bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of care home placement in people diagnosed with dementia in a New Zealand memory service
Authors: Cullum Sarah , Yates Susan , Varghese Chris , Coomarasamy Christin , Whittington Rosie , Cheung Gary
Published: December 2020

Background

As the global population ages the burden of dementia is expected to rise across all cultures around the world. Much of the social sector costs of dementia care in high income countries is due to residential care. The aim of this study is to investigate the sociodemographic and clinical characteristics that predict care home placement in people diagnosed with dementia at a New Zealand memory service.

Method

This cohort study used routinely collected clinical data gathered on referrals to the Memory Service at Middlemore Hospital in South Auckland between 2013 and 2019. Survival analysis was carried out using Cox regression models to determine significant risk factors and their associations with care home placement.

Result

Comparison by ethnic group showed that NZ Europeans were on average older compared to Māori and Pacific Islanders, and were more likely to be living alone. As might be expected, age, more severe cognitive impairment and living alone were independently associated with increased risk of care home placement. After adjustment for these factors, Māori and Pacific Islanders were still less likely to be placed in a care home. People diagnosed with mixed dementia were more likely to be placed in a care home than those diagnosed with other dementia subtypes. Prescription of antipsychotics was highly associated with care home placement however we were unable to establish if antipsychotics were prescribed before or after placement.

Conclusion

These data will help us to understand differences in adverse outcomes in people with dementia. The ability of Māori and Pacific Islanders to continue to care for their family member with dementia needs to be examined in more detail, as the findings might empower and enable other families to postpone care home placement.
Cognitive test norms and comparison to normal cognition and mild cognitive impairment: A population‐based study among community‐dwelling Filipinos
Authors: Dominguez Jacqueline C. , Citron Raphael Louis B. , De Guzman Ma Fe P. , Guevarra Anne Cristine Deocariza , Yu Justine Megan F. , Galvez Francy Joy , Natividad Boots P. , Phung Thien Kieu Thi
Published: December 2020

Background

Clinicians use neuropsychological assessment to screen individuals for cognitive impairment since it more convenient and can detect impaired parts of cognition to provide early treatment. This study is aimed to differentiate the cognitive performance on the Alzheimer’s Disease Assessment Scale – Cognition (ADAS‐Cog) among the older adults with normal cognition and with MCI.

Method

The sample composed of 302 participants aged ≥60 years old who met the score of 25 in the Mini‐mental status examination (MMSE). Psychologists would then administer cognitive measures (ADAS‐Cog, logical memory recognition and delayed recall, verbal fluency on animals and vegetables, digit span forward and backward, digit symbol, and trailmaking A and B) upon meeting. ADAS‐Cog total and subtest scores were compared across the two groups. Receiver operating characteristics (ROC) analysis were performed and, sensitivity and specificity were calculated.

Result

Most of the participants are female (81.8%) compared to males (17.9%). 64.2% has normal cognition while 35.8% of them have MCI. The mean age was 69.16 (±5.77) years and mean years of education of 9.11 (±3.57). The MCI group they have a cut‐off ADAS‐Cog score of 13.57(±5.49) (sensitivity= 0.63; specificity= 0.69) while the normal group have a score of 9.96 (±4.79). It also showed significant difference (t=5.971; p≤0.01) among the groups; domains showed a significant relationship i.e.: word list recall, naming, commands, ideational praxis, orientation, word list recognition (p≤0.01) and constructional praxis (p=0.015). Other cognitive measures besides digit symbol (t=1.578; p=0.116) are significant i.e. logical memory recognition and recall, verbal fluency on animals and vegetables, digit span forward and backward, and trailmaking A and B (p≤0.01).

Conclusion

The ADAS‐Cog is inapplicable as a screening tool for MCI but specific for MCI diagnosis. There is significant difference found between functional impairment among MCI and normal cognition in the overall and subtests scores.
Are amyloid and tau synergistic? How to interpret an amyloid/tau interaction on cognitive decline in clinically normal adults
Authors: Buckley Rachel F. , Chou Hsiang‐Chin Lori , Properzi Michael J , Papp Kathryn V. , Chhatwal Jasmeer P. , Rentz Dorene , Johnson Keith A. , Sperling Reisa A. , Schultz Aaron P.
Published: December 2020

Background

Many recent studies have examined interactions between β‐amyloid (Aβ) and tau‐PET to predict clinical progression. Ab and tau are moderately correlated in clinically‐normal older adults (r∼0.4‐0.5, p<0.001; Figure 3B), which complicates statistical modelling of interactive effects. Multi‐collinearity can result in conflated interactions that reflect nonlinear effects (square of shared variance) rather than true interactions between separate channels of information. Here, we use simulated and real data to examine the extent to which an Aβ and tau interaction reflects ‘true’ synergism vs. conflated shared variance in predicting cognitive decline.

Method

We first ran simulations to illustrate how interactions between collinear variables inflates the association with shared sources of variance: we simulated two collinear independent variables by generating three random sources of variance (one shared variance [v1] and two unique sources of variance [v2 and v3]) (Figure 1). extracted two principal components from these simulated variables (PC1shared and PC2unique) and ran correlations between a PC1*PC2 interaction and different combinations of the simulated v1‐v3 sources of variance (Figure 1). We also examined real data (Aβ‐PET, entorhinal and inferior temporal tau‐PET, and longitudinal PACC) from the Harvard Aging Brain Study (n=224; Agemean=72.0 (sd=7.3), Female=59%) and ADNI (n=291; Agemean=71.8 (sd=6.5), Female=47%), in order to compare the pattern of effects with the simulated results.

Result

The PC1shared, and its square, PC1shared
2, were strongly associated with shared variance and its square (v1 and v1
2; see Figure 2). A Principal Components Analysis (PCA) of Aβ and entorhinal tau in HABS and ADNI cohorts resulted in a PC1shared and PC1shared
2 that closely associated with PACC slopes, mirroring the simulated results showing collinear interactions are more likely to represent conflated shared variance (see Figure 3A). Interactions between Aβ with inferior temporal tau were less extreme, suggesting additional associations between PACC slopes and PC2unique.

Conclusion

Our results suggest an Aβ and tau interaction should be interpreted with caution, as this may represent the non‐linear effects of shared variance, rather than the interaction of two (Aβ and tau) unique sources of variance. That is, PC1shared can be interpreted as a squared term, e.g. tau2 or Aβ2, rather than reflecting something truly synergistic between the proteinopathies to influence cognitive decline.
Attitudes towards memory research participation: Focus groups with elderly African Americans viewing a community‐created educational video
Authors: Chin Shehan , Umpierre Mari , Neugroschl Judith , Sewell Margaret , Ugwu Nkemdilim , Evans Kirsten , Sano Mary
Published: December 2020

Background

Alzheimer’s Disease (AD) disproportionately impacts African Americans (AA) but they are underrepresented in clinical research. A previous study (Sewell et al., AAIC 2019), found that the use of an educational video (Memory Research: Is it right for me?) created by the ADRC in collaboration with our primarily Latino Community Advisory Board was, in conjunction with Q&A sessions, effective at increasing interest in research among Latinos. The aim of the current pilot study was to engage community AA elders in focus groups to explore their feedback as regards clarity, relatability, and effectiveness of the video as a tool to engage them in conversations about research participation.

Method

A Moderator’s Guide was created to ask the interviewees to evaluate the video re relatability, clarity and whether it impacted interest in participating in research. General questions were asked regarding knowledge of research and memory health. Two hour‐long focus groups were conducted with 14 participants who watched the video. An ADRC faculty member used the Moderator’s Guide to prompt responses while an observer took notes.

Results

Mean age 72; 93% female; 93% AA; 7% Latino; 86% > high school graduates, 14% < 6th grade. Groups were transcribed, and data was coded to extrapolate themes using Grounded Theory techniques. One theme pertaining to attitudes toward research participation was fear (43% of participants) and included concerns that there would be side effects from medications or overly personal questions; the second theme was the video increased curiosity but a need for more information (e.g. requests for more details, and for specifics of how research is conducted) (62%). Participants also stated that the video clarified their understanding and decreased fear of research participation. As regards relatability, one member noted that the video should have included men and African Americans.

Conclusion

The video was well‐received in primarily AA focus groups. Themes included both fear of research but also curiosity and a desire to know more. Given these encouraging results, a quantitative research study with a larger sample further exploring these themes and looking at the effectiveness of this recruitment strategy in increasing research participation is warranted.
Machine‐learning based EEG biomarker for early screening of amnestic mild cognitive impairment (aMCI)
Authors: Youn Young Chul , Kang Seung Wan , Lee Hannah , Park Ukeob
Published: December 2020

Background

aMCI is the most progressive prodromal stage of dementia. For early screening of dementia, it is very important to discriminate aMCI from age‐related physiologic cognitive decline. In addition, community‐based screening tool requires appropriate, less expensive technology. We developed QEEG biomarker algorithm using mixed machine‐learning methods, and validated it

Method

Nineteen channels of EEGs were measured from 382 community‐based normal subjects and 182 aMCI who showed standardized delayed verbal memory score under 16 percentiles. Various linear and non‐linear quantitative features were generated from single EEG such as frequency band power, power ratio, peak alpha frequency, cortical source current density, functional connectivity based on imaginary coherence and non‐linear complexity. Independent t‐test and least absolute shrinkage and selection operator (LASSO) were used to select the best combination of features. Probability index score for aMCI was developed by combination with logistic regression and penalized linear regression methods with 73 aMCI and 75 community‐based normal subjects. Probability index score could be ranged from 0 to 100, and higher score was referred to as more severe memory impairment due to underlying pathologic progression. Five fold validation was done to fit the best model for largest area under curve (AUC).

Result

The probability index score for aMCI was validated with blinded independent EEG dataset from 3 hospitals in Korea. The test set consisted of 307 community‐based normal and 109 aMCI subjects. When index score of 60 was applied at cut‐off value to discriminated aMCI from age‐related normal memory declined, the sensitivity was 93% and specificity was 90%. AUC was 0.93 (95% CI: 0.89–0.96)

Conclusion

QEEG findings of aMCI were different from those of age‐related normal memory declined. Above aMCI probability index score showed promising result. Individual EEGs are much various, and just single specific EEG feature or single machine‐learning method couldn’t be enough to show the significant discriminating power. Careful selection of EEG features and curation of different machine‐learning and statistical models is recommended. This EEG biomarker should be tested for larger aMCI and normal subject populations, and continuously revised and upgraded.
Effects of sub‐chronic oral caffeine consumption on memory and the hippocampal Akt, GSK‐3β and ERK in mice
Authors: Moosavi Maryam , Esmaeili Zahra , SoukhakLari Roksana , Moezi Leila , Pirsalami Fatema , Farrokhi Majid Reza , Kazerouni Armaghan
Published: December 2020

Background

Caffeine, one of the most widely consumed psychoactive substance in the world, has been shown to affect mood, memory, alertness, and cognitive performance. However, the literature about the effects of caffeine intake on memory is equivocal. This study aimed to assess the effect of sub‐chronic oral gavage of caffeine on memory and the phosphorylation levels of hippocampal Akt (protein kinase B), GSK‐3β (Glycogen Synthase Kinase‐3beta) and ERK (extracellular signal‐regulated kinase) in mice.

Method

Adult male NMRI mice were administered with sub‐chronic caffeine at the doses of 0.25, 0.5, 0.75 and 1.5 mg/kg/oral gavage for 10 days before training which continued until the retention day of passive avoidance task. Upon completion of the behavioral assessments, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of Akt, GSK‐3β and ERK proteins.

Result

The results showed that sub‐chronic caffeine ingestion at the dose of 0.5 mg/kg improves memory in mice. Furthermore, the memory enhancing dose of caffeine (0.5 mg/kg) elevated the phosphorylated to total ratios of hippocampal Akt, GSK‐3β and ERK.

Conclusion

This study suggests that sub‐chronic low dose of caffeine improves memory and increases the phosphorylation of hippocampal Akt, GSK‐3β and ERK proteins.
Differences in quantitative electroencephalogram and voxel‐based volumetry between encoding and retrieval in amnestic mild cognitive impairment
Authors: Youn Young Chul , Yeo So Eun , Jung Ho Tae , Kang Dong Won , Lee Hannah , Kang Seung Wan
Published: December 2020

Background

Amnestic mild cognitive impairment (aMCI) has been considered as prodromal stage of Alzheimer’s disease. Memory impairment can be classified into encoding failure (EF) and retrieval failure (RF).

Objects

The aim of this study is to classify patients with single‐dominant aMCI according to the type of memory impairment (EF and RF) and to examine the quantitative EEG and MRI brain volume with significant differences between the groups.

Method

This study used the EEG data of patients who visited Chung‐Ang University Hospital Department of Neurology from January 2012 to May 2019 and were diagnosed with single‐dominant aMCI. A total of 165 collected EEG data were classified into 87 EF (73.76 ±8.26 years) and 78 RF (73.42 ± 7.88 years) based on the results of the Seoul Verbal Learning Test. EEG was done using the standard 10–20 system (21 electrodes) using a digital electroencephalograph (Comet AS40 amplifier EEG GRASS; Telefactor, USA). The stored EEG data were subjected to quantitative EEG analysis through noise preprocessing using iSyncBrain™ (iMediSync, Inc., Korea), and group analysis was performed according to two types. Subjects were also performed 3D T1 MRI and voxel based morphometry using Computational Anatomy Toolbox for SPM 12.

Result

The beta2 band power(frequency range : 15∼20Hz) in the relative power spectrum showed statistically significant difference between the two groups in the Cz and parietal electrodes(P3, Pz, P4) (p<0.05). Also, broad area around occipito‐parietal region showed significant increase of TB2R(Theta/Beta2 power ratio) both sensor and source level analysis. Increasing pattern of TB2R was also observed in both parahippocampal area. There was no significant difference of regional brain volumes between aMCI with EF and RF.

Conclusion

EF and RF of aMCI showed no structural differences, but functional differences, suggesting the possibility of different stages or pathologies of cognitive impairments.
Neuropsychiatric symptoms in early stage autosomal dominant and sporadic Alzheimer’s disease
Authors: Pawar Sanjay , Montoya Lucy , Barrera Lillibeth , Mora Livier , Cortez‐Sanchez Kristyan , Brook Jenny , Ringman John M.
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) in AD, though more prevalent and severe in advanced disease, can occur as early features, with case reports suggesting more robust NPS in autosomal dominant Alzheimer disease (ADAD). The characterization of NPS in person with ADAD and their comparison to late‐onset Alzheimer’s disease (LOAD) enhances our ability to anticipate such symptoms and provides insight into differences in the underlying pathology of the two forms of the disease.

Method

Informants of 19 participants with mutations known to cause ADAD (mean age 45.58, 36.8% male) and 115 participants with LOAD (mean age 74.71, 42.6% male) were administered the full Neuropsychiatric Inventory (NPI) to assess the presence, frequency, and severity of 12 NPS, namely delusions, hallucinations, agitation, depression, anxiety, elation, apathy, disinhibition, irritability, aberrant motor behavior, sleep, and eating disorders. All participants had Clinical Dementia Rating (CDR) scores of 0.5. Chi‐square tests were used to compare the prevalence of NPS between ADAD and LOAD patients using both NPI screening and subquestions.

Result

ADAD and LOAD groups did not significantly differ in terms of MMSE score, CDR Sum of Boxes, gender, or years of education though ADAD subjects were more likely to be of Latinx origin (84% vs. 23%, p<0.001). ADAD and LOAD subjects did not differ on any qualifying questions, except for apathy, which was more common in ADAD mutation carriers (20.9% of LOAD subjects vs. 44.4% of ADAD subjects, p=0.039). Positive responses to subquestions regarding whether the participant was less affectionate and less interested in family were more commonly endorsed in ADAD.

Conclusion

Although apathy was more prevalent in ADAD subjects, the difference was not large and was not maintained when controlling for multiple comparisons. We therefore failed to identify robust differences in NPS between ADAD and LOAD. Our findings are limited by the small sample size of ADAD subjects but suggest that NPS are not markedly different in the early stages of ADAD and LOAD.
Regression‐based normative data for the Rey Auditory Verbal Learning Test in Norwegian and Swedish adults ages 40 to 80
Authors: Espenes Jacob , Eliassen Ingvild Vøllo , Fladby Tormod , Eckerström Marie , Wallin Anders , Waterloo Knut , Hessen Erik , Kirsebom Bjørn‐Eivind
Published: December 2020

Background

Adequate memory assessment is important in neuropsychological evaluation of middle‐aged and older adults with suspected mild cognitive impairment (MCI) and/or Alzheimer’s disease. The Rey Auditory Verbal Learning Test (RAVLT) is a widely used measure of episodic verbal memory. To our knowledge, culturally adapted and demographically adjusted normative data for the RAVLT are currently not available for Scandinavian adults. The objective of this study was to develop regression‐based norms for the Rey Auditory Verbal Learning Test (RAVLT) for Scandinavian adults aged 40 to 80 years. We also test the validity and demographic adjustment of these norms in a clinical sample of participants with mild cognitive impairment.

Methods

Participants were cognitively normal healthy controls from the Norwegian Dementia Disease Initiation cohort (n=72), and the Swedish Gothenburg MCI study (n=124). Using a regression‐based norming procedure, we estimated effects of age, gender and years of education on RAVLT test scores. The newly developed norms were applied in an independent sample of adults with MCI (n=59) from the DDI cohort, and we compared performance between the two groups using independent t‐tests.

Results

Lower age, female gender and more years of education predicted higher performance on the RAVLT. The norms successfully adjusted for the demographic variables in the MCI sample, and performance was significantly higher in the healthy control group (p<.001).

Conclusion

We propose regression‐based norms the RAVLT adjusting for the effects of age, gender and education. The norms may be used for assessment of Norwegian and Swedish adults between the ages of 40 and 80 years, with between 6 and 22 years of education.
Polygenic risk score for Alzheimer’s disease and its association with eye movement performance
Authors: Coors Annabell , Imtiaz Mohammed Aslam , Aziz N. Ahmad , Ettinger Ulrich , Breteler Monique M.B.
Published: December 2020

Background

Many neurodegenerative disorders are characterised by changes in specific eye movement (EM) outcomes. Individuals with Alzheimer’s disease (AD) make more antisaccade errors and correct a lower proportion of those errors compared to controls. EM impairments occur at an early stage of neuropathological changes and have, therefore, been discussed as a potential biomarker. Despite high test‐retest correlations for measures of EM performance and an estimated heritability of >40% for antisaccade performance, genetic association studies identified only a few single‐nucleotide polymorphisms (SNPs) related to EM performance. Polygenic risk scores (PRSs) are advantageous as they summarize the effects of many SNPs into a single score. Therefore, we assessed whether higher genetic risk for AD in healthy participants was associated with higher antisaccade error rate and lower correction rate of antisaccade errors.

Method

The analyses were based on data of the first 2,000 participants (aged 30‐95) of the Rhineland Study, a community‐based prospective cohort study in Bonn, Germany. Genotyping was performed on Omni 2.5 exome arrays. We created PRS for AD by including all SNPs that reached genome‐wide significance at a threshold of p=5x10‐7in stage one of the GWAS of the “IGAP consortium”. Missing SNPs were imputed using the 1000 Genomes reference panel. We examined the association between genetic risk for AD and antisaccade error rate using multivariable regression with PRS as predictor and antisaccade error rate as outcome variables. For antisaccade correction rate we used a one‐inflated beta regression model as the residuals were severely skewed. Ancestry, age, age2, sex, visual acuity and education were added as covariates in both regression models.

Result

Polygenic risk for AD was associated with neither antisaccade error rate nor the proportion of uncorrected errors in those who did not correct all of their errors. However, a higher PRS for AD was associated with a lower odds of correcting all mistakes (odds ratio=0.85 (95%‐CI:0.73‐1.00) per one standard deviation increase in PRS).

Conclusion

Polygenic risk for AD was associated with error correction rate in healthy individuals. Our findings suggest that eye movement performance may be a potential biomarker for early‐stage AD‐related neuropathological changes in the general population.
Red cell distribution width (RDW) and the risk of dementia in the oldest‐old: The Monzino 80‐plus population‐based study
Authors: Galbussera Alessia A , Tettamanti Mauro , Riva Emma , Mandelli Sara , Forloni Gianluigi , Lucca Ugo
Published: December 2020

Background

The red cell distribution width (RDW) is one of the routine parameters of a complete blood count measuring the range of variation of red cell volume, with higher values indicating greater heterogeneity in cell size. Higher RDW has been associated with poorer cognitive performance, prevalent dementia, and severity of leukoaraiosis in middle‐aged and older adults. Elevated RDW has been linked with systemic inflammatory processes, dysfunction of microcirculation, indices of oxidative stress. Existing literature on the subject is however very scanty. Objective of the present study was to explore the association of RDW with prevalent and incident dementia among the oldest‐old participants in the Monzino 80‐plus study.

Method

A RDW measurement was available for 812 participants in a door‐to‐door, prospective population‐based study on the prevalence and incidence of dementia among 80‐years and older residents in the province of Varese, Italy. Diagnosis of dementia was made according to DSM‐IV criteria. Potential confounders included in "fully”‐adjusted models: age, sex, education, smoking history, alcohol consumption, hospital admission during the previous year, history of diabetes, hypertension, myocardial infarction, heart failure, respiratory failure, renal failure, stroke, TIA, parkinsonism, cancer.

Result

Participants were on average 90.7 (5.3) years old, 74.5% women, and had a mean (SD) 5.0 (2.4) years of education. Mean RDW increased with age (p for trend <0.0001). Compared to the lowest quartile of RDW (≤12.8%), the highest (≥14.4%) was significantly associated with increased odds of having dementia (age‐, sex‐, and education‐adjusted OR: 1.64; 95%CI: 1.05‐2.56; p=0.0310). When the model was fully‐adjusted, the association was no longer significant (OR: 1.39; 95%CI: 0.86‐2.25; p=0.1795). Over a 15‐year follow‐up 225 subjects were diagnosed with dementia out of 465 participants without at baseline. Oldest‐old in the highest quartile of RDW did not have a significantly increased risk of incident dementia with respect to those in the lowest (univariate analysis, HR: 1.29; 95%CI: 0.87‐1.93; p=0.2109). Similar results were obtained using RDW as a continuous variable in both cross‐sectional and longitudinal analyses.

Conclusion

In the present prospective population‐based study in the oldest‐old, elevated RDW was not significantly associated with an increased risk of developing dementia.
Low plasma cortisol and large hippocampal volume are associated with reduced risk of clinical progression in MCI
Authors: Huijbers Willem , Kirschbaum Clemens , Wirth Miranka ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

High cortisol concentration, a biomarker of hypothalamic‐pituitary‐adrenal (HPA) axis activation, and low hippocampal volume have been linked to increased risk for Alzheimer’s disease (AD). This longitudinal study evaluates the impact of baseline plasma cortisol levels on hippocampal atrophy and on clinical progression in patients with mild cognitive impairment (MCI).

Method

Participants with mild cognitive impairment (MCI, n=305) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) based on measures of plasma cortisol (at baseline) and hippocampal volume. We assessed relationships between plasma cortisol levels, hippocampal volume, and risk of progression to clinical AD over a variable study period of up to 100 months.

Result

Higher plasma cortisol levels were related to greater decline in hippocampal volume in MCI patients, adjusting for baseline volume (Figure 1, left). Hippocampal volume at baseline predicted progression to clinical AD, while plasma cortisol alone did not. Plasma cortisol interacted with hippocampal volume (Figure 1, right), such that MCI patients with relatively large hippocampal volumes and low plasma cortisol levels at baseline were less likely to progress to clinical AD.

Conclusion

This study demonstrates the involvement of plasma cortisol in hippocampal degeneration and risk of clinical progression in MCI patients. Our findings suggest that regulation of HPA axis activation may be protective against neural degradation and clinical decline in these high‐risk individuals.
Multimodal phenotyping of synaptic damage along the Alzheimer disease continuum
Authors: Jelic Vesna
Published: December 2020

Background

Dysfunction of brain neuronal connections is one of the earliest and best correlates of cognitive deficits in patients with Alzheimer disease (AD), preceding neuronal cell death. There is no established biomarker test for early synaptic pathology. In this context, EEG and novel CSF synaptic markers are of great interest as they complementarily mirror functional and molecular aspects of synaptic dysfunction.

Method

QEEG power, synchronisation, microstates and topographical analysis of generators of EEG activity were calculated from a naturalistic Memory Clinic cohort consisting of 637 individuals with different stages of cognitive impairment from subjective cognitive decline (SCD), mild cognitive impairment (MCI) and AD dementia, as well as 308 healthy elderly controls from the Swedish national aging study. Patients performed lumbar puncture and CSF was analysed for routine AD biomarkers and saved for further analysis of novel synaptic markers. In 67 MCI and AD patients FDG‐PET was performed.

Result

In patients, Global Field Power (GFP) in slow delta and theta frequency has inverse correlation with amyloid pathology while GFP in fast alpha and beta frequencies correlate with markers of neurodegeneration, Figure 1 a. A similar pattern of association between CSF biomarkers and Global Field Synchronisation (GSF) was found in fast alpha and beta frequencies, Figure 1b. Analysis of resting EEG microstates topography revealed association between CSF Aβ42 levels and alterations in the topography of symmetrical microstate class C, while alterations in the topography of asymmetrical microstate class B was associated with CSF p‐tau levels. There is a significant gradient‐like increase in mean contributions of asymmetrical classes A and B and decrease in contribution of symmetrical classes C and D with the more severe stage of cognitive impairment, Figure 2. In AD and MCI patients with CSF verified amyloid pathology brain glucose hypometabolism in temporoparietal lobes is significantly associated with altered EEG functional connectivity and “disconnection” of the same regions of interest on standardized EEG functional imaging technique sLORETA.

Conclusion

There is a selective association of qEEG power, global and regional connectivity and microstates parameters with molecular AD pathology. Ongoing study is exploring if there is a similar association with novel CSF synaptic marker neurogranin.
Brain free‐water increases mediate the association of blood cardiovascular biomarkers with longitudinal cognitive decline in prodromal and clinical dementia
Authors: Ji Fang , Pasternak Ofer , Chai Yuek Ling , Liu Siwei , Ong Marcus Qin Wen , Tan Boon Yeow , Richards Arthur Mark , Kan Cheuk Ni , Venketasubramanian Narayanaswamy , Chen Christopher , Lai Mitchell Kim Peng , Zhou Juan Helen
Published: December 2020

Background

There is increasing awareness of the “Heart‐Brain Connection”, where cardiovascular function may potentially contribute to cognition. Brain free‐water (FW) increases, a novel imaging marker reflecting extracellular water molecule alteration, has been associated with cerebrovascular disease (CeVD) and cognitive impairment. We have previously shown an association between blood cardiovascular biomarkers (BCBs) and cognitive impairment. However, no study has examined the association between FW and BCBs. We hypothesized that FW would be related to BCB and would mediate the effects of BCBs on cognition.

Method

BCBs (N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), high sensitivity cardiac troponin T (hs‐cTnT), growth differentiation factor 15 (GDF‐15)) were measured in 232 patients (134 cognitive impairment no dementia, and 98 dementia with and without CeVD), who also underwent T1 and diffusion MRI. The FW method was applied to derive individual FW maps from diffusion MRI. We tested the association of BCBs with skeletonised white matter (WM)‐FW or surfaced grey matter (GM)‐FW by regression. Moreover, we measured the mediation effects of FW on the association of BCBs with baseline cognition and longitudinal decline by path analysis.

Result

Higher BCBs were associated with widespread WM‐FW increases (Figure‐1) and GM‐FW increases primarily in the default mode, executive control and somatomotor networks (Figure‐2). Both higher WM‐FW and GM‐FW mediated the associations of BCBs with baseline (cross‐sectional) global cognitive impairment (Figure‐3A) and longitudinal decline over 5 years (Figure‐3B). For individual cognitive domains, the higher mean WM‐FW and network‐specific GM‐FW mediated the associations of higher BCBs with baseline memory and executive function deficits (not shown) and longitudinal decline (Figure‐4). Specifically, higher GM‐FW in the executive control network was responsible for executive function impairment, while GM‐FW in the default mode network mediated the relationship with memory dysfunction, both cross‐sectionally and longitudinally.

Conclusion

This is the first report of an association between BCBs and FW. Importantly, we found that markers of cardiovascular dysfunction could affect baseline cognition and longitudinal cognitive changes through widespread WM and GM network‐specific FW abnormalities in memory‐clinic patients. Further research is needed to investigate if the use of such accessible cardiovascular blood biomarkers could facilitate management and treatment of cognitive impairment and dementia.
Mediterranean versus western diet effects on cerebral cortical thickness and volume in cynomolgus macaques
Authors: Shively Carol A. , Frye Brett M. , Register Thomas C. , Andrews Rachel N. , Appt Susan E. , Vitolins Mara Z. , Uberseder Beth , Silverstein‐Metzler Marnie G. , Chen Haiying , Whitlow Christopher T. , Barcus Richard A. , Lockhart Samuel N. , Corbitt Sarah E. , Craft Suzanne
Published: December 2020

Background

Associations between diet, cognitive decline and neurodegenerative disease, including Alzheimer’s Disease (AD), have been reported, but whether these relationships are causal is difficult to determine in human studies. Cynomolgus macaques (Macaca fascicularis), like humans, are omnivorous, have complex central nervous systems, and are susceptible to diet‐induced diseases. Similar to humans, these nonhuman primates accumulate amyloid and tauopathies with age, and diabetes accelerates age‐related amyloid accumulation. Thus, these primates are appropriate models for investigations of diet effects on the brain.

Method

Using structural magnetic resonance imaging, we examined diet effects on brain anatomy by measuring the thicknesses and volumes of AD‐signature cortical regions of interest (ROIs) in 38 middle‐aged females, at baseline and after consumption of either a Mediterranean (MED) or Western (WEST) diet for 36 months (∼ equivalent to a 9‐year follow up in humans).

Result

Using repeated measures analysis, cortical thicknesses were significantly increased in the WEST diet group in the angular gyrus (p<0.001), inferior temporal gyrus (p<0.001), middle temporal gyrus (p<0.001), superior temporal gyrus (p<0.001), supramarginal gyrus (p<0.001), fusiform gyrus (p<0.01), precuneus (p<0.001), parahippocampal gyrus (p<0.01), and an AD meta‐ROI (p<0.001). WEST diet also resulted in increases in total brain volume (p<0.02) and gray matter (p<0.01) and decreases in cerebrospinal fluid (p<0.01), white matter (p<0.01), and deep gray matter (striatum and thalamus) (p<0.05). In contrast to the patterns observed in the WEST diet group, thicknesses and volumes generally remained unchanged between baseline and 31 months treatment in animals consuming the MED diet.

Conclusion

Taken together, these findings demonstrate that WEST diets likely induce widespread structural shifts, which may increase risk of cognitive decline and neuropathology; whereas MED diets may exact a stabilizing influence on the brain. This study provides important insights about the significance of diet on brain structure, and lays the groundwork for future investigations to uncover the molecular underpinnings of diet‐induced changes in the brain.
Sleep disturbance and incident Alzheimer’s disease: A UK Biobank study of 502,538 middle‐aged to older participants
Authors: Gao Lei , Li Peng , Cui Longcong , Wong Patricia M , Johnson‐Akeju Oluwaseun , Lane Jacqueline , Saxena Richa , Scheer Frank , Hu Kun
Published: December 2020

Background

Recent cross‐sectional studies have suggested a link between sleep disturbance and worse neurocognitive function. We hypothesized that sleep disturbance traits (short/long habitual sleep duration, insomnia, daytime somnolence, and napping), and sleep apnea were linked to the development of incident Alzheimer’s disease (AD) in a large, prospective cohort spanning over a decade.

Method

We studied 502,538 participants from the UK Biobank, free from AD at baseline (mean age 57, range: 37‐73), who have been followed for up to 12 years. AD date of diagnosis was obtained through algorithmic combinations of coded information from hospital admissions (diagnoses and procedures) and death registries. Cox proportional hazards models were performed to examine the association between sleep disturbance with incident AD during follow‐up. Sleep disturbance traits include: self‐reported sleep duration (short <6hrs/intermediate 6‐9h/long>9h), daytime somnolence (often/rarely), napping (usually/rarely). Sleep apnea presence was derived from ICD‐10 diagnosis and/or self‐report. Our core models with individual sleep disturbance traits were adjusted for age, sex, education, and ethnicity. The full model adjusted for major comorbidities [the Townsend deprivation index ‐ a measure of socioeconomic status, body mass index, physical activity, major cardiovascular diseases and risk factors (hypertension, high cholesterol, smoking, diabetes, AF, angina/MI, peripheral vascular disease), neurological diseases (stroke/TIA, dementia, Parkinson’s), respiratory diseases (COPD, fibrosis), alcohol use, depression/anxiety, and medication use (benzodiazepines, sedatives/sleep aides, antipsychotics, steroids and opioids)].

Result

In total, 932 developed AD after 6.4 years (SD=1.9). In our full model, long habitual sleep (>9h), but not short sleep (<6h), saw a two‐fold increased risk (HR 2.04, 95% CI: 1.55‐2.67 p<0.0001) compared to intermediate sleep (6‐9h) duration. Daytime somnolence was independently predictive of AD (HR 1.56, 95% CI: 1.18‐2.03, p=0.001). These effects remained after controlling for sleep apnea, which was only predictive in the core model (HR 2.05, 95% CI: 1.23‐3.42, p=0.006).

Conclusion

Long habitual sleep duration and daytime somnolence may be early, independent markers of AD. Further work examining objective measures of sleep duration and sleep disturbance within this population is ongoing, and may help confirm our findings. If replicated, future trials may be warranted to test whether optimizing sleep health reduces the risk of developing AD.
Evaluating vascular cognitive impairment and dementia due to small‐vessel disease using plasma levels of PLGF and VEGF‐A
Authors: Winder Zachary , Lee Tiffany , Fardo David W , Cheng Qiang , Goldstein Larry , Nelson Peter T. , Schmitt Frederick A. , Jicha Gregory A. , Wilcock Donna M.
Published: December 2020

Background

Vascular Cognitive Impairment and Dementia (VCID) refers to cerebrovascular disease‐associated cognitive disorders. VCID may manifest clinically with mild cognitive impairment (MCI) or dementia. Depending on diagnostic criteria, dementia may be attributed to VCID in about 20% of cases. Arteriolosclerosis, microinfarctions, and microhemorrhages characterize a major subgroup of VCID pathologies, collectively referred to as small‐vessel disease (SVD). In this study, we evaluated the association of SVD with plasma levels of PLGF and VEGF‐A. We hypothesize that up‐regulation of these molecules in blood are part of the mechanism and/or reaction of the brain to SVD due to their roles in blood‐brain‐barrier breakdown and aberrant angiogenesis.

Method

Plasma samples from participants in the University of Kentucky Alzheimer’s Disease Center’s prospective cohort study were collected and analyzed using Meso Scale Discovery and Quanterix Simoa digitized immunoassay techniques to measure angiogenic and inflammatory biomarker levels. Unsupervised clustering analysis was used to identify unique subsets within the MCI patient population based on their plasma biomarker profile. Paired t‐tests were used to compare plasma levels of PLGF and VEGF‐A in patients diagnosed with VCID‐SVD and age‐matched controls. Supervised machine learning was then used to classify patients into groups based on the severity of their chronic vascular pathology using plasma angiogenic and inflammatory biomarkers.

Result

Clustering analysis identified a subset of MCI participants with elevated levels of VEGF‐A (p < 0.001), MMP1 (p < 0.001), and IL8 (p < 0.001). Whereas participants with VCID‐SVD had significantly elevated levels of PLGF compared to age‐matched controls (p < 0.01), a non‐significant increase in VEGF‐A was also found. Additionally, supervised classification analysis yielded a model with 52.4% accuracy in assigning patients to one of three groups of chronic vascular grading on cross validation.

Conclusion

These experiments provide evidence for the utility of using plasma biomarkers such as PLGF and VEGF‐A in assessing SVD in patients with varied stages of VCID, ranging from MCI to dementia. In the future, analyzing plasma PLGF and VEGF‐A levels alongside imaging biomarkers may improve the accuracy of the diagnosis of VCID, monitoring of disease progression, and potentially provide a biomarker to assess therapeutic response.
Relationship between cerebrovascular reactivity and cognition among people with risk of cognitive decline
Authors: Kim Donghoon , Hughes Timothy M. , Hugenschmidt Christina E. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D. , Whitlow Christopher T. , Okonmah‐Obazee Stephanie , Bobinski Matthew , Jung Youngkyoo
Published: December 2020

Background

It has been shown that cerebrovascular reactivity (CVR) is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal is not straight‐forward since other physiological parameters, such as oxygen utilization and blood volume, also contribute to its measurements. In this study, we measured cerebral blood flow (CBF) using a dynamic arterial spin labeling (ASL) technique during a hypercapnia challenge and tested if CVR is related to risk factors of cognitive decline and cognitive performance.

Method

Sixty‐three subjects (age: 70.17±7.09 yrs, M/F: 18/45; BMI: 27.63±5.07; years in education: 15.79±2.38 yrs; 7 diabetes; 17 hypertension; MMSE score: 28.49±1.40) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including ASL during a hypercapnia challenge with a RespirAct computer‐controlled gas blender, targeting 10mmHg higher end‐tidal CO2 level than the baseline while end‐tidal O2 level is maintained. Pseudo‐continuous ASL (PCASL) was collected during a 3‐minute baseline and a 2‐minute hypercapnic period. The whole brain CVR was obtained by calculating a percent change of CBF per the end‐tidal CO2 elevation in mmHg between the baseline and the hypercapnic challenge (Figure 1). A partial volume correction on CVR and baseline CBF was applied and the whole brain gray matter CVRgm and CBFgm were calculated. Linear regression analyses were performed (CVRgm or CBFgm ∼age+sex+BMI+years of education+diabetes+hypertension+MMSE) to examine the relationship between CVRgm or CBFgm and global cognitive performance (MMSE score).

Result

CVRgm is positively associated with the MMSE scores (β=0.208, p=0.016) independent of other covariates (Figure 2). CBFgm is negatively associated with age (β=‐0.552, p=0.013) and BMI (β=‐0.623, p=0.037) with the adjustment for all other covariates (Figure 3).

Conclusion

This study demonstrated that CVRgm is related to lower MMSE scores, while resting CBFgm showed significant relationships with age and BMI. Therefore, CVRgm may be a sensitive imaging parameter relating vascular and cognitive function.
In vivo locus coeruleus imaging in Alzheimer’s and Parkinson’s disease
Authors: Betts Matthew J. , Pape Johanna , Spottke Annika , Teipel Stefan J. , Kilimann Ingo , Galazky Imke , Jessen Frank , Düzel Emrah
Published: December 2020

Background

The locus coeruleus (LC) plays an important role in numerous cognitive functions such as working memory, learning and attention. Novel magnetic resonance imaging (MRI) techniques now provide an opportunity to quantify structural features of the LC in vivo which may help to understand the contribution of LC neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study we aimed to use in vivo T1‐weighted Fast Low Angle Shot (FLASH) imaging to visualize and quantify LC MRI contrast in AD and PD and to determine the relationship between LC MRI contrast and cognition.

Method

Baseline data from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study comprising 48 healthy elderly adults, 27 individuals with subjective cognitive decline (SCD), 16 individuals with mild cognitive impairment (MCI), 11 individuals with AD together with 30 patients with idiopathic PD were analysed. All subjects were scanned at 3T using a 3D T1‐weighted FLASH sequence (0.75mm isotropic resolution whole brain acquisition). FLASH images were sinc interpolated and upsampled to 0.375mm3 resolution prior to manual segmentation of the LC. Median LC signal intensity was determined relative to reference regions delineated in the rostral pontomesencephalic area.

Result

A significant decrease in LC MRI contrast in AD and PD was observed compared to healthy controls. However no significant decrease in LC MRI contrast was observed in SCD and MCI compared to healthy controls or between AD and PD patients. In AD, a linear regression analysis across groups (n=102), revealed a significant negative correlation between LC MRI contrast and performance in the backward digit span (DS)/total (DS) test. In PD, a significant positive correlation between LC MRI contrast and slower performance in the Trail Making Test (TMT)‐A and B, was observed.

Conclusion

The results confirm that T1‐weighted FLASH imaging using 3 T MRI can identify substantial LC degeneration in vivo and is associated with impaired working memory and attention in AD and PD, respectively. Collectively these results indicate that in vivo LC imaging may help to track LC degeneration and understand the pathological underpinnings of cognitive dysfunction in neurodegenerative disease.