bluuebunny/crossref_metadata_2025 huggingface dataset:
Season of birth and the risk of dementia in the general population: A long‐term, prospective cohort study
Authors: Mooldijk Sanne S , Licher Silvan , Vinke Elisabeth J , Vernooij Meike W , Ikram M. Kamran , Ikram M. Arfan
Published: December 2020

Background

Environmental exposures early in life are important for shaping brain development. Season of birth as a proxy for these exposures has been associated with the risk of brain diseases in adolescence and mid‐life, such as schizophrenia and depression. We investigated the link between season of birth and risk of dementia. We further explored underlying structural pathways by studying the link with brain changes on MRI.

Method

Within the Dutch prospective population‐based Rotterdam Study, we assessed dementia incidence in 12,964 persons born between 1887 and 1960. We used Cox proportional hazard models to determine the relationship between season of birth with incident dementia, and Alzheimer’s disease (AD), with summer births as reference. In addition, we compared dementia incidence among participants born in a cold winter compared to those born in a normal winter. All models were adjusted for age and sex, and additionally for education, ethnicity, income, APOE‐ε4 genotype, cardiovascular risk factors and depressive symptoms. Furthermore, we examined the association between season of birth with volumetric and microstructural integrity markers on brain MRI in 5,436 dementia‐free participants.

Result

During 26 years of follow up, 1,633 participants developed dementia, of whom 1,282 had AD. The risk of dementia in both winter and fall born participants was higher than those born in summer (Figure 1, age and sex adjusted hazard ratio (HR) 1.14 [95% confidence interval (CI) 1.00‐1.40] and 1.17 [1.02‐1.34], respectively), with stronger effect sizes for AD (1.24 [1.06‐1.45] and 1.23 [1.05‐1.45], respectively). In addition, we found a higher risk for participants born in a cold or very cold winter HR 1.08 [0.88‐1.34] and 1.14 [0.87‐1.48], respectively, compared to those born in a normal winter. Further adjustment did not change these associations. We did not find an association between season of birth and any of the brain imaging markers measured in late life.

Conclusion

In this western European population of community‐dwelling individuals, winter and fall births are associated with a higher incidence of dementia, especially of AD. We did not find evidence for changes in structural and microstructural brain markers as an underlying mechanism.
Impact of bioinformatic pipelines and reference databases on 16S rRNA gene sequencing in patients with cognitive impairment
Authors: Marizzoni Moira , Gurry Thomas , Lopizzo Nicola , Salvatore Marco , Franzese Monica , Mirabelli Peppino , Frisoni Giovanni B , Cattaneo Annamaria
Published: December 2020

Background

Sequencing of 16S ribosomal RNA (rRNA) gene is the most used technique for the identification of Alzheimer’s specific differences in the relative abundance of specific organisms. Several bioinformatic pipelines have been developed so far to characterize complex gut microbial communities. This study aims at evaluating the effect of bioinformatic pipelines and reference databases on the taxonomic classification of bacteria in the stools of patients with cognitive impairment.

Method

DNA from frozen stool samples of 40 subjects was extracted using QIAamp Fast DNA stool kit after mechanical disruption (bead‐beating) and amplified using primers targeting the V3‐V4 region of the bacterial 16S rRNA gene. Sequencing was performed according to the 16S‐protocol on MiSeq (Illumina). Sequence read files were analysed using 4 commonly used pipelines run on a Linux workstation: QIIME2 (Bokulich, Microbiome, 2018), Bioconductor (Callahan, F1000Research 2016, version 29 oct 2018), UPARSE (Edgar, Nat Methods, 2013) and mothur (Kozich, Applied and Environmental Microbiology, 2013). SILVA 132 and RDP v16 reference databases were used in all analyses. For UPARSE and mothur, sequences were clustered into OTUs at 99% identity threshold. Differences of relative abundances of phyla and genera were evaluated across pipelines using Friedman rank sum test.

Result

The identification of phyla but not their quantification was consistent among all the pipelines using both databases (p<0.001). At genus level, all pipelines identified Bacteroidetes, Alistipes, Faecalibacterium and Ruminococcus as the most abundant genera, regardless of the database applied for taxonomic assignment. Again, their relative abundance was different across pipelines and databases (p<0.001).

Conclusion

The comparison between different studies should take analytical pipeline and database used for taxonomic assignation into account. To overcome these limitations, the scientific community should quickly converge towards a consensus pipeline for guarantee research reproducibility.
Characterization of monomeric and soluble aggregated Aβ in Down’s syndrome and Alzheimer’s disease brains
Authors: Gkanatsiou Eleni , Sahlin Charlotte , Portelius Erik , Johannesson Malin , Söderberg Linda , Fälting Johanna , Basun Hans , Möller Christer , Odergren Tomas , Zetterberg Henrik , Blennow Kaj , Lannfelt Lars , Brinkmalm Gunnar
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the two hallmarks, amyloid plaques and neurofibrillary tangles in the brain. The plaques consist of aggregated beta amyloid (Aβ) peptides, formed by proteolytic cleavages of amyloid precursor protein (APP). Down’s syndrome (DS) is a genetic disease with an extra copy of chromosome 21, harbouring the APP gene. DS individuals are at increased risk to develop amyloid pathology. Most DS have substantial amyloid pathology at their 40s, with clinical signs of deterioration before the age of 60. Our aim was to compare the Aβ peptide pattern in DS and AD brains, to better understand the difference between them.

Methods

Immunoprecipitation (IP) in combination with mass spectrometry was used to identify both soluble and insoluble Aβ peptides, as well as to characterise the composition of Aβ oligomers/protofibrils. Two different antibody combinations were used; 6E10+4G8 to identify total Aβ peptide contents and the Aβ protofibril selective antibody mAb158 to identify the Aβ peptides present in oligomers/protofibrils. Before IP, cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (TBS soluble) and formic acid (insoluble) fractions.

Results

From IP with 6E10+4G8 several truncated Aβ peptides were identified in all groups, including: 1‐X, 2‐X, 3‐X, 4‐X, 5‐X, 11‐X and –X to 15 as well as post‐translationally modified peptides with oxidation and pyroglutamation. Similarities were observed when comparing the Aβ peptide processing in AD and DS, with the exception of –X to 15 Aβ peptides for which the pattern is different. By using mAb158, Aβ1‐40, Aβ1‐42 and Aβ4‐42 were identified. Higher relative AβX‐42 signals were obtained compared to samples IP’d with 6E10+4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at aa42.

Conclusion

All Aβ peptides found in AD are also present in DS (with amyloid pathology) indicating a generally similar pathway of Aβ peptide production, apart from –X to 15. Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility to exploit the potential utility of a treatment with clinical benefit in sporadic AD for subjects with DS.
Plasma phospho‐tau217 is a potential early diagnostic and prognostic biomarker of Alzheimer’s disease
Authors: Janelidze Shorena , Mattsson Niklas , Smith Ruben , Stomrud Erik , Palmqvist Sebastian , Dage Jeffrey L. , Hansson Oskar
Published: December 2020

Background

There is an urgent need for inexpensive and minimally invasive blood biomarkers of Alzheimer’s disease (AD) that could be used to detect early disease changes.

Method

We measured plasma levels of tau phosphorylated at threonine 217 (P‐tau217) in the prospective Swedish BioFINDER (BF) I and II studies (n=1057). BF‐II included cognitively unimpaired individuals (CU, n=275) and patients with mild cognitive impairment (MCI, n=161), AD dementia (n=114) and non‐AD neurodegenerative diseases (n=91) who underwent tau‐PET imaging using [18F]RO948. A subcohort of 157 participants had two or three tau‐PET scans on average 1.0 years apart (range 0.1‐1.6 years). In BF‐I, 264 CU and 152 MCI were followed longitudinally with clinical examinations to determine conversion to AD dementia (mean follow‐up 4.9 years, range 1.0‐8.6 years).

Result

Plasma P‐tau217 levels were increased in CU individuals with abnormal amyloid‐β (Aβ)‐PET but still normal tau‐PET in the earliest Braak I‐II (entorhinal) ROI (Aβ‐PETpos/tau‐PETneg group vs Aβ‐PETneg/tau‐PETneg group, p<0.001). Furthermore, when testing the relation to global Aβ load in non‐linear spline models (Figure 1), we found that plasma P‐tau217 started to increase at Aβ‐PET SUVR of 0.39, which preceded the increase in tau‐PET measures (Aβ‐PET SUVR 0.42‐0.62). In line with these data, the majority of cases that were discordant for plasma P‐tau217 and tau‐PET in Braak I‐II were positive for P‐tau217 and negative for tau‐PET (P‐tau217pos/tau‐PETneg, n=68 [72%] and P‐tau217neg/tau‐PETpos, n=27 [ 28%]). Among participants with normal baseline tau‐PET, the rates of longitudinal increase in tau‐PET in the Braak I‐II ROI were higher in cases with abnormal plasma the P‐tau217 at baseline (p=0.017). Finally, in non‐demented individuals, abnormal levels of P‐tau217 were associated with increased risk of future AD dementia (hazard ratio 5.4; 95% confidence interval 3.5‐8.4; p<0.001).

Conclusion

Plasma P‐tau217 levels increase in early stages of AD when insoluble tau aggregates are not yet detectable by tau‐PET and predict both subsequent increase in tau‐PET as well as conversion to AD dementia. Plasma p‐tau217 holds promise as a marker for early AD‐pathology.
Plasma carotenoids and medial temporal lobe atrophy in older adults
Authors: Thomas Aline , Proust‐Lima Cécile , Baillet Marion , Helmer Catherine , Delcourt Cécile , Foubert‐Samier Alexandra , Catheline Gwenaelle , Féart Catherine , Samieri Cécilia
Published: December 2020

Background

Carotenoids are vegetable pigments uniquely provided by diet which have antioxidant, immunomodulatory and specific neuroprotective properties. Carotenes (found in orange‐yellow fruits and vegetables) are precursors of retinoids, key signaling molecules for synaptic plasticity. The xanthophylls, lutein and zeaxanthin (found in green vegetables, orange‐yellow fruits and corn) cross the blood‐brain barrier, may decrease lipid peroxidation and stabilize lipid‐protein structures in neuronal membranes. Limited epidemiological studies on dietary carotenoids (assessed by questionnaires) reported inconsistent associations with brain aging using cognitive change as an outcome (and not neuroimaging or clinical dementia or Alzheimer’s disease diagnosis). However, blood carotenoids levels were associated with lower risk of dementia over 10 years, in a large cohort of older adults, the Three‐City (3C) study. Here, we further investigated whether blood carotenoids were also associated with the 10‐year atrophy of the medial temporal lobe (MTL), a central biomarker of neurodegeneration in aging.

Method

We included 461 dementia‐free participants from the 3C study (age ≥65), who had plasma carotenoid (α and β‐carotene, lycopene, lutein, zeaxanthin, β‐cryptoxanthin) measures at baseline and who underwent at least one of the three repeated brain imaging exams performed in the subsequent 10 years. Linear mixed models were used to assess the association between plasma carotenoids and MTL volume change assessed using FreeSurfer 5.1 segmentation software.

Result

Over a median follow‐up of 5.1 years (maximum 11.8 years), higher plasma levels of total carotenoids and of β‐carotene were associated with lower decline in MTL volume (P = .04 and P = .008, respectively). The mean differences in MTL volume change for each increase of 1 SD were 0.02 (95% CI, 0.001; 0.04) cm3/year and 0.02 (0.01; 0.04) cm3/year for total carotenoids and β‐carotene, respectively. Other carotenoids were not significantly associated with MTL atrophy.

Conclusion

The associations found between plasma total carotenoids and β‐carotene and 10‐year atrophy of the MTL in this large cohort of older adults suggest a beneficial role of carotenoids for the prevention of age‐related neurodegeneration.
Usefulness of cognitive training program using virtual reality and mixed reality
Authors: Park So‐Hee , Baek Joon Hyun , Lee SangHoon , Kang Seung Wan , Jang Jun Seok , Na Hae Ri
Published: December 2020

Background

Nowadays virtual reality (VR) and mixed reality (MR) is used as a psychological and occupational therapeutic option to the patients of depression, phobia, post traumatic stress disorder and stroke patients. VR and MR have a number of advantages because it is entertaining, thus motivating the patient. Therefore VR and MR can be used for cognitive therapy to the elderly cognitive declined people because it can give attention, motivation and stimulation to them. Our previous pilot study showed that cognitive training program using VR and MR improved cognitive function, depressive mood and electrophysiologic brain activity on Mild cognitive impairment (MCI) patients. This is the extensive study to show the usefulness of VR and MR using cognitive training on MCI patients, which added more session, program and enrolled more patient in comparison with previous pilot study.

Method

This study was an 8‐week, single‐blind study of 20 patients with MCI. The cognitive training program included art therapy, aerobic exercises, memory training, including face‐name association, object recall training, and spaced retrieval; visuo‐motor organization using software; similarity and ruled based categorization; and behavior modification and sequencing (e.g., making change, paying bills) using VR and MR and computerized program. Neuropsychological function was assessed using K‐MMSE (Korean Mini‐Mental State Examination), Clinical dementia rating(CDR), Alzheimer`s Disease Assessment Scale‐Cognition(ADAS‐cog), Korean version of short form Geriatric Depression Scale(SGDS‐K) and Neuropsychiatric Inventory(NPI). Quantitative electroencephalogram (EEG) was assessed on cognitive training days before treatment and after each treatment phase. Then EEG was analyzed by using “iSyncbrain” which is cloud‐based, AI‐driven EEG analysis platform.

Result

After two months (8 sessions) of treatment, cognitive function, neuropsychiatric symptoms and depression, which were assessed by using MMSE, NPI and SGDS respectively, showed significant improvements (p<0.05). Also there were significant increase of the EEG alpha/theta ratio on both dorsolateral prefrontal cortex and right parietal cortex, which may imply improvement of frontal and visuospatial function. However, there were no statistically significant differences except Source ROI Power and connectivity.

Conclusion

Cognitive training program using VR and MR showed improvement of cognitive function, depressive mood and electrophysiologic brain activity.
Preliminary validation of the Brief Assessment of Impaired Cognition (BASIC) and the Brief Assessment of Impaired Cognition Questionnaire (BASIC‐Q) for identification of mild cognitive impairment
Authors: Jørgensen Kasper , Nielsen Rune , Nielsen Ann , Waldorff Frans Boch , Waldemar Gunhild
Published: December 2020

Background

The aim of this study was to perform a preliminary validation of the Brief Assessment of Impaired Cognition (BASIC)1 and the Brief Assessment of Impaired Cognition Questionnaire (BASIC‐Q)2 for identification of mild cognitive impairment (MCI).

Method

A total of 163 socio‐demographically matched patients (MCI, n = 42, and dementia, n = 121) and control participants (n = 83) were included in the study. BASIC includes the components: self‐report, informant report, and two brief cognitive tests, whereas BASIC‐Q includes the components: self‐report, informant report, and orientation. BASIC takes about 5 minutes to administer and BASIC‐Q a little less.

Result

A high discriminative validity for MCI versus control participants was found for both BASIC (sensitivity 0.85, specificity 0.89) and BASIC‐Q (sensitivity 0.88, specificity 0.88). In comparison, the MMSE had low sensitivity (0.61) and moderate specificity (0.72). All components of BASIC and BASIC‐Q contributed significantly to differentiate MCI from control participants. The components of BASIC and BASIC‐Q also contributed significantly to differentiate MCI from dementia except for self‐report, which was identical in the two groups.

Conclusion

The results indicate that BASIC and BASIC‐Q are equally efficient and valid instruments for identification of MCI in a memory clinic setting. Self‐report and informant report are equally valid measures of cognitive impairment early in the process of decline, but as dementia sets in the validity of self‐report becomes inferior to informant report, possibly reflecting loss of insight. In contrast, the validity of informant report seems to increase with the progression of cognitive impairment. Further studies are warranted to replicate and expand on these findings. References: 1. Jorgensen K, Nielsen TR, Nielsen A, Waldorff FB, Hogh P, Jakobsen S, et al. Brief Assessment of Impaired Cognition (BASIC)‐Validation of a new dementia case‐finding instrument integrating cognitive assessment with patient and informant report. Int J Geriatr Psychiatry. 2019;34(11):1724‐33. 2. Jorgensen K, Nielsen TR, Nielsen A, Waldorff FB, Waldemar G. Brief Assessment of Impaired Cognition Questionnaire (BASIC‐Q) – development and validation of a new tool for identification of cognitive impairment in community settings (submitted for publication). 2019.
Patients’ versus caregivers’ reports of quality of life in elderly patients with cognitive impairment
Authors: Shin Il‐Seon , Kim Sung‐Wan , Kim Jae‐Min
Published: December 2020

Background

A few studies have examined the differences between patient and caregiver reported Quality of Life (QOL) in patients with dementia. The purpose of this study was to investigate the differences between patient and caregiver ratings on QOL in elderly patients with cognitive impairment and assessed the relationship of patient QOL and cognitive function, and depression.

Method

Forty‐seven elderly patients with cognitive impairment and their caregivers participated. Patient QOL was assessed using by the Korean version of Quality of Life‐Alzheimer's Disease (KQOL‐AD) scale. Each patient and caregiver rated the patient QOL. Korean Mini Mental Status Exam in the Korean version of the CERAD assessment packet(MMSE‐KC) and Short form of the Geriatric Depression Scale(SGDS) were also assessed.

Result

There were no significant differences between patient and caregiver ratings on all QOL items except marriage. There were significant correlations between patient and caregiver reports of patient on all QOL items except marriage and total KQOL‐AD scores. Total KQOL‐AD Scores of patient QOL were positively significant correlated with MMSE‐KC scores and were negatively significant correlated with SGDS scores.

Conclusion

Patient and caregiver reported QOL in elderly patients with cognitive impairment did not differ. Elderly patients seem to be able to assess their own QOL properly although they have impairment in cognitive function. Depression of elderly patients with cognitive impairment adversely affects patient QOL.
Cognitive evolution of Alzheimer’s disease patients according to the serverity of obstructive sleep apnea
Authors: Carnes Anna , Piñol Gerard , Dakterzada Faride , Targa Adriano , Benitez Ivan David , Huerto Raquel , Barbe Ferran
Published: December 2020

Background

To investigate the effect of OSA on the cognitive evolution of patients with AD.

Method

In this prospective, single‐center study (NCT02814045), patients with mild‐moderate AD with and without untreated OSA were evaluated at the baseline and after 12, 24 and 36 months of follow‐up. OSA was defined as an apnea‐hypopnea index (AHI) >15/h. The primary outcome was measured by the cognitive scores on the Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐cog) and Mini‐Mental State Examination (MMSE).

Result

The cohort included 146 patients with 125 validated PSGs, from which 40 patients were diagnosed as non‐OSA (32%) and 85 as OSA (68%). The median [IQR] age of the eligible individuals was 75.0 [72.0;80.0] years and the majority was composed of women (57.25%). In addition, the mean (SD) MMSE score at the baseline was 23.53 (2.23). In the ADAS‐cog score, the mean (SD) change at the 12 months of follow‐up was 2.97 (5.73) and 0.29 (5.65) for the non‐OSA and OSA group, respectively. The estimated mean (95%) difference between the groups was ‐2.76 (0.12 to 0.16) (p=0.033). No cognitive changes were observed at several cognitive domains evaluated. There was a cognitive decline along the 3 years of follow‐up according to the MMSE score (p<0.001) (Figure 1), but no differences between the groups were observed.

Conclusion

OSA was not associated with a worse cognitive evolution after 36 months of follow‐up. Further studies will be necessary to improve the understanding of the OSA impact on the cognitive evolution of AD patients.
Multiview analysis of clinical and MRI/PET imaging and socio‐demographic data in Alzheimer’s disease
Authors: Antelmi Luigi , Ayache Nicholas , Robert Philippe , Lorenzi Marco
Published: December 2020

Background

The joint analysis of heterogeneous data in Alzheimer’s Disease (AD) is important for better clinical diagnosis and to understand the relationship between biomarkers. Anamnestic questionnaires, imaging data, and psychological tests, for example, provide specific, complementary, and sometimes overlapping views on the patient’s latent state. A method providing an interpretable representation of the relationship between this heterogeneous information could be used for improving clinical assessment and for better understanding the complex dynamics of the pathology.

Method

We propose a novel approach for the multi‐modal analysis of heterogeneous data. The model assumes a latent factor across data observed through different modalities (e.g., clinical scores, structural imaging, functional imaging, …), and jointly estimates the parameters linking the latent factor to the observations.

Result

We applied our model to clinical, socio‐demographic, and MRI/PET imaging data from 504 subjects of the ADNI cohort. Our method allows to identify the joint effect of age and pathology (Figure 1) in describing clinical condition, and to unveil the joint relationship among the biomarkers through the generative sampling process (Figure 2). It allows to infer the subject state in the age‐pathology coordinates, to follow its evolution in time, and to predict imaging data if missing.

Conclusion

Our model allowed to link clinical and multi‐modal imaging data to identify a unique latent representation highly correlated with disease status and age. The estimated parameters also highlight clinically meaningful relationships across multi‐modal observations, such as the lowering of clinical and psychological performances with brain temporal atrophy, amyloid uptake, and impaired glucose metabolism. Our model can be used to develop optimal strategies for disease classification, quantification, and prediction. Acknowledgment: This work has been supported by (1) the French government, through the UCAJEDI Investments in the Future project managed by the National Research Agency (ANR) with the reference number ANR‐15‐IDEX‐01; (2) the grant AAP Santé 06 2017‐260 DGA‐DSH, and by the Inria Sophia Antipolis‐Méditerranée, “NEF” computation cluster.
Pattern of cortical thinning in patients with mild cognitive impairment associated with obstructive sleep apnea compared to patients with age‐associated mild cognitive impairment
Authors: Thanapornsangsuth Poosanu , Chokesuwattanaskul Anthipa , Phanthumchinda Kammant , Likitjaroen Yuttachai
Published: December 2020

Background

Obstructive sleep apnea (OSA) is a reversible cause of mild cognitive impairment (MCI). There are evidences that OSA associated with decline of brain cortex. The pattern of cortical thinning in OSA associated MCI has not been well characterized. This study sought to assess pattern of cortical thinning in MCI patients with OSA (MCI‐OSA).

Method

We analyzed magnetic resonance images (MRI) of MCI‐OSA and age associated (MCI‐AA) to determine difference in cortical atrophy pattern between two groups. Firstly, cortical surfaces were reconstructed from each patient’s MRI. Cortical thickness measurement was then processed on these surfaces. At last, thickness comparison between the two groups was performed using vertex‐by‐vertex general linear model (GLM) and standard t‐test.

Result

Subjects were consecutively recruited including 22 MCI‐OSA patients and 20 MCI‐AA patients. Compared to MCI‐AA, MCI‐OSA patients has larger brain volume (p=0.002). Using GLM, we found 3 large clusters in the left anterior cingulate, the left and right lateral occipital cortices that were significantly thinner in MCI‐OSA (p<0.001, p=0.005, p=0.001, respectively). Using t‐test, we found 11 cortical regions with different thicknesses between the two groups. Only the left anterior cingulate cortex remained significantly thinner in the MCI‐OSA group using both methods.

Conclusion

We demonstrated that MCI‐OSA patients had significant thinning of left anterior cingulate gyrus as compared to MCI‐AA despite having larger brain volume.
Evaluation of adaption skills in older adults using behavioural and EEG repeated measurements during a visual oddball object detection task
Authors: Delgado Laura M. Rueda , Nolan Hugh , Buick Alison R , Barbey Florentine , Dyer John , McGuinness Bernadette , Passmore Anthony Peter , Murphy Brian
Published: December 2020

Background

Adaptation to new demands is a fundamental skill that relies on the neuroplasticity of the brain. The breadth of this adaptation (an aspect of cognitive function) is reduced with ageing and is further perturbed with amnesic mild cognitive impairment. Perturbed adaptation skills could be a potential marker of early cognitive deficits, which is key for early diagnosis. Here we aim to investigate behavioural and neurophysiological adaptation to a gamified tablet‐based version of the visual oddball paradigm in older adults across 12 weeks.

Method

89 neurotypical older adults (mean age: 58.7 years, SD: 8.89; mean MoCA score: 27.1, SD: 1.8; 77.5% female) were asked to perform a gamified 2‐stimulus visual oddball paradigm 5 times a week during a 3‐month period, while neurophysiology was recorded with a 16‐channel EEG headset designed for unsupervised use in the home. A session event‐related potential (ERP) was calculated per channel, which was then downsampled into 8‐ms bins. To assess the effect of session on the ERP signal and on the average reaction time (RT), we statistically tested two mixed effects models (per channel‐temporal bin): i) a reference model, with covariates and subject as a random effect; and ii) an across‐sessions model, with Session added as a fixed effect to the reference model.

Result

Behaviourally, RTs to Target stimulus were significantly faster across sessions. RTs in the first session and the rate of improvement between the 1st and 2nd sessions were modulated by the MoCA score. In response to the Target stimulus, there were amplitude increases with session overlapping the P300 component on frontal channels (FCz, Fpz), and on parietal channels (CPz, Cz, P3, P4). In response to the Non Target stimulus, there was a higher amplitude with Session in FC3 between 209.9‐242 ms, and in Fpz between 482.6‐514.7 ms.

Conclusion

A gamified visual oddball task is sensitive to MoCA score categorization at baseline and early stages of adaptation in neurotypical subjects. Potential neurophysiological adaptation, accompanying the behavioural adaptation, is suggested by EEG P300 amplitudes that increase across sessions.
Alzheimer’s and related dementia (ADRD) episode payments and 30‐day readmission rate and timing comparing skilled nursing facility and home health discharge destinations in a statewide collaborative
Authors: Kamdar Neil , Syrjamaki John , Mahmoudi Elham
Published: December 2020

Background

ADRD patients are high resource utilizers for hospitals and health systems with higher levels of hospitalization than their non‐ADRD counterparts. Quantifying the cost and readmissions based on where patients are discharged can provide additional information on the resource expenditure for this patient population. This study examined medical and surgical hospitalizations in a statewide collaborative to estimate total 30‐day episode payments and all‐cause readmissions for ADRD patients in a matched cohort of those discharged to skilled nursing facilities (SNF) versus home health (HH).

Method

We performed a retrospective cross‐sectional analysis of adults with ADRD using the Michigan Value Collaborative (MVC), which is a Blue Cross Blue Shield funded clinical quality initiative. This dataset uses administrative claims representing Medicare and private insurance using 30 and 90‐day episode based price standardized payments. The study period covered 2012 to 2017.We conducted bivariate analyses of baseline demographic characteristics and comorbid conditions for medical and surgical episodes among ADRD patients with SNF versus HH post‐discharge payments. Controlling for selection bias, we performed propensity score matching for ADRD patients with SNF versus HH 1:1 at a caliper of 0.001 without replacement adjusting for age, sex, 79 hierarchical condition categories (HCC), 27 different medical/surgical hospitalization types, and insurance status (Blue Cross Blue Shield or Medicare). Post‐matched differences on risk adjusted, winsorized, price standardized 30‐day medical/surgical episode payments and all‐cause readmissions were compared.

Result

After propensity matching, there were 6,024 SNF and HH ADRD matched pairs. Total 30‐day episode payments were significantly higher for SNF users ($41,719; 95% CI: $41,325, $42,112) compared to their HH counterparts ($24,132; 95% CI: $23,806, $24,458) with a difference of $17,587 (95% CI Diff: $17,075, $18,098). Furthermore, ADRD patients with SNF utilization had higher readmissions (29.1%; 95% CI: 27.9%, 30.2%) than those discharged for HH (21.4%; 95% CI: 20.4%, 22.4%; Rate Diff 7.7%; 95% CI Rate Diff: 6.2%, 9.3%). Substantially higher total post‐discharge episode payments were seen for SNF utilizers (Diff: $18,126; 95% CI Diff: $17,720, $18,531).

Conclusion

Our study demonstrates total 30‐day episode payments, readmissions, and post‐discharge payments are substantially higher for SNF ADRD patients compared to HH in a matched cohort.
The association between a parental family history of dementia and modifiable risk factors for dementia among middle‐aged individuals: A propensity score‐matched study
Authors: Vrijsen Joyce , Abu‐Hanna Ameen , De Rooij Sophia , Smidt Nynke
Published: December 2020

Background

Individuals with a positive parental family history (PFH) of dementia have an increased risk to develop dementia in the future. It is unclear whether this risk is caused by genetic factors or by modifiable‐risk‐factors for dementia, as parents and their children often share their psychosocial behavior. The aim of this study is to investigate the association between a positive PFH of late‐onset‐dementia and modifiable‐risk‐factors for dementia among middle‐aged individuals.

Method

A subsample of Lifelines (n=89,869; 35‐65years), a population‐based cohort study in The Netherlands, was used. Multiple‐imputation‐using‐Chained‐Equations (MICE) was used to replace missing values. We assessed in each imputed dataset, the association between modifiable‐risk‐factors (hypertension, cardiovascular diseases, obesity, diabetes, physical inactivity, smoking, depression, high cholesterol, unhealthy diet, excessive alcohol use, stress, social inactivity, renal dysfunction and the Lifestyle‐for‐Brain‐Health(LIBRA) score) and a PFH‐of‐dementia in two steps. First, each individual with a PFH‐of‐dementia was matched based on age, gender, education, and depending on the risk‐factor also on other potential confounders, to an individual without a PFH‐of‐dementia (ratio 1:1), using propensity‐score‐matching (PSM). Second, we used logistic, linear and multinomial regression analyses on the matched dataset to obtain the effect estimate. Effect estimates in the imputed datasets were then pooled using Rubin’s rules.

Results

After PMS, the study population consisted of 26,604 individuals with a positive PFH‐of‐dementia (mean age=46.1years(7.6); 63% female; 3% low education) and 26,604 participants without a PFH‐of‐dementia (mean age=45.1(5.1); 59% female; 1% low education). Individuals with a PFH‐of‐dementia had more often hypertension (OR=1.20;95%‐CI:1.14,1.25), high cholesterol (OR=1.35;95%‐CI:1.25,1.45), diabetes (OR=1.29;95%‐CI:1.14,1.47), cardiovascular diseases (OR=1.54;95%‐CI:1.28,1.84), depressive symptoms (OR=1.25;95%‐CI:1.09,1.42), and obesity (OR=1.15;95%‐CI:1.08,1.22) compared to individuals without a PFH‐of‐dementia. Although individuals with a PFH‐of‐dementia were more often physically active (OR=1.07;95%‐CI:1.03,1.10), they were more often current‐smokers (OR=1.12;95%‐CI:1.07,1.18).

Conclusion

Middle‐aged individuals with a PFH of late‐onset‐dementia have more often modifiable‐risk‐factors for dementia compared to their peers without a PFH of late‐onset dementia. Middle‐aged individuals with a PFH of late‐onset‐dementia is a group at risk for dementia. Further research should explore whether this group is willing to assess their dementia risk and subsequently change their health behavior in order to prevent or postpone dementia and increase healthy ageing.
The significance of reticulon4A as a potential indicator of neurodegeneration
Authors: Kulczynska‐Przybik Agnieszka , Kułakowska Alina , Tarasiuk Joanna , Dulewicz Maciej , Kurzyna Piotr , Borawska Renata , Kochanowicz Jan , Mroczko Barbara
Published: December 2020

Background

Neurodegeneration characterizes by dysfunction, progressive atrophy and loss of neurons, which is presented in both neurodegenerative as well as demyelinating disorders. Both groups of diseases share common pathological hallmarks: neuroinflammation and gradual loss of neurons and axons, which lead to the central nervous system (CNS) damage and the development of these disorders. Mounting evidence has supported the reticulon4A (RTN4A) role in the pathogenesis of some neurodegenerative and demyelinating disorders, including MS. RTN4A also known as Nogo‐A protein, contributes to neuroinflammation and demyelination. Moreover, this protein acts as a relevant inhibitor of neurite outgrowth and axonal regeneration. Therefore, the objectives of the present study were evaluation of Nogo‐A and Tau levels in the cerebrospinal fluid (CSF) of MS patients and subjects from the control group, as well as the assessment of a relationships between concentrations of immunoglobulins, albumin, immunoglobulins and albumin quotients, as well as oligoclonal bands.

Method

The concentrations of Nogo‐A and Tau proteins were measured in the CSF of 15 MS patients and 16 subjects from control group by means of quantitative technique ELISA. CSF and serum concentrations of albumin and immunoglobulins were measured by using nephelometer. To evaluate the integrity of the blood‐CSF barrier and intrathecal immunoglobulins production, albumin and immunoglobulins quotients were calculated. Furthermore, the oligioclonal bands were assessed by using isoelectofocusing method.

Result

The CSF concentrations of Nogo‐A was significantly higher in MS group in comparison with controls. The increased CSF level of the protein was observed significantly correlate with the concentration of Tau protein in MS patients. Furthermore, we revealed associations between Nogo‐A protein and CSF levels of albumin, Tau and QIgG in the whole study group.

Conclusion

Our preliminary results indicate a potential role of Nogo‐A protein in the neurodegenerative pathology of MS. Moreover, it seems that reticuon4A is a promising candidate biomarker for demyelinating disorders, including MS, but these investigations need to be further clarified using a larger study group. The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.
Recurrent vascular insult leads to memory impairment and synaptic dysfunction detected as F‐actin loss
Authors: Diwakar Latha , Maurya Shashank Kumar , Ravindranath Vijayalakshmi
Published: December 2020

Background

Vascular dementia may begin as mild cognitive changes due to blockade of blood vessels that worsen gradually as a result of multiple minor strokes. Such vascular insults occurring in the aging human brain can induce various types of cerebral tissue lesions like hemorrhage, infarction, hippocampal sclerosis and white matter lesions leading to cognitive decline. Studies have shown that multi‐infarct dementia is accounted for most cases of vascular dementia. We wanted to develop an animal model to study the vascular pathology affecting synaptic function during such multiple vascular insult to pave way for better understanding of vascular dementia.

Method

Vasoconstriction was induced by ET‐1, a 21 amino acid peptide. C57/BL6J mice aged 4‐5 months was implanted with cannula on left side of the hemisphere. ET‐1 2ug/2ul was injected through guide cannula into the intracerebroventricular space of lateral ventricle. The animals were injected with 3 doses of ET‐1 at interval of three weeks for each dose for a period of 9 weeks, at the end of dosing mice were subjected behavioral task. Animals were sacrificed, different brain regions like cortex and hippocampus were dissected out to process for biochemical analysis.

Result

Animals were injected for a period of three weeks to make sure that animal completely recovers from first vascular insult. There was significant difference in novel object task, contextual fear conditioning test and Morris water maze in ET‐1 injected mice indicating memory deficits. Gait analysis demonstrated discrepancies in stride and stance length in chronic ET‐1 injected mice compared to vehicle control. Actin treadmilling plays important role in maintaining F/G‐actin equilibrium for optimal synaptic function. Hence, we wanted to know whether chronic vascular insult affects F/G‐actin equilibrium and our results demonstrated that synaptic dysfunction seen as F‐actin disassembly might be contributing to behavioral dysfunction.

Conclusion

Repeated vascular insult resulted in irreversible learning and memory deficits in ET‐1 injected mice compared to controls leading to vascular dementia. Gait analysis indicated changes in stride and stance length after three injections of ET‐1. We observed loss of F‐actin in synaptosomes prepared from cortex of mice with chronic dose of ET‐1.
Syk inhibitor reduces oligomeric tau associated with GSK3β inactivation and autophagy activation
Authors: Yamaguchi Tomohisa , Hamano Tadanori , Sada Kiyonao , Kanaan Nicholas M. , Sasaki Hirohito , Yen Shu‐Hui , Asano Rei , Enomoto Soichi , Shirafuji Norimichi , Ueno Asako , Ikawa Masamichi , Yamamura Osamu , Nakamoto Yasunari
Published: December 2020

Background

Neurofibrillary tangle (NFT), composed of highly phosphorylated tau is one of the pathological hallmarks of Alzheimer’s disease (AD). Spleen tyrosine kinase (Syk) is non receptor type tyrosine kinase, and has various physiological functions, including histamine release in mast cells, phagocytosis in macrophage, and B cell differentiation. The possibility of Syk inhibitor for clinical application was proposed in allergic rhinitis, rheumatoid arthritis, and immunologic thrombocytopenia. The possible relationship between Syk and AD has been reported recently. We have examined the effects of Syk specific inhibitor BAY61‐3606 on phosphorylation levels of tau protein and oligomeric tau by using cell culture model of tauopathy, M1C cells.

Methods

We utilized human neuroblastoma cell line M1C cells, which expresses wild type tau protein (4R0N) via tetracycline off induction (Tet Off induction). Reduction of phosphorylated tau protein and oligomeric tau protein by Syk inhibitor was examined by using various phospho‐tau antibodies, and tau oligomer specific antibody. Influences of activity of autophagy by Syk inhibitor was also examined by western blot analysis.

Results

In this cell line, 72kDa of Syk protein was identified by Western blot analysis. Phosphorylated tau detected by various phospho‐tau antibodies, including PHF‐1, CP13, and AT270 was decreased by 1, 10 μM of Syk inhibitor. One of the patholoigical form of tau, caspase cleaved tau detected by TauC3 was also decreased by Syk inhibitor. Oligomeric tau, which detected by tau oligomer specific antibody, TOC1 was also decreased by Syk inhibitor. Syk inhibitor also inactivated glycogen synthase kinase 3β (GSK3β). Syk inhibitor upregulated autophagy detected by increase of LC3‐II, and reduction of P62. In summary, Syk inhibitor decreased phosphorylated tau as well as total tau by upregulating autophagy, and inactivating tau kinases, including GSK3β. Finally, oligomeric tau was reduced by Syk inhibitor.

Conclusion

Syk inhibitor may have promising for the treatment of tauopathy, including AD.
Cross‐cultural validation of the motivation to change lifestyle and health behaviours for dementia risk reduction scale in the Dutch general population
Authors: Joxhorst Tessa , Vrijsen Joyce , Niebuur Jacobien , Smidt Nynke
Published: December 2020

Background

Since treatment options for curing dementia are unavailable to date, prevention of dementia is the key in decreasing the burden of dementia for patients, their families, and caregivers, as well as societies as a whole. Around one third of all dementia cases worldwide is estimated to be attributable to nine modifiable risk factors (Livingston et al., 2017). Although behavioural change is crucial for dementia risk reduction, changing health behaviour is complex. Currently, no valid scale exists to measure attitudes and beliefs towards lifestyle change for dementia risk reduction in the Netherlands. This study aims to validate the Motivation to Change Lifestyle and Health Behaviors for Dementia Risk Reduction (MCLHB‐DRR) scale (Kim et al., 2014) in the Dutch general population.

Method

Translation and back‐translation of the MCLHB‐DRR scale (7 factors, 27 items) was performed to establish a well‐translated Dutch version of the questionnaire. Data were collected by an online survey ‘Lifestyle and dementia’ among a random sample of 4500 residents of the municipality of Groningen (the Netherlands) aged between 30 and 80 years. Exploratory and Confirmatory Factor Analyses (EFA and CFA) were conducted to assess construct validity. Cronbach’s alpha was calculated to assess internal consistency.

Result

Results of the EFA (N = 618) pointed towards a seven‐factor solution with a nearly perfectly clean factor structure. Deletion of four problematic items resulted in a clean factor structure. Fit indices from CFA after deleting these four items indicated an excellent model fit (RMSEA = 0.043, CFI = 0.960, TLI = 0.951, χ²/df = 2.130). Cronbach’s alphas ranged from 0.69 to 0.93, indicating good internal consistency.

Conclusion

The Dutch version of the MCLHB‐DRR scale (7 factors, 23 items) is a valid instrument to assess the attitudes and beliefs towards lifestyle and health behavioural changes for dementia risk reduction in the Dutch general population aged between 30 and 80 years old. Before the MCLHB‐DRR scale can be used in intervention studies aimed at dementia risk reduction in the Netherlands, insight in the reproducibility and responsiveness is needed.
APOE‐e4, microbiota and inflammation in healthy elderly
Authors: Marizzoni Moira , Cattaneo Annamaria , Mirabelli Peppino , Mombelli Elisa , Andryszak Paulina , Nicolosi Valentina , Roux‐Lombard Pascale , Salvatore Marco , Frisoni Giovanni B.
Published: December 2020

Background

Apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for AD and has different roles in modulating the disease process along with the continuum from intact cognition to dementia due to AD, with its strongest influence at the earliest stages. The aim of this study is to test our hypothesis that places APOEε4 as a trigger in the perturbation of gut microbiota homeostasis.

Method

Fecal samples were collected from 28 cognitively intact elderly with known APOE genotype. Bacterial 16S rRNA gene was sequenced according to the 16S‐protocol on MiSeq (Illumina). Taxonomic abundance was computed with the free software package QIIME 2 (Quantitative Insights into Microbial Ecology; Bokulich, Microbiome, 2018; https://qiime2.org/). Plasma levels of cytokines were measured using a commercially available multiplex beads immunoassay, based on the Luminex platform.

Result

APOEε4 carriers showed altered abundance in 5 genera (LEfSe, p<0.048), 3 more (Bifidobacterium, Actinomyces, Lactococcus) and 2 less (Ruminococcaceae UCG‐003, Candidatus Melainabacteria) abundant, as well as decreased blood levels of IL‐8 (p=0.047) compared with non‐carriers. Elevated abundance of Bifidobacterium, Actinomyces, Lactococcus were associated with decreased levels of IL‐8 and IL‐6 (rho<‐0.41, p<0.040).

Conclusion

Structural microbiota alterations are associated with the restraint of some peripheral pro‐inflammatory signaling pathways in healthy subjects at genetic risk for AD. As a “good” form of inflammation (i.e. I‐6, IL1‐beta, TNF‐alpha) has been proposed to be beneficial in the early phases of the disease in several AD mouse models (Chakrabarty, J Neurosci 2010; Shaftel, J Neurosci 2007), these preliminary data suggest that the deleterious impact of the APOE4 allele on AD development might start in the gut.