. How these criteria should be operationalized by clinicians is unclear. We previously developed a model to select patients in which CSF measurements have added value [1]. Now, we study whether the model can also be used to select patients for amyloid PET.

Method

We included 348 subjects (223 controls, 125 Alzheimer’s disease dementia) from ADNI2, with available neuropsychology, MRI and Florbetapir PET. Positive (AD like) and negative (normal) amyloid PET were simulated to estimate whether knowledge of amyloid status would impact (confidence in) diagnosis. These simulated markers were added to available demographic, neuropsychology and MRI data in each patient to see whether the diagnostic confidence increased. If the confidence exceeded a predefined cut‐off (probability of correct class (PCC)≥0.80), then the patient was selected for amyloid PET (computerized decision support approach). We compared this approach with proportion of PET scans and patients diagnosed with sufficient confidence (PCC ≥0.80) based on an algorithm without amyloid PET (only neuropsychology and MRI), and amyloid PET for all patients (see Figure 1).

Result

The computerized decision support approach recommended amyloid PET in 11%, which yielded a diagnosis with sufficient confidence in 75% of all patients. This approach was most efficient when compared to amyloid PET in none (0% amyloid, 71% diagnosed), or amyloid PET for all (100% amyloid, 71% diagnosed). Results were comparable for CSF instead of amyloid PET.

Conclusion

The previous developed computerized decision support approach showed favorable results in selecting patients for amyloid PET testing. In this clear‐cut comparison between controls and AD, amyloid PET adds little over clinical measures – but a similar framework may help to support decision making in more realistic and challenging clinical situations. Expansion of this study is needed with a real life cohort consisting of patients with different types of dementia. In this way, the approach can support clinicians in making a balanced decision in ordering additional biomarker testing. Reference: (1) Rhodius‐Meester HFM et al. Selection of memory clinic patients for CSF, PLoS One. 2020;15(1).
Survival differences in ethnic minorities with dementia: A systematic review and meta‐analysis
Authors: Co Melissa , Couch Elyse , Gao Qian , Martinez Andrea , Das‐Munshi Jayati , Prina Matthew
Published: December 2020

Background

In the US and UK, some minority ethnic (ME) groups are thought to be at higher risk for developing dementia while simultaneously accessing care less frequently. Despite this, studies from both countries have suggested that ME groups may actually survive longer after a dementia diagnosis. We conducted a systematic review and meta‐analysis to investigate survival differences in dementia between ethnic groups in the literature.

Method

We searched Embase, Global Health, Ovid MEDLINE, and PsycINFO from inception to November 2018 for longitudinal observational studies which quantified racial/ethnic differences in mortality in dementia. Studies were included if they used ethnicity or race as a predictor for all‐cause mortality and reported a comparison between multiple ethnic groups, regardless of whether this was the primary aim. Records were screened for inclusion in double. Study quality was assessed using the Newcastle‐Ottawa Scale. Narrative synthesis was used to analyze and report findings of all eligible studies. A subset of studies from the US was included in a random‐effects meta‐analysis with robust variance estimation.

Result

We identified 21 eligible articles: 17 from the US, three from the UK, and one from the Netherlands. Across countries, all studies but one found lower or no difference in survival in ME groups as compared to the reference population. In the US, five out of 12 studies reported lower mortality in African American/Black ethnic groups and seven out of nine reported lower mortality in Hispanic/Latino groups as compared to non‐Hispanic White groups. From the meta‐analysis (six studies; n=101,502), the pooled hazard ratio (HR) for all ME subgroups compared to reference was 0.77 (99% c.i. 0.48‐1.24), although heterogeneity was high. Separate meta‐analyses of Black/African American and Hispanic/Latino groups found lower hazard of mortality in both (Black/African American: HR=0.86, 95% c.i. 0.82‐0.91, I2 = 17%; Hispanic/Latino: HR=0.65, 95% c.i. 0.50‐0.84, I2 = 86%). Overall, study quality was mixed, and studies rarely reported how ethnicity was ascertained or defined.

Conclusion

Available literature indicates that ME groups, particularly Hispanic American and African American groups, may have lower risk of mortality in dementia. Lack of consistency in reporting ethnicity is an issue in the literature.
Neurofilament light and cognitive performance: Associations with amyloid and vascular pathologies in individuals with mild cognitive impairment
Authors: Bos Isabelle , Vos Stephanie J.B. , ten Kate Mara , Scheltens Philip , Engelborghs Sebastiaan , Frisoni Giovanni B , Blin Olivier , Richardson Jill , Bordet Régis , Verhey Frans R.J. , Tsolaki Magda , Popp Julius , Lovestone Simon , Streffer Johannes , Andreasson Ulf , Blennow Kaj , Barkhof Frederik , Zetterberg Henrik , Visser Pieter Jelle
Published: December 2020

Background

Neurodegenerative, amyloid and vascular pathologies have all been associated with cognitive performance, but their interrelationship remains uncertain. We investigated the associations between cerebrospinal fluid (CSF) neurofilament light (NfL), a biomarker for neurodegeneration, with four different cognitive measures in individuals with mild cognitive impairment (MCI) with and without biomarker evidence of amyloid and vascular pathologies.

Method

We included 314 individuals with MCI from the EMIF‐AD Multimodal Biomarker Discovery study based on availability of data on CSF markers, MRI markers and cognitive data. CSF amyloid‐β42/40 ratio was used to determine amyloid status (A‐/A+). Vascular status (V‐/V+) was based on the presence of at least one abnormal vascular MRI marker (Fazekas≧2, lacunes>0, microbleeds>0). Linear mixed models, with center as random factor, were used to test associations between NfL and four pooled cognitive outcome measures (memory z‐score, language z‐score, executive functioning z‐score and an attention z‐score) and the interaction with amyloid and vascular status.

Result

On average individuals were 69.2 (SD 7.6) years old and 51% were female. Seventyseven (25%) were classified as A‐V‐, 49 (16%) as A‐V+, 103 as A+V‐ (33%) and 85 (27%) as A+V+. The A+V+ group had significantly higher levels of NfL compared to the A‐V‐ group (p=0.026). There were no other differences between the groups on NfL levels. We found that NfL levels were associated with lower memory (β=‐0.019, p=0.037) and language (β=‐0.022, p=0.019) scores, but not with attention or executive functioning scores. In addition, the associations between NfL levels and memory scores were driven by the individuals with vascular pathology (A‐V+ p=0.007, A+V+ p=0.044) and the association with language scores was driven by the A‐V+ group (p=0.040). Figure 1 shows the relationship between cognitive outcome measures and NfL levels in the AV groups.

Conclusion

Higher NfL levels were associated with lower memory and language scores, in particular in patients with vascular pathology. NfL was not associated with attention and executive functioning scores and it was not associated with cognitive performance in patients with isolated amyloid pathology. These results could indicate that high NfL levels in prodromal Alzheimer’s disease may be proxy for underlying vascular pathology.
Is hippocampal volume an accurate and reliable early marker of Alzheimer’s disease?
Authors: Gentreau Mélissa , Maller Jerome J , Meslin Chantal , Cyprien Fabienne , Ritchie Karen , Artero Sylvaine
Published: December 2020

Background

It is challenging to predict when and which individuals will progress to Alzheimer's disease (AD) to facilitate enrollment in clinical trials. Hippocampal volume (HV) considered as a fundamental structure for cognition is one of the key emerging imaging markers to improve Alzheimer’s disease risk prediction. There are numerous examples of HV reduction among patients with AD and those at risk for AD. However most evidence is derived from research cohorts or clinical populations with short follow‐up, and the extent to which hippocampal degeneration predict long‐term AD remains somewhat unclear. Moreover, hippocampus being damaged by a variety of stimuli including nutrition, sleep, inactivity, stress and depressive symptoms, it may also play a role on mild cognitive decline in the context of normal aging. To address this issue we studied the long term association between HV and the risk of 1) incident dementia and 2) mild cognitive decline in normal aging.

Method

We studied 510 dementia‐free persons from the ESPRIT cohort, aged over 65 years. All participants underwent magnetic resonance imaging (1.5 T) at baseline. We used both manual and automated methods (Freesurfer 6.0) to measure HV. A cognitive test battery (global cognition, visual memory, executive function, verbal fluency) was performed, and participants were followed by neurologists for incident dementia at 2, 4, 7, 10, 12 and 15 years. We tested the association between HV and the risk of dementia and mild cognitive decline using respectively Cox proportional hazards and linear mixed models.

Result

42 participants developed AD. After adjustment by potential confounder (age, sex, education, ApoE4, depression, antidepressive drugs, alcohol, sleep, baseline MMSE score, intracranial volume) right and left HV were significantly associated with dementia (p<0.01) but also with mild cognitive decline in normal aging (p<0.02).

Conclusion

In a community‐dwelling population, we report evidence that HV predict both long term incident dementia and mild cognitive decline in normal ageing casting doubt on the utility of this structure as an early biomarker of AD using only a single measure. However, this measure could be used in general population framework to target subject at risk of cognitive decline and to develop preventive strategies.
Establishment of a reversal learning assay in rats to investigate the effects of novel compounds on executive function
Authors: Dunphy‐Doherty Fionn , Rouine Jennifer , Kozareva Danka , Sokolowska Ewa , Prenderville Jack
Published: December 2020

Background

Cognitive ability declines with age, ranging from normal age‐related decline (Craik and Bialystok, 2006), to mild cognitive impairment (Gauthier et al., 2006), and to dementias like Alzheimer’s disease (Perry and Hodges, 1999). One domain which is particularly affected is executive function (Lien et al., 2008). Attentional set‐shifting and reversal learning tasks have been widely used to quantify executive dysfunction in older humans (Robbins et al., 1998) and rats (Schoenbaum et al., 2006). Here, we describe the establishment of an operant conditioning task to assess reversal learning in rats. We investigated a series of pharmacological interventions, including drugs affecting cholinergic and serotonergic transmission, previously shown to have pro‐cognitive effects in animal models and humans.

Method

The reversal learning task utilises a rule learning (non‐match response) protocol with a reversal (match response) component. After a week’s habituation to the operant chambers and the task, male Sprague Dawley rats (n = 10 per group) were trained to a criteria of above 90% correct on the non‐match response (approximately 10 days). Following reversal of the correct response to the match response, rats received daily drug administration prior to the task. The reversal learning phase of the task continued until rats again achieved criteria (90% correct response).

Result

A number of compounds have been assessed in this reversal paradigm. Pro‐cognitive effects have been observed both using nicotine (acetylcholine receptor agonist; P<0.05 on sessions 5‐8 of reversal compared to control) and SB‐399885 (5‐HT6 antagonist; P<0.05 on session 7 of reversal compared to control). A breakdown of test sessions into smaller trial bins has yielded a better temporal resolution of the data to assess changes within as well as between testing sessions.

Conclusion

These data demonstrate the successful establishment of an operant reversal learning task in rats. The task is sensitive to pharmacological intervention and therefore can be used to investigate the potential pro‐cognitive effects of drugs under development for treatment of cognitive dysfunction associated with psychiatric and neurodegenerative disease. Future studies in aged animals and disease models will explore the possibility of employing the task to assess disease specific deficits in executive functioning.
A cost‐consequence analysis of early detection of AD in the MOPEAD project — A project within the EU research agenda IMI‐2
Authors: Wimo Anders , Belger Mark , Bon Jaka , Vugt Marjolein , Jessen Frank , Kramberger Milica G , Jamilis Laura , Johansson Gunilla , Rodrigo Adrián , Rodriguez‐Gomez Octavio , Sannemann Lena , Stoekenbroek Malou , Stomrud Erik , Gurrutxaga Miren , Valero Sergi , Vermunt Lisa , Waterink Lisa , Winblad Bengt , Zwan Marissa D. , Boada Mercè ,   MOPEAD
Published: December 2020

Background

“Models of Patient Engagement for Alzheimer's Disease” (MOPEAD), is a project within the EU‐Innovative Medicines Initiative (IMI‐2) research agenda, aiming at improving early detection of Alzheimer´s disease (AD).

Methods

Four screening strategies (“runs“) were tested in five countries (Germany, the Netherlands, Slovenia, Spain and Sweden): Run 1 used a web approach, Run 2 held open houses at memory clinics, Runs 3 and 4 took place at clinics (primary care and type2‐diabetes specialist settings respectively). Persons at risk of AD were offered referral to a memory clinic (WP3). The primary health economic outcome was the cost per true positive case (TP) of mild cognitive impairment (MCI) or AD from the screened population. Also costs per screened case, cost per case entering the memory clinic and the number needed to screen (NNS) to identify a TP case were analysed. A comprehensive sensitivity analysis was accomplished.

Results

Of 2847 screened persons, 1117 screened positive, 398 were evaluated at WP3 and of those, 236 were diagnosed with AD or MCI. The cost per TP of those screened was 1,190€ in Run 4, 1,530€ in Run 3, 2,722€ in Run 2 and 3,115€ in Run 1. The results in the sensitivity analysis that was regarded as best to reflect real world were 1,443€/TP in Run 4, 1,856€ in Run 3, 2,714€ in Run 2 and 3,098€ in Run 1. The NNS was 6 in Run 4, 8 in Runs 2 and 3 and 30 in Run 1. The cost per screened was 103€ in Run 1, 338€ in Run 2, 204€ in Run 3 and 212€ in Run 4. There were great country differences.

Conclusion

Although Runs 3 and 4 had lower costs per TP/screened population than Runs 1 and 2, the capacity of Runs 3 and 4 to identify cases with AD‐risk must be discussed. Thus, new diagnostic strategies (Runs 1 and 2) may be valuable after modifications. For example, one challenge in Run 1 was to get in touch with people who screened positive, and in Run 2, the cost‐effectiveness may improve by integrating Run 2‐screening and memory clinics (diagnose confirmation).
Attitudes towards people with dementia: Questionnaire validation and comparison between Germany and China
Authors: Zhu Lin , Schall Arthur , Tesky Valentina Antonia , Paulitsch Michael , Pantel Johannes
Published: December 2020

Background

In both professional and family settings, attitudes towards dementia influence the way this group of patients is treated. It is therefore of great importance to conduct research into intercultural differences in attitudes towards dementia and then to adapt concepts of care to better suit the target population. This project examines the question whether differences exist in attitudes towards persons with dementia between Germany and China.

Method

The Dementia Attitudes Scale (DAS) has been validated for different European languages (English, German, French, Italian). For this study the DAS was professionally translated and validated for the Chinese language (Mandarin). Samples were recruited of the general population and of professional hospital nurses in both countries (total N of recruits: 195).

Result

Internal consistency was very good for both the Chinese and German versions of the DAS (Cronbach’s alpha > 0.8). The two groups differed in terms of experience with persons with dementia: Respondents in the German group had significantly more experience of interacting with persons with dementia. With regard to attitudes towards persons with dementia, the Chinese group had a more negative attitude than the German group. A comparison of the two sub‐groups “qualified personnel” with “general population” showed that professional knowledge has a positive influence.

Conclusion

This pilot study revealed differences in attitudes toward people with dementia between Germany and China. The reason for this (e.g. knowledge/education, cultural differences, personal experience) should be addressed in future studies. Ultimately this may help to increase the well‐being and quality of life of persons with dementia over the long term and in a culturally sensitive manner
A new biological assay of Aβ clearance: The Aβ mid‐domain immunoassay
Authors: Torsetnes Silje Bøen , Wettergreen Marianne , Nordengen Kaja , Gisladottir Berglind , Sharma Kulbhushan , Christensen Erik , Fladby Tormod
Published: December 2020

Background

Decreased Aβ clearance is thought to precede the clinical AD symptoms by a decade or more. Clearance of Aβ include phagocytosis and degradation are two important components. Innate immune‐linked genetic risk factors contribute to AD, and innate immune cells – microglia in the brain and monocytes/macrophages in the peripheral blood – phagocytize and degrade Aβ. Based on this, we hypothesize that intra‐ and extracellular Aβ fragments, specifically mid‐domain Aβ, reflect phagocytic activity or Aβ degradation efficiency. Our objective was thus to develop an assay measuring intra‐ and extracellular Aβ mid‐domain peptides in relevant biological specimens.

Method

Firstly, a panel of sheep monoclonal antibodies (mAbs by Bioventix Ltd, UK) was raised against the Aβ20‐34 peptide. Secondly, an anticomplex antibody (HuCal, BioRad, CA, USA) was screened for, needing to be selective for only Aβ20‐34 bound to the most sensitive sheep mAb. Throughout these processes, immunoprecipitation and reversed phase liquid chromatography mass spectrometry (IP LCMS) were used to map the affinity and selectivity of the best performing antibodies pair (sheep mAb 2A9 and HuCal H3). Thirdly and finally, an immunoassay on the Quanterix Single Molecule Array (Simoa, Quanterix, MA, USA) platform was developed, resulting in our final product.

Result

IP LCMS experiments showed that sheep mAb 2A9 bound to a mid‐domain peptide is needed for complex formation with HuCal H3. In selectivity mapping, where endogenous Aβ was screened for in CSF using these antibodies in a sandwich, a preferential binding of AβX‐34>>AβX‐40 was demonstrated. The two antibodies applied in a new immunoassay on the Simoa platform, gave a sensitive immunoassay detecting Aβ mid‐domain peptides with a LOD<0.5 pg/ml. Thus detecting endogenous levels both in CSF and in blood derived samples such as serum, plasma and monocyte lysates. Various samples from healthy subjects, study participants in AD intervention studies, and other clinical samples are currently being analyzed.

Conclusion

Here, we present the first immunoassay able to detect endogenous catabolic Aβ peptides in a range of biological tissue fluids. This functional assay thus paves the way for novel studies on Aβ clearance and catabolism and may serve as a tool for peripheral blood measurement in both disease progression‐ and intervention studies.
Management of sleep disturbances in people with dementia living in care homes: The SIESTA qualitative study
Authors: Webster Lucy A , Powell Kingsley , Gonzales Sergi Costafreda , Livingston Gill
Published: December 2020

Background

Sleep disturbances, including difficulty falling asleep, night time awakening, and excessive daytime sleepiness, effect nearly 40% of people with dementia living in care homes. Though hypnotic medications are commonly used, they are not recommended as they have been linked to increased risk of falls and mortality, and have little efficacy. There are currently no evidence‐based treatments. Through the SIESTA qualitative study (Sleep problems In dEmentia: interviews with care home STAff), we aimed to explore the alternative ways that sleep disturbances in residents with dementia are managed by care home staff.

Method

We interviewed 18 nurses and care assistants working both day and night shifts at four care homes in the UK providing residential and nursing care. We used a topic guide to explore staff experience of sleep disturbance in residents with dementia. The interviews were audio‐recorded, transcribed, and analyzed thematically by two researchers independently.

Result

All staff described a range of strategies they used to manage sleep disturbance in residents with dementia. Often this began with preventative techniques in the daytime, with staff ensuring where possible residents stayed active, ate well, and took part in activities to avoid napping. In the evening time staff settled residents into a dark, noise free, comfortable bedroom environment. When residents woke during the night‐time they were often given caffeinated tea or food, particularly if they had not eaten or drank much in the day due to napping. Tea and comfort were often used together, with staff sitting with the resident providing company and reassurance. If someone was agitated staff would think about pain and discomfort, and would use telecare to monitor residents who often left their bed at night and were a safety risk. As the last resort, sleep medications were used, but staff described how they only worked sometimes, as well as the side effects.

Conclusion

Staff used a range of techniques and described how these often worked in reducing, maintaining or preventing sleep disturbance, however, some of the strategies reported by staff to deal with sleep disturbances such as feeding or providing caffeinated tea at night might be counter‐productive.
Enhancing family quality‐of‐life outcomes: The NEUROQUALYFAM project
Authors: Ortega Eva González ,   NEUROQUALYFAM group
Published: December 2020

Background

Neurodegenerative diseases (ND) have a great impact on both patients and their relatives, since the latter play an essential role in the care process. Consequently, the families require support to perform this function with higher levels of wellbeing. The objective of the NEUROQUALYFAM project (Interreg V‐A Spain‐Portugal, POCTEP) is to analyze the quality of life of families of people with ND, to identify their needs and to plan family‐centered support resources in order to offer high‐quality social health services for people with ND and their families.

Method

The study sample will consist of 300 families from the Spanish‐Portuguese cross‐border area. The Family Quality of Life Survey ‐ Dementia (FQoLS) will be translated, adapted and validated (DiZazzo‐Miller & Samuel, 2011) to assess their quality of life. Focus groups with families and professionals from health, social services and the third sector will be conducted to identify needs and support resources. The “section 2‐Support and Services” of the validated Spanish version of the Beach Center Family Quality of Life Scale (Verdugo, Rodríguez and Sainz, 2012) will be adapted for families of people with ND to identify the types of support needed and to what extent they are provided. A confirmatory factor analysis will be conducted to examine the validity of the construct FQoLS‐ ND. A top‐down content analysis will be undertaken for qualitative data.

Result

The project will provide: (a) a procedure to evaluate the quality of life of families of people with ND; (b) the identification and mapping of unmet support needs regarding the health and social system; (c) the planning of a family‐centered support system for the improvement of health and wellbeing outcomes, and (d) the design of a comprehensive ICT platform of support resources that enhances training, information exchange and collaborative networks between and among families and professionals.

Conclusion

The project NEUROQUALYFAM provides a research and intervention model that might be applied in other regions and countries. It strengthens cooperation between the institutions (health and social services, third sector) to improve the quality of family life and optimize support resources for family caregivers.
Reliability of wrist‐worn accelerometry devices and algorithms for sleep detection
Authors: Peraza Luis R , Joules Richard , Dauvilliers Yves , Wolz Robin
Published: December 2020

Background

Wearable devices have shown great potential for obtaining measures of real world evidence in clinical trials, but standardization and variability between different devices remain one of the barriers for systematic deployment. In this investigation, we present a neural network algorithm for sleep detection, Deep Learning Sleep (DLS), and compare its reliability across different datasets and two widely used sleep algorithms.

Method

A publically available dataset TUD (Borazio; ICHI 2014, N=45) and the CONTEXT dataset collected in Montpellier, IXI (Wolz; Alzheimer’s & Dementia 2017, N=45) were used to compare algorithm performance. Each dataset provided one‐night accelerometry data alongside polysomnography (PSG) per participant. DLS performance was compared against two other algorithms for sleep segment detection; Cole‐Kripke, CK (Cole; Sleep 1992), and estimation of stationary segments or ESS (Borazio; ICHI 2014). Then, cross‐validations were implemented with the datasets; e.g. training with dataset TUD and testing on dataset IXI, and vice versa.

Result

The cross‐validations experiments showed no significant differences in performance (sleep detection: 85‐89% sensitivity, 43‐45% specificity and 72‐74% accuracy) for the DLS algorithm. On the contrary, CK and ESS showed significant differences in their performances across experiments, and CK showed the highest difference for specificity (mean specificity = 27‐52%), demonstrating that CK and ESS algorithms are susceptible to different devices and/or data sources (Figure 1).

Conclusion

The CK and ESS algorithms showed susceptibility to different devices or data sources (e.g. clinical groups) and this raises questions about their reliability. In conclusion, we presented a deep learning based algorithm (DLS) that showed high robustness against different data sources as well as high accuracy when compared against the gold standard PSG.
Transcript analysis using long‐read sequencing reveals the complex splicing profile of AD‐associated gene ABCA7
Authors: Duchateau Lena , Küçükali Fahri , Van Dongen Jasper , Bossaerts Liene , Hens Elisabeth , De Roeck Arne , Mateiu Ligia , Van Broeckhoven Christine , Sleegers Kristel
Published: December 2020

Background

The ATP‐Binding Cassette Subfamily A member 7 (ABCA7) gene is one of most alluring risk genes for Alzheimer’s disease (AD). Of special interest are alternative splice events that are a) able to rescue the effect of premature termination codon (PTC) mutations, possibly explaining the wide range in phenotype and onset age of PTC mutation carriers, and b) associated with an elongated intronic variable number of tandem repeat (VNTR). However, our knowledge of alternative splice events in ABCA7 is limited. Here, we analyze the ABCA7 transcript using long‐read sequencing in a unique population of ABCA7 PTC carriers. Moreover, we look for possible association between rescue splicing and AD onset age.

Methods

We characterized the ABCA7 transcript of 28 AD patients (24 PTC carriers), 17 controls (11 PTC carriers) and 5 mild cognitive impairment patients using targeted long‐read cDNA sequencing on an Oxford Nanopore MinION platform. RNA was extracted from 47 lymphoblastoid cell lines, as well as 4 hippocampi and 2 prefrontal cortices. Alternative splice events and rescue events were quantified using the full‐length alternative isoform analysis of RNA (FLAIR) pipeline and an in‐house R script.

Result

All PTC mutation carriers displayed nonsense‐mediated mRNA degradation escape (mutant reads <5%‐67% of total reads). Rescue events were found in 17 carriers. While most carriers displayed a rescue/canonical splicing ratio <0.02, this ratio went up to 3.21. Rescue however did not have a strong association with onset age (p = 0.2) or phenotype (p = 0.8). We identified 199 previously undescribed splice events with an alternative/canonical ratio of at least 0.05. This is an almost 4‐fold increase compared to the 53 known junctions. Moreover, 15 of these alternative splice events occur more frequently than the corresponding canonical event (ratio>1). This seems to occur more frequently in AD patients (n = 20) than controls (n = 8) (OR = 2.74), to higher extent in brain tissue and more frequently outside the transmembrane domains, nucleotide‐binding domains or extracellular loops.

Conclusion

Our results highlight a complexity of the ABCA7 transcript that has not been described before. Moreover, splicing seems to occur more frequently in AD patients. These results suggest that ABCA7 splicing might be an important mechanism in AD.
Validation of the Spanish version of the Mini‐Linguistic State Examination for the diagnosis of primary progressive aphasia
Authors: Matias‐Guiu Jordi A. , Pytel Vanesa , Patel Nikil , Delgado‐Álvarez Alfonso , Matias‐Guiu Jorge , Garrard Peter , Cuetos Fernando
Published: December 2020

Background

Primary progressive aphasia (PPA) is a clinical syndrome of neurodegenerative origin with three main clinical variants (nonfluent, semantic, and logopenic). Clinical diagnosis and accurate classification into the three clinical variants is challenging and often time‐consuming. The Mini‐Linguistic State Examination (MLSE) has been recently developed as a short language test specifically designed for language assessment in neurodegenerative disorders. Our aim was to adapt and validate the Spanish version of MLSE for PPA diagnosis.

Method

Cross‐sectional study involving 70 patients with PPA and 42 healthy controls were evaluated with the MLSE. Patients were independently diagnosed and classified according to a comprehensive cognitive and advanced neuroimaging.

Result

Internal consistency was 0.702. Influence of age and education was very low. The area under the curve for discriminating PPA patients and healthy controls was 0.989. Effect sizes were moderate‐large for the discrimination between PPA and healthy controls. In addition, motor speech, phonology and semantics subscores discriminated between the three clinical variants.

Conclusion

Our study provides a useful and brief language test for the diagnosis of PPA with excellent properties for both clinical routine assessment and research purposes.
The difference in cortical thickness between posterior cortical atrophy patients and age‐associated memory impairment subjects
Authors: Likitjaroen Yuttachai , Phanthumchinda Kammant
Published: December 2020

Background

Posterior Cortical Atrophy (PCA) is a variant of Alzheimer’s disease. The Perceptual‐motor function deficits are the presentations. Here, we used the imaging technique to demonstrate the pattern of cortical thinning in PCA patients compared to age‐associated memory impairment (AAMI) subjects

Method

Fourteen PCA patients and 20 AAMI subjects were recruited from Neurocognitive Clinic, King Chulalongkorn Memorial Hospital, Thailand. All PCA patients met the criteria and structural brain magnetic resonance imaging revealed predominantly atrophy of the parieto‐occipital area. 11 PCA patients had FDG‐PET confirmed. Cortical surfaces of all participants were reconstructed using freesurfer software. The cortical thickness were compared between the two groups.

Result

Eight of PCA and 17 of AAMI were female. The mean age of PCA group and AAMI group were 63.87 and 75.88 respectively (P<0.001). Brain segmented volume was not different (P=0.081). Cortical volume was significantly lower on the right hemisphere in PCA group (P=0.047). The white matter volume in PCA group was lower on both hemispheres (right p=0.017, left P=0.027). The whole brain analysis revealed PCA had significantly thinner cortical areas on the left hemisphere including superiorparietal, supramarginal, transversetemporal, superiortemporal, lateraloccipital, isthmuscingulate, entorhinal as well as the right hemisphere including superiorparietal, supramarginal, superiortemporal, insula, lateraloccipital, temporalpole, entorhinal and lingual. We also found the area where PCA group are significantly thicker than AAMI group in the frontal lobe and primary visual area on both hemisphere.

Conclusion

We demonstrated a diffused cortical thinning pattern in PCA compared to age‐matched AAMI group. The significant cortical thinning in PCA were profound on parietal, occipital and posterior temporal on both hemisphere. Furthermore, we found the predominant decline of white matter volume in PCA. Frontal areas and primary visual cortex were spared which may be due to younger age or the nature of the disease.
The genetic association between ACE1 and Alzheimer’s disease
Authors: Guzel Ozge , Tayler Hannah Mary , Skrobot Olivia Anna , Miners Scott , Kehoe Patrick Gavin
Published: December 2020

Background

ACE1 is a reported risk gene for Alzheimer’s disease (AD), highlighted by several meta‐analysis and recent GWAS studies (Marioni et al., 2018; Kunkle et al., 2019) . ACE1 encodes angiotensin II converting enzyme‐1 (ACE‐1), a rate‐limiting enzyme in the classical renin‐angiotensin system (cRAS) and is overactivated in AD (Miners et al., 2008, Miners et al., 2009). ACE‐1 generates Ang‐II, itself elevated in AD, and is increased in relation to parenchymal Aβ load. We investigated the relationship between the ACE1 variant (rs4343) (Abdollahi et al., 2008) (a proxy marker for the more commonly studied indel polymorphism) and Aβ plaque and tau tangle load (assessed by IHC) and levels of Aβ40 and Aβ42 (soluble and insoluble) and Ang‐II level, measured by ELISA.

Method

We studied a total cohort of 318 dementia cases (AD, Mixed AD and vascular dementia) and 116 controls from the South West Dementia Brain Bank, University of Bristol, UK. The ACE1 indel proxy polymorphism, rs4343, was genotyped using PCR based method. The A and G alleles for rs4343 are equivalent to the insertion and deletion variation in ACE1, respectively. Parenchymal Aβ plaque and tau tangle load was quantified by computer‐assisted field fraction analysis in the frontal and parietal cortex for 134 AD and Mixed dementia cases. Aβ40 and Aβ42, and Ang‐II level, was also measured by ELISA in 254 dementia cases and controls. We performed logistic regression to determine the association between ACE1 genotype and AD and non‐parametric Mann‐Whitney U test to determine the association between ACE1 genotype and Aβ and tau pathology.

Result

G/G homozygotes were associated with reduced risk of AD and Mixed dementia (p = 0.037). AD and Mixed dementia cases with the G/G genotype also had significantly lower (p = 0.0109) parenchymal Aβ load in the frontal cortex compared with A/A and A/G genotypes, but this was not evident in the parietal cortex. We will further explore the relationship between rs4343 variants and levels of Aβ (soluble and insoluble) and Ang‐II and examine the potential interaction with tau pathology.

Conclusion

Our initial findings indicate that the ACE1 rs4343 polymorphism may associate with both AD risk and AD‐related Aβ pathology.
Correlation of Aβ‐pE(3) and ptau in human and mouse brain
Authors: Temmel Magdalena , Neddens Joerg , Flunkert Stefanie , Walker Lauren , Attems Johannes , Hutter‐Paier Birgit
Published: December 2020

Background

Senile plaques frequently contain pyroglutamate amyloid β (Aβ‐pE(3)), a N‐terminally truncated Aβ species that is more closely linked to Alzheimer’s Disease (AD) compared to other Aβ species. Tau protein is highly phosphorylated at several residues in AD, specifically tau protein phosphorylated (ptau) at Ser202/Thr205 is known to be increased in AD. First studies suggest that the two pathologies of plaques and tau phosphorylation might be linked to each other.

Method

To evaluate if Aβ‐pE(3) and ptau Ser202/Thr205 levels correlate in human and transgenic AD mouse models we analyzed human cortical and hippocampal brain tissue of different Braak stages as well as murine brain tissue of two transgenic mouse models for levels of Aβ‐pE(3) and ptau Ser202/Thr205 and correlated the data.

Result

Our results show that Aβ‐pE(3) formation increases already at early Braak stages while ptau Ser202/Thr205 mostly increases at later stages. Further analyses revealed strong correlations between the two pathologies in the temporal, frontal, cingulate and occipital cortex. However, correlation in the hippocampus was weaker. Evaluation of murine transgenic brain tissue demonstrated a slow but steady increase of Aβ‐pE(3) from 6 to 12 months of age in the cortex and hippocampus of APPSL mice and a very early and strong Aβ‐pE(3) increase in 5xFAD mice. ptau Ser202/Thr205 levels increased at the age of 9 months in APPSL mice and already at 6 months in 5xFAD mice.

Conclusion

Our results show that Aβ‐pE(3) and ptau Ser202/Thr205 levels strongly correlate in human as well as murine brain tissues, suggesting that tau phosphorylation might be amplified by Aβ‐pE(3).
Neuroimaging biomarkers in prodromal DLB
Authors: Kantarci Kejal
Published: December 2020

Background

Patients with dementia with Lewy bodies (DLB) are characterized by hypometabolism in the parieto‐occipital cortex and the cingulate island sign on F18‐fluorodeoxyglucose (FDG) PET, lower medial temporal F18‐Flortaucipir uptake on tau PET, and lower volumes of the basal forebrain gray matter nuclei on MRI. Whether this pattern of imaging findings is present as early as the prodromal stage of DLB is unknown. We investigated the pattern of hypometabolism, atrophy, and Flortaucipir uptake in patients with mild cognitive impairment (MCI) who progressed to DLB and compared them to MCI patients who progressed to Alzheimer’s disease dementia (ADdem).

Method

Patients with MCI who underwent FDG PET (n=17), Flortaucipir PET (n=9) and MRI (n=28) at baseline and progressed to probable DLB were included. We also included a cognitively unimpaired cohort of controls and MCI patients who progressed to probable ADdem (MCI‐AD) for comparison. Voxel‐base analysis on SPM12 and region‐based analysis were performed to compare the clinical groups.

Result

Patients with MCI‐DLB had profound hypometabolism in the parieto‐occipital region extending into the temporal lobes, substantia nigra and thalamus. When compared to MCI‐AD, the hippocampal and posterior cingulate metabolism were relatively preserved in patients with MCI‐DLB, accompanied by greater hypometabolism in the substantia nigra in MCI‐DLB than MCI‐AD. MCI‐DLB patients were also characterized by greater atrophy in the substantia innominata (nucleus basalis of Meynert and the diagonal band) on MRI. F‐18 Flortaucipir uptake in MCI‐DLB was comparable to the control group, but significantly lower than MCI‐AD particularly in the medial temporal lobes.

Conclusion

Imaging biomarkers can identify neurodegenerative changes associated with the prodromal phase of DLB. Prodromal DLB patients are characterized by greater atrophy in basal forebrain nuclei, suggesting that the degeneration of the cholinergic system occur as early as the prodromal stage in DLB. Preservation of medial temporal metabolism, the cingulate island sign, and substantia nigra hypometabolism on FDG PET and lower medial temporal F18‐ Flortaucipir uptake can be used to distinguish prodromal DLB and prodromal ADdem.
Assessment of the contribution of common genetic variants associated with Alzheimer’s disease on neuropathological burden and clinical characteristics in the Brains for Dementia Research cohort
Authors: Hannon Eilis , Brookes Keeley J. , Shireby Gemma , Attems Johannes , Sims Rebecca , Cairns Nigel J. , Morgan Kevin , Thomas Alan J. , Francis Paul T. , Mill Jonathan
Published: December 2020

Background

In addition to the well‐established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer’s disease (AD). Individually these variants confer only a small increase on an individual’s overall risk; however, combined into a polygenic risk score (PRS), they represent a powerful tool in genetic epidemiology for the investigation of correlates of high genetic risk. We investigated the clinical and neuropathological outcomes associated with high PRS for AD in the Brains for Dementia Research (BDR) cohort.

Method

693 individuals in the BDR cohort with high quality genetic data and neuropathology measurements, including staging assessments (Braak and Thal) and established diagnostic criteria were included in this study. PRS were calculated for each individual as the number of genetic risk alleles, weighted by the log odds ratio, using the results of the largest available GWAS of AD. Statistical analysis was performed using regression models whilst controlling for age at death, sex and brain bank.

Result

We report statistically significant associations between APOE genotype and Braak neurofibrillary tangle stage, a measure of tauopathy, and Thal stage, a measure of Aβ plaque propagation. We also found significant associations between AD PRS and multiple measures of neuropathology (Braak stage, Thal stage, Lewy body stage, and severe cerebral amyloid angiopathy). In order to determine if APOE and AD PRS represent independent predictors of tauopathy (Braak stage) and b‐amyloidosis (Thal stage), we performed a joint analysis finding that APOE and PRS combine in an additive manner to influence both measures of neuropathology.

Conclusion

The results from this study characterise how genetic risk for AD influence both the clinical and pathological features of dementia and increases our understanding of the interaction between APOE status and other genetic risk factors.