bluuebunny/crossref_metadata_2025 huggingface dataset:
Study partner factors on cognitive function index scores among participants screened for the A4 study
Authors: Voeller Emily K , Choi Jiyoon , Sperling Reisa A. , Aisen Paul S , Raman Rema
Published: December 2020

Background

The Cognitive Function Index (CFI) is an evaluation of participants’ cognitive and functional decline. Alzheimer’s disease (AD) clinical trials, including Preclinical trials, require participants to have a study partner (SP) to help evaluate participant cognitive and functional performance. Past studies in early AD dementia and Mild Cognitive Impairment populations have shown that spousal SPs are more accurate at providing cognitive information than non‐spousal SPs. We aimed to investigate if SP variables are associated with participant and SP reported CFI score among cognitively normal participants screened for the A4 Study.

Method

6155 Participants and 5953 Study Partners completed the screening CFI in the A4 Study. The CFI is a 14‐item questionnaire completed by both the SP and the participant with higher scores meaning increased decline over the past year. SPs were categorized as: Spouse, Adult Child, Friend/Companion, and Other. SPs were also categorized based on the number of weekly hours spent with the participant in‐person (more vs less than 68 hours per week). Associations with participant and SP reported screening CFI were assessed using a multiple regression model adjusting for participant age, gender and education, but without adjustments for multiple comparisons.

Results

SPs were female for 40% of female participants and 90% of male participants. Spousal SPs report spending 103 +/‐ 42 hours per week with the participants, while the other groups reported much fewer hours (Adult child: 17 +/‐30, Friend/Companion: 21 +/‐ 35, Other: 27 +/‐ 40). There was no association between SP group and participant CFI score. There was an observed association between SP group and SP CFI score (F=6.54, p < 0.001). Friends/Companions (beta=‐0.30+/‐0.19, p<0.001) and Other (beta=‐0.19 +/‐0.11, p=0.07) groups reported lower scores on the CFI than Spouses. There were no differences by SP gender or number of hours spent in person per week.

Conclusion

This cross‐sectional analyses showed preliminary evidence that SP type can influence the SP score on the screening CFI although there is no evidence of SP influence on participant reported CFI. Longitudinal data, when available at trial end, will help assess these associations over time and if study partner type can predict future cognitive decline.
Mechanism for the protective effect of APOE ε2 against Alzheimer disease is linked to tau and the classical complement pathway
Authors: Jun Gyungah R. , Zhu Congcong , Panitch Rebecca , Chung Jaeyoon , Hu Junming , Wang Li‐San , Lunetta Kathryn L. , Haines Jonathan L. , Mayeux Richard , Pericak‐Vance Margaret A. , Schellenberg Gerard D. , Stein Thor D. , Farrer Lindsay A. ,   The Alzheimer's Disease Genetics Consortium
Published: December 2020

Background

Recent reports suggest that the rare APOE Christchurch mutation and APOE2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the APOE2 protective effect linking to tau is largely unknown.

Method

We conducted a genome‐wide association study (GWAS) for AD among 2,120 APOE2 carriers from the Alzheimer Disease Genetics Consortium (ADGC), and prioritized by gene network analysis and methylation profiling of CpG sites in the locus using the Religious Orders Study and Memory and Aging Project (ROSMAP) data. We also performed differential gene expression analysis among APOE2/3 subjects in prefrontal cortex tissue from 44 AD and 75 control brains of the Framingham Heart Study (FHS), Boston University Alzheimer’s Disease Center (BUADC), and ROSMAP. We validated the relationships between protein levels of the top‐ranked genes and levels of tau and amyloid beta proteins in prefrontal cortex area of 193 FHS/BUADC brains.

Result

Of the significant genetic associations with AD (P < 10−6), PPP2CB was the key node in APOE2‐related gene networks and contained the most significant CpG site (P = 5.2 × 10−4) located 2,814 bp upstream of the top‐ranked GWAS variant. The complement genes C4A and C4B were the top‐ranked differentially expressed genes (P < 2 × 10−4) with reduced expression in APOE2/3 controls compared in APOE2/3 cases or other carriers. Furthermore, the level of PPP2CB protein was significantly associated with increased levels of C4B protein (P = 8.2 × 10−7), and the C4A level was associated with increased pTau231/tTau ratio (P = 0.006). Protein levels of C4A, C4B, and PPP2CB were not associated with amyloid beta 42 (Aβ42) or pTau181/tTau ratio. We were unable to confirm previous reports on the role of C1q, since the C1q level was not associated with any of these phenotypes.

Conclusion

This is the first to report the molecular link between a tau phosphatase and the classical complement pathway, especially C4, as a mechanism for the ε2 protective effect against AD. Our findings may lead to the development of novel therapeutic targets for AD by mimicking the neuroprotective effect of APOE2.
Implicit response incompatibility slowed down asymptomatic individuals with Alzheimer’s disease pathology
Authors: Hung Shao‐Min , Wu Daw‐An , Harrington Michael G , Shimojo Shinsuke , Arakaki Xianghong
Published: December 2020

Background

Alzheimer patients exhibit explicit decline of cognitive abilities. However, such decline, by definition, does not appear pre‐symptomatically. Here we introduced a subliminal incompatibility paradigm where a masked word was either congruent or incongruent to the response to the subsequent target stimulus. We examined if implicit response incompatibility led to performance decline in asymptomatic individuals with Alzheimer’s disease pathology, serving as a possible early marker of the disease.

Method

Cognitively healthy (CH) participants (demographically matched) were recruited from the local community, consisting of two subgroups based on cerebrospinal fluid (CSF) proteins: with normal amyloid/tau ratio (CH‐NAT, n = 20) or pathological amyloid/tau ratio (CH‐PAT, pre‐symptomatic AD, n = 20). A task‐switching Stroop task was implemented. Each trial contained two stimuli, and participants had to name the color or word of a colored word for each stimulus with button press. If the two stimuli involved different task demands (e.g. color naming and word naming), it was a switching trial. Otherwise it was a non‐switching trial. In‐between the two stimuli, a forward‐ and backward‐masked word congruent (i.e. same button press) or incongruent to the response to the subsequent stimulus was inserted.

Result

Final analysis included only the trials with both stimuli correctly responded. On average, participants had near‐ceiling performance with ∼95% accuracy. In a mixed ANOVA with one between‐subject factor (CH‐PAT/CH‐NAT) and three within‐subject factors (word/color naming, switching or non‐switching, and masked word congruent or incongruent), we analyzed the reaction time of the target (second) stimulus. We found significant main effects of word/color and switching. That is, participants responded significantly slower (1) to color of the stimulus (typical Stroop effect) and (2) when they had to switch attention across different stimulus features in a trial (color to word or vice versa). Critically there was an interaction between switching and congruency. Further analysis showed that during switching, incongruent trials slowed down significantly. Such effect was only evident in CH‐PATs (p = 0.00005), but not CH‐NATs (p = 0.1).

Conclusion

During a challenging task‐switching condition, the behavioral performance of asymptomatic individuals with Alzheimer’s disease pathology was significantly affected by implicit response incompatibility.
Does feature binding account for functional decline in patients with mild cognitive impairment? Evidence from the Details of Function of Everyday Life Questionnaire (DoFEL)
Authors: Calia Clara , O'Donal Freddie , Pickett Eleanor , Parra Mario A.
Published: December 2020

Background

Available functional scales used to discriminate normal and abnormal ageing are informative of basic abilities (e.g., bathing, grooming, feeding, etc.). These are complex functions and the tools used to assess them lack theories from cognitive ageing. These features have rendered them insensitivity to the early stages of dementia such as that caused by Alzheimer’s disease (AD). To overcome these limitations, we need to improve our understanding of the cognitive underpinnings of functional decline. The ability to bind information in memory (i.e., feature binding) declines from the preclinical stages of AD. It remains unknown whether such subtle cognitive deficits can underpin decline of instrumental activities of everyday life (IADL, e.g., managing finances, using technologies, shopping) found in the prodromal stages of AD. To address this need we have developed a theory‐driven scale namely Details of Function of Everyday Life Questionnaire (DoFEL). We used DoFEL to investigate if cognitive constructs such as memory binding can account for impairment of specific abilities that support instrumental functions.

Methods

Participants (N=168) completed a neuropsychological test battery, comprising of a set of novel and traditional neuropsychological tasks known to be useful in the early detection of AD. Binomial logistic regression was utilised to evaluate the predictive effect of DoFEL relative to other scales such as the Addenbrooke's cognitive examination (ACE).

Results

A stratified model incorporating the Shopping and Money, Work and Social Life and Domestic Chores domains of the DoFEL, X2(3)=48.57, p < 0.001, R2 = 0.70, AUC=0.94, demonstrated comparable accuracy to that of the ACE‐R scores, X2(1)=47.61, p < 0.001, R2 = 0.71, AUC=0.94. The DoFEL scores informing on conjunctive binding abilities had a moderately high accuracy and Nagelkerke's R2 results, indicating a higher predictive power to discriminate between healthy older adults and individuals with MCI.

Conclusions

Functional composite measures integrating feature binding constructs within measures of IADL impairment are plausible future indicators of early cognitive decline in prodromal AD. Further research is required to evaluate the validity of DoFEL and its sensitivity across the whole AD continuum.
Disparities in brain‐behavior relationships among Latinos and white non‐Latinos
Authors: Calcetas Amanda , Smirnov Denis S. , Salmon David P.
Published: December 2020

Background

With a growing racial and ethnic disparity in the aging population, it is important to understand factors that could influence relationships between neurodegeneration and cognitive decline. Differences in early socioeconomic exposure, educational background, and/or lack of culturally and linguistically appropriate testing protocols could impact the ability to see or interpret such relationships. We examined this issue by comparing the association between MRI‐derived measures of cortical thickness and performance on tests of global cognitive function, memory and language in elderly Latino and Non‐Latino White (NLW) individuals before and after adjustment for education.

Methods

Participants were 36 Latino and 126 NLW elderly individuals with cognitive impairment (i.e., Mild Cognitive Impairment, Alzheimer Dementia), and 33 Latino and 95 NLW cognitively normal controls (NC). Participants were evaluated annually at the Shiley‐Marcos Alzheimer's Research Center (ADRC) where they received cognitive assessment that included measures of global cognitive function (i.e., MMSE), memory (Logical Memory Test, Word List Learning) and language (Category Fluency Test). MRI scans were performed within 6 months of testing and measures of hippocampal volume and cortical thickness were determined using Freesurfer procedures.

Results

Demographically, the Latino NC group was younger (71.0+7.9) than the Latino‐Impaired group (73.2+10.8) and both NLW groups (NLW NC=72.8+5.7; NLW‐Impaired: 74.4+7.7; p < 0.01). Latino‐Impaired (9.9+4.8) had fewer years of education than Latino NC (13.8+3.2), and both Latino groups fewer than the NLW groups (NC=16.5+2.2; Impaired: 16.2+2.9). Regression analyses showed that MMSE, Word List Learning, Logical Memory, and Category Fluency were associated with entorhinal cortical thickness or hippocampal volume in the Latino and NLW groups. Furthermore, these associations were stronger in the Latino‐Impaired group than in the NLW Impaired group (all p’s < 0.05). However, these latter differences no longer reached significance when adjusted for education (i.e., in regression analyses or when the overall Latino group was restricted to the education range of the NLW group.

Conclusions

The large education gap between elderly Latinos and NLWs can influence perceived differences in the association between measures of neurodegeneration and cognitive decline. Further investigation of cultural and ethnic influences on the manifestation of dementia and its underlying causes is needed.
Risk factors for falls in preclinical and prodromal Alzheimer’s disease and dementia due to Alzheimer’s disease: Findings from the Australian Imaging, Biomarker and Lifestyle study of ageing (AIBL)
Authors: Huynh Andrew , Woodward Michael , Zeimer Henry , Zisis Georgios , Martins Ralph N , Rainey‐Smith Stephanie R , Brown Belinda M , Fernando Warnakulasuriya , Gardener Samantha L , Rowe Christopher C , Masters Colin L , Yates Paul A
Published: December 2020

Background

Literature suggests that preclinical Alzheimer’s disease (AD) is associated with increased falls risk1. Falls are a major cause of morbidity and mortality in older people, particularly people living with dementia. We aimed to identify factors associated with falls in older Australians with baseline Aβ PET imaging.

Method

Participants from the Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL), with baseline 11C‐PiB PET and 18‐monthly review for 6 years, including self‐reported falls. Participants with severe illness, alcohol abuse and cerebrovascular disease were excluded. Multivariable logistic regression was used to identify factors associated with falls, including Aβ PET status (elevated/not elevated as previously published).

Result

293 participants (mean age 72.6 years, 52% female, 62% cognitively‐normal, 20% Mild Cognitive Impairment, 18% AD) reported 50 falls during the study period. Female gender (adjusted odds ratio [aOR] 3.17, 95% CI 1.53‐6.58, p=0.002), impaired vision (aOR 2.32, 95% CI 1.08‐4.99, p=0.031) and an education greater than 12 years (aOR 2.40, 95% CI 1.20‐4.82, p=0.014) were associated with incident falls. Age (p=0.172), elevated Aβ (p=0.549) and cognitive status (p=0.799) were not associated with falls.

Conclusion

While our findings that female gender and visual impairment are associated with increased risk of falls are consistent with prior reports, the association with higher education is intriguing and warrants further investigation. Recruitment methods and reporting biases may contribute to the lack of observed association between falls and Aβ or cognitive diagnosis compared with other studies. Future analyses should also include cerebrovascular disease, physical activity, medications and alcohol intake. 1 Stark SL et al. Preclinical Alzheimer disease and risk of falls. Neurology. 2013 Jul 30; 81(5): 437–443.
Description of longitudinal cranial imaging and cognitive changes in the Strong Heart Study
Authors: Suchy‐Dicey Astrid M , Verney Steven P , Nelson Lonnie A , Grabowski Thomas J , Buchwald Dedra
Published: December 2020

Background

Little is known about cognitive impairment and dementia in American Indians, who are underrepresented in most studies of Alzheimer’s disease and related dementias.

Method

The Strong Heart Study recruited 4,549 American Indians aged 45‐75 from 3 major geographic regions in 1989‐1991. In 2010‐2013 and again in 2017‐2019, all eligible surviving participants were recruited for comprehensive cranial magnetic resonance imaging, cognitive, and clinical examinations. Neurological data collected included history of stroke and neurological symptoms. Cognitive data included Modified Mini Mental Status Examination, Weschler Adult Intelligence Scale, Controlled Word Association Test, California Verbal Learning Test, Wide Range Achievement Test, Montreal Cognitive Assessment, Craft Story Recall, Benson Figure Copy, Number Span test, Category Fluency, Trail Making test, Multilingual Naming Test, Functional Activities Questionnaire. Physical function tests included Short Physical Performance Battery, dynamometric grip strength, and Halstead finger tapping test. Mood and quality of life tests included Short Form 36 and Centers for Epidemiologic Studies Depression scale. Clinical examination included anthropometric measures, blood pressure, and basic blood and urine laboratory assays including serum glucose, lipids, creatinine, and albumin. Neuroradiologists blinded to clinical data examined MRI for vascular and structural findings, including presence and location of infarcts, hemorrhages, white matter hyperintensities, sulcal widening, ventricle enlargement, and volumetric estimates of hippocampus, parahippocampal gyrus, thalamus, and frontal lobe. Neuropsychologist panels adjudicated cognitive impairment and dementia by case review.

Result

This report describes the structure and methods used to collect these longitudinal data, including the cognitive examinations, the neuropsychological data cleaning, and the panel‐based case reviews. We also include basic epidemiologic description of the data, including changes in cranial imaging findings and cognitive and functional examinations between the two neurological examinations (approximate follow‐up time: 7 years).

Conclusion

This report adds to existing literature with the first longitudinal description of cranial imaging and cognitive testing data in American Indian elders, as well as the first cognitive measurements related to Alzheimer’s disease, in this population. These data may be used to estimate incidence and prevalence of vascular brain injury, structural atrophy, imaging markers related to Alzheimer’s disease, and cognitive function in this understudied population.
The amyloid plaque proteome in different subtypes of Alzheimer’s disease
Authors: Drummond Eleanor , Pires Geoffrey , Kanshin Evgeny , Askenazi Manor , Ueberheide Beatrix , Wisniewski Thomas
Published: December 2020

Background

Amyloid plaques contain many proteins in addition to beta amyloid (Aß). Previous studies examining individual plaque‐associated proteins have shown that the presence of these proteins is important: they provide insight into Alzheimer’s disease (AD) pathogenesis, and they are potential biomarkers and/or therapeutic targets for AD. However, a comprehensive analysis of all proteins enriched in amyloid plaques has not yet been done. Therefore, the aim of this study was to use an unbiased proteomic approach to identify all proteins consistently enriched in amyloid plaques in different subtypes of Alzheimer’s disease.

Method

We used label‐free quantitative mass spectrometry to identify all proteins significantly enriched in microdissected amyloid plaques in comparison to surrounding, non‐plaque tissue in two subtypes of AD; sporadic early onset AD (EOAD; age at death <65; n = 5) and Down syndrome with AD (DS; n = 5). Validation was performed using immunohistochemistry and by comparison with published proteomics databases.

Result

116 proteins were consistently enriched in plaques in EOAD and DS in addition to Aß. The five most highly enriched proteins in plaques were the same in both subtypes of AD; COL25A1 (136 fold enriched in plaques), SMOC1 (87 fold enriched), MDK (59 fold enriched), NTN1 (55 fold enriched), and HTRA1 (49 fold enriched). Amyloid plaques were most significantly enriched in vesicle proteins (predominantly endosomal/lysosomal proteins; enrichment FDR = 5.71 × 10−19), therefore suggesting that the endosomal/lysosomal system may have an important role in amyloid plaque formation. We also identified 53 novel proteins enriched in plaques: 12 of these proteins have been previously associated with either Aß or APP, but not yet known to be present in plaques, while 41 of these proteins have not yet been associated with Aß. Immunohistochemistry validated the enrichment of selected novel plaque proteins such as all ERM family members (ezrin, radixin, moesin), which interact with the actin cytoskeleton and have important roles in endosome transport and maturation.

Conclusion

Amyloid plaques are enriched in >100 proteins in addition to Aß. We have identified many novel amyloid plaque proteins, which may be potential therapeutic targets and/or biomarkers for AD.
Leveraging mouse genetic diversity to investigate the role of brain myeloid cells in Alzheimer’s disease
Authors: Yang Hongtian Stanley , Onos Kristen , Choi Kwangbom , Keezer Kelly , Diemler Cory , Hewes Amanda , O'Rourke Rita , O'Rourke Sarah , Gastoukian Nils , Harder Jeffrey , Skelly Daniel , Sasner Michael , Carter Gregory W. , Howell Gareth
Published: December 2020

Background

Myeloid cells have been strongly implicated in Alzheimer’s Disease and related dementias (ADRDs). Our previous study showed genetic diversity significantly modified brain myeloid cell responses and AD‐relevant phenotypes in mice. Therefore, incorporating natural genetic variation into mouse models is indispensable to understand the role of myeloid cells in AD. This study aims to characterize brain myeloid cells in our genetically diverse AD panel to determine their functions in ADRDs.

Methods

Brain myeloid cells were isolated from 8‐9 months‐old female mice from our genetically diverse AD mouse panel [C57BL/6J (B6), PWK/PhJ, WSB/EiJ and CAST/EiJ strains, each carrying APP/PS1] using magnetic activated cell sorting and were subjected to single‐cell RNA‐sequencing (scRNA‐seq). Data were processed using a customized pipeline allowing strain‐specific genome alignment followed by downstream analyses using Seurat and edgeR packages. Differences in myeloid cell responses between strains are being validated using functional assays in primary microglial cultures and immunofluorescence. To identify the putative genetic variations that drive and/or modify differences in myeloid cell responses, quantitative trait locus mapping of microglia number and morphology is being performed in brains from 120 Diversity Outbred (DO) mice, derived from eight mouse strains including those listed above.

Results

scRNA‐seq uncovered heterogeneous clusters of myeloid cells that vary significantly in cell abundance and gene expression between both wild‐type and APP/PS1 of B6, PWK, WSB and CAST mice. There was a significantly lower percentage of disease‐associated microglia in WSB.APP/PS1 mice and a significantly higher percentage of interferon‐responding microglia in PWK.APP/PS1 mice, compared to other AD strains. These data agreed with previously determined phenotype differences between strains. Differential gene expression analyses (all data compared to the B6 strain) revealed robust APP/PS1‐responding genes unique to strain background (strain by genotype effect) including Rpl29, Irf7, Cd36, H2‐Eb1, Lag3 and Cd34 in CAST; Ramp, Tmem176a, Tmem176b, Sepp1 and Inpp5d in PWK, and Ccl6, Slamf8, Nme1 and Pcna in WSB strain. Validation by primary culture and analyses of DO mice are underway.

Conclusion

As in humans, mouse genetic diversity significantly impacts the landscape and dynamics of brain myeloid cells in AD. These studies will improve the translatability of myeloid‐based therapies for ADRDs.
Idiosyncratic neurolinguistic presentations of Chinese speaking primary progressive aphasia individuals
Authors: Tee Boon Lead , Tempini Maria Luisa Gorno , Chen Ta‐Fu , Lo Raymond Y. , Wong Adrian
Published: December 2020

Background

Past research on Primary Progressive Aphasia(PPA) has been centered around English language, thus there is limited knowledge to the presentations of linguistic features that differ from the English language. Chinese language possesses numerous linguistic features that contrast significantly from the English language. Chinese language is a tonal and numeral classifier language; hence tones are lexically contrastive and numeral cannot quantify a noun without classifiers. As more than 40% and 20% of living languages worldwide are tonal and numeral classifier languages, investigating these idiosyncratic neurolinguistics features in non‐English speaking PPA individuals may refine the clinical practice paradigm to be more adaptable worldwide.

Method

The CLAP (Chinese Language Assessment for PPA) project aims to investigate the neurolinguistics features of Chinese speaking PPA individuals. The CLAP battery consists of fourteen speech and language tasks and this presentation focuses on the tonal and numeral classifier performances as they are idiosyncratic traits of the Chinese language. The tonal perception function is assessed via tonal identification, tonal discrimination, tone‐picture matching, and tone‐word matching tasks. The tonal production performance is evaluated through serial tone reading, repetition of tonal tongue‐twisters, and multi‐tone multi‐repetition tasks. To illustrate classifier function, participants are tasked with producing the accurate classifiers after visual and auditory stimuli of the nouns.

Result

The CLAP project recruited 13 healthy controls and 20 PPA individuals (5 nfvPPA, 6 svPPA, and 9 lvPPA) that are native Chinese speakers. Individuals with svPPA were noted to perform significantly lower in the tone‐picture matching task (p=0.024) and classifier task (p<0.0001). Volumes in left inferior temporal and bilateral temporal poles were significantly correlated with the performance in the tone‐picture matching and classifier task respectively. Conversely, individuals with nfvPPA scored substantially lower than healthy controls in all three tone production tasks (p<0.0001, p=0.024, p<0.0001) and lower than other PPA variants in tonal tongue‐twisters tasks. Performance in tonal tongue‐twister tasks was found to correlate with the degree of atrophy in left inferior and superior frontal regions.

Conclusion

Tone and classifier tasks can potentially serve as diagnostic and classification tools for PPA individuals that speaks Chinese language and other tonal and numeral classifier languages.
Comparative proteomic analysis of skin fibroblasts of patients with familial Alzheimer's and healthy controls: Searching for new therapeutic targets
Authors: Lopez‐Toledo Gustavo , del Carmen Silva‐Lucero Maria , Arias‐Montaño Jose Antonio , del CCardenas‐Aguayo Mariaarmen
Published: December 2020

Background

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss, neuronal degeneration and synaptic dysfunction, resulting in atrophy of the affected regions. The identification of early biomarkers for AD diagnosis has been a challenge due to the high individual variability in markers expression, thus the use of peripheral cells other than neuronal cells such as bone marrow or dental pulp mesenchymal cells, blood cells and fibroblasts represents an opportunity for the detection of early pathological changes of Alzheimer's disease patients. Moreover, neuronal cells differentiated from reprogram somatic cells, recapitulate brain cell pathological associated changes.

Method

We study the proteome using 2D‐PAGE and protein identification by mass spectrometry. Skin fibroblasts were cultured from patients with a mutation in Presenilin‐1 (A246E or M146L) and from control individuals of the Coriell Institute cell repository in Earl MEM salts medium with 15% non‐inactivated Fetal Bovine Serum. Fibroblast phenotype was confirmed by immunodetection of vimentin and S100A4 markers. We use Western Blot and qPCR techniques to evaluate changes in the expression of genes and proteins of particular pathways involved in the neurodegeneration of AD.

Result

Differences in protein expression in fibroblasts were identified between affected individuals and controls, related to cell adhesion, cytoskeleton, energy and glucose metabolism, ubiquitin‐proteasome pathway, autophagy and signal transduction, which have been previously found affected in neurons from AD patients.

Conclusion

Our results indicate that samples derived from fibroblasts from AD patients have a unique protein profile with respect to controls, both at expression level and proteins patterns, showing that peripheral cells can be useful in modeling degenerative pathways and biomarker identification for Alzheimer's disease.
The use of genetic risk prediction to study prodromal Alzheimer’s disease in the PISA study
Authors: Lupton Michelle K. , Fazlollahi Amir , Ceslis Amelia , Fripp Jurgen , Rose Stephen , Salvado Olivier , Robinson Gail , Guo Christine , Breakspear Michael , Martin Nick
Published: December 2020

Background

Neuropathology accumulates for decades prior to the onset of cognitive decline in Alzheimer’s disease (AD). Interventions to modify the course of the disease have the greatest potential to avert neuronal death and later disease burden if they are introduced during this crucial window. Our prospective cohort study, “Prospective Imaging Study of Ageing: Genes, Brain and Behaviour” (PISA) aims to characterise the natural history of AD at its prodromal phase. Using genetic risk prediction we have identified middle‐aged and older Australians at high risk of dementia to enable the discovery of biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease conversion.

Method

We utilized APOE genotype and polygenic risk scores (PRS) to identify individuals at high and low risk of AD. We have leveraged our extensive in‐house cohorts, comprising ∼15,000 individuals aged 40‐70 years with available genome wide genotyping data to generate a genetically enriched cohort for investigating prodromal markers for AD. Online surveys and cognitive testing are used to collect information from a national sample currently totally nearly 3,000 participants. Subjects (N = 400) from a defined at‐risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment and/or early AD) have taken part in onsite visits for lifestyle monitoring, cognitive testing, blood sample donation, MRI and PET imaging.

Result

A high prediction accuracy for AD with an AUC of 78.2% can be achieved by a prediction model including APOE genotype, and PRS (containing GWAS association SNPs with P value <0.5) with the PRS adding significant predictive value over APOE alone. The association of genetic factors with baseline imaging and neuropsychological phenotypes will be presented as well as multivariate analysis investigating the influence of genetic risk on inter‐individual phenotypic relationships.

Conclusion

The PISA study is an at risk AD cohort enriched by genome‐wide risk prediction, aiming to validate early markers of prodromal Alzheimer’s disease that can be utilized in middle age. This study will help elucidate changes in early prodromal AD risk variants observed in middle age, and evaluate which measures show the earliest changes.
Montreal Cognitive Assessment 5‐minute protocol is accurate in screening for mild cognitive impairment in the rural African population
Authors: Masika Golden Mwakibo , Yu Doris S.F. , Li Polly W.C. , Wong Adrian , Lin Rose S.Y. , Lee Diana T.F.
Published: December 2020

Background

The prevalence of dementia in Tanzania, as in other developing countries is progressively increasing.1 Yet the screening instruments for the pre‐clinical stage of the diseases are lacking. This study examined the diagnostic accuracy of the Montreal Cognitive Assessment‐5‐minutes protocol (MoCA‐5‐min) among older adult in the rural Tanzania.

Methods

After cultural adaptation following Brislin’s approach,2 the MoCA‐5‐min and the IDEA cognitive screening were concurrently administered to community‐dwelling older adults (n=202) in Chamwino district and 40 re‐evaluated at 6 weeks. Exploratory factor analysis (EFA) using principal component method and oblique rotation was performed to determine the underlying factor structure of the scale. The concurrent and the diagnostic accuracy of the MoCA‐5‐min were examined by comparing its score with IDEA cognitive screening and the psychiatrist’s diagnosis using DSM‐V criteria respectively.

Results

The EFA found that all the MoCA‐5‐min items highly loaded into one component, with factor loading ranging from 0.550 to 0.879. The intraclass correlation coefficient for 6 weeks test‐retest reliability was 0.85. Its strong significant correlation with the IDEA screening (Pearson's r = 0.614, p < 0.001) demonstrated a good concurrent validity. Using the psychiatrist’s rating as a gold standard, the area under the curve (AUC) was 0.861, (95% CI = 0.799 – 0.922) (Figure 1). With the optimal cut‐off score for MCI at 22, the sensitivity was 80% and specificity was 74%. As for dementia, at a score of 16 the sensitivity was 90% and specificity was 80%, whereas the AUC was 0.910, (95%CI = 0.852 – 0.967) (Figure 2). Upon stratifying the sample into different age groups, the optimal cut‐off scores tended to decrease with the increase in age (Table 1).

Conclusion

The MoCA‐5‐min is reliable and provides a valid and accurate measure of cognitive decline among older population in the rural settings of Tanzania. The use of varying cut‐off scores across age groups may ensure a more precise discriminatory power of the MoCA‐5‐min. References: 1. WHO. Dementia: Key facts [Internet]. World Health Organization ‐ Fact Sheets. 2019 [cited 2019 Nov 11]. p. 1–5. Available from: https://www.who.int/news‐room/fact‐sheets/detail/dementia. 2. Brislin RW. Back‐translation for cross‐cultural research. J Crosss Cult Psychol. 1970;1(3):185–216.
Alzheimer’s disease risk factor mutations in patients diagnosed with Creutzfelt‐Jakob disease
Authors: Bagyinszky Eva , Farrer Lindsay A. , Farrell John , Van Vo Giau , Shim KyuHwan , An Seong Soo , Kim SangYun
Published: December 2020

Background

CJD is a fatal neurodegenerative disease without successful therapy. Many variants in PRNP gene was established as causative gene for Creutzfeldt‐Jakob disease, but it does not define all CJD cases. Pathological overlap may be possible between CJD and AD.

Method

In this study, 40 DNA Korean CJD patients were analyzed by whole exome sequencing and their in‐depth analyses. Complex genetic screening analyses were performed on genes, associated with neurodegenerative disease, including Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementia (FTD). Rare and possible damaging variants were filtered, and analyzed with pathway analysis tools, such as ClueGo or STRING.

Result

Six PRNP variants were identified among patients. The majority of possible CJD patients did not reveal strong genetic correlations with PRNP, APP, PSEN1 and PSEN2 genes. Instead significant numbers of variants were identified from the genes, which were previously indicated as risk factors in other neurodegenerative diseases, including Alzheimer’s disease.

Conclusion

Such involvements of risk genes of AD and PD could suggest few common disease pathways among the various neurodegenerative diseases. Further studies will be carried out on assess their involvement in CJD and its disease progression.
Vitamin B12 may prevent Aβ oligomer‐induced neurotoxicity in Alzheimer's disease
Authors: Kimura Atsushi Michael , Tsuji Mayumi , Yasumoto Taro , Oguchi Tatsunori , Mori Yukiko , Yano Satoshi , Kinnno Ryuta , Nakamura Shiro , Inoue Tomio , Teplow David B. , Kiuchi Yuji , Ono Kenjiro
Published: December 2020

Background

Excessive accumulation of β‐amyloid peptide (Aβ) is one of the major mechanisms that cause neuronal death in Alzheimer's disease (AD). We’ve previously shown protofibrils, one of the accumulated Aβ oligomers, are implicated to play a major role. Vitamin B12 (VB12) is an important micronutrient required for brain development and has received attention because of its ability to improve cognitive status in Mild Cognitive Impairment(MCI).However, the protective effects of VB12 against Aβ oligomer‐induced neurotoxicity remain unclear. Recently, we found blood VB12 levels in AD patients are significantly associated with some of the major cognitive functions. Besides, it was associated with left hippocampal blood flow.The purpose of this study was to clarify the mechanism of the protective effect of VB12 against the Aβ oligomer‐induced neurotoxicity.

Method

Aβ(1‐42) oligomer was eluted using size exclusion chromatography. Neuronal damage was induced in human neuroblastoma cells (SH‐SY5Y) using 5 μM Aβ oligomer. SH‐SY5Y cells were treated with VB12 (50 μM) for 30 min ‐3 hours in combination with Aβ oligomer. Cytotoxicity of Aβ oligomer‐exposed cells was assessed by the 3‐[4,5‐dimethylthiazole‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT) and mitochondrial membrane potential (MMP) analyses. Oxidative stress was evaluated by measuring products of reactive oxygen species (ROS), mitochondrial ROS and phospholipid peroxides of plasma cell membranes.

Result

Aβ oligomers (1, 2.5, 5 and 10 μM) exposure decreased cell viability in a dose‐dependent manner. However, treatment with VB12 significantly recovered the cell viability that was reduced by treatment with Aβ oligomer. MMP significantly decreased with Aβ oligomer and the decrease was significantly suppressed with treatment with VB12, indicating that mitochondria were involved in the neuronal damage induced by Aβ oligomer exposure. Aβ oligomer increased intracellular ROS, mitochondrial ROS and phospholipid peroxides of the plasma membrane, and the increase in Aβ oligomer‐induced oxidative stress was reduced by VB12 treatment.

Conclusion

These results suggested that the collapse of mitochondria induced by oxidative stress associated with Aβ oligomer exposure was suppressed by treatment with VB12. VB12 may be provided as a therapeutic agent for the prevention of neuronal damage and as a candidate for the treatment of cognitive impairments in AD patients.
Characterising mild behavioural impairment in Asian mild cognitive impairment and cognitively normal individuals
Authors: Wong Fennie , Ng Kok Pin , Yatawara Chathuri , Low Audrey , Ismail Zahinoor , Kandiah Nagaendran
Published: December 2020

Background

Mild Behavioural Impairment (MBI) is a neurobehavioral syndrome characterized by later‐life emergent and sustained neuropsychiatric symptoms that is associated with higher risk of incident cognitive decline and dementia. While MBI is common in both subjective and mild cognitive impairment (MCI), most findings are based on Caucasians and the literature of MBI among Asians remains sparse. Here, we aim to investigate the frequency of MBI and its relationship with cognition, sleep and mood symptoms among cognitively intact (CN) and MCI Asians.

Method

162 subjects (80 CN and 82 MCI) with a Clinical Dementia Rating of 0 or 0.5 were recruited from an outpatient neurology clinic (National Neuroscience Institute, Singapore). All subjects were administered a comprehensive neuropsychological assessment, the Pittsburgh Sleep Quality Index (PSQI) and the MBI‐checklist (MBI‐C). The presence of MBI was determined based on published cut‐offs of 6.5 for MCI and 8.5 for CN. Regression models evaluated the relationships between MBI and cognition, sleep and mood.

Result

29 out of 162 subjects (17.9%) had MBI (28.0% of MCI and 7.5% of CN). Subjects with MBI had poorer global cognition (p=.029) and attention/working memory (p=.049). Specifically, we found that interest and impulse control subdomains of the MBI‐C were associated with poorer performance on the global cognition tests. In addition, those with MBI had sleep‐related daytime dysfunction (p=.008), poorer GDS and DASS scores (p<.01 or p<.001).

Conclusion

MBI in common among our Asian cohort and is associated with poorer cognitive performance, sleep and mood symptoms. Our findings further support the utility of MBI in clinical practice to identify individuals with early presentation of neurodegenerative diseases so as to provide a window of opportunity for early interventions to improve clinical outcomes.
Which pre‐analytical confounder matters the most in the comparison of two cohorts? Tubes and storage fill volume put to the test
Authors: Bastard Nathalie Le , Nadal Alicia , Armengol Elisenda , Torres Soraya , Estellés Teresa , Illán‐Gala Ignacio , Huyck Els , Parnetti Lucilla , Lleó Alberto , Alcolea Daniel
Published: December 2020

Background

The tubes used for collection and storage and their fill volumes have been identified as critical elements for standardized CSF collection as they have proven to significantly influence recovery of CSF biomarker levels and β‐amyloid1‐42 (Aβ1‐42) in particular. The aim of the current study was to compare different collection protocols in terms of CSF biomarker recovery to assess the potential impact on studies establishing cut‐off values.

Method

Two pre‐analytical protocols, used in two experienced CSF biomarker testing sites in Europe, were compared by exchanging the collection and storage tubes. In addition, two different fill volumes were tested for the largest storage tube. In total, six protocols were compared of which protocol 1 and 2 represent the routine practice in the respective sites (Table 1). Twelve consecutive patients were sampled according to all six protocols and the order of the protocols was sequentially assigned per patient. CSF biomarker analyses were done using the LUMIPULSE G platform and related assays. A linear mixed effects model was applied using R.

Result

Protocols 1 and 3, both of which used storage tube 1 with a 0.5 mL fill volume, resulted in significantly lower CSF Aβ1‐42 and CSF Aβ1‐42/Aβ1‐40 ratio compared to all other protocols (p<0.001). Compared to protocol 6, which gave the highest recovery for the Aβ markers, the relative difference in Aβ1‐42 was ‐13.9% (95% CI: ‐16.1% to ‐11.6%) for protocol 1 and ‐14.8% (95% CI: ‐17.1% to ‐12.6%) for protocol 3. For the Aβ1‐42/Aβ1‐40 ratio, this resulted in a difference of ‐6.7% (95%CI: ‐8.8% to ‐4.5%) and ‐6.3% (95%CI: ‐8.5% to ‐4.1%) for protocol 1 and 3, respectively. No significant differences were observed for total Tau and hyperphosphorylated Tau.

Conclusion

In the current study, and with the tubes studied in these protocols, CSF biomarker recovery did not depend on the tubes in which the samples were collected or stored. However, fill volume did have a significant impact on the Aβ1‐42 levels and the Aβ1‐42/Aβ1‐40 ratio, implying that the combination of tube plus fill volume is a factor that needs to be taken into account when comparing studies calculating cut‐off values.
Neurodegeneration in medial temporal lobe subregions propagates within distinct functional networks in the AD continuum
Authors: de Flores Robin , Das Sandhitsu R. , Xie Long , Wisse Laura , Shah Preya , Yushkevich Paul A. , Wolk David A.
Published: December 2020

Background

The medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks: the anterior‐temporal (AT) and the posterior‐medial (PM) systems. As neurodegeneration is thought to occur along specific networks, our aim was to evaluate whether atrophy in perirhinal (PRC) vs parahippocampal cortices (PHC) ‐ two MTL nodes of the AT vs PM systems, respectively ‐ covary over time with distinct brain regions reflecting the AT vs PM networks.

Method

Longitudinal T1‐weighted images (up to 3 scans, span: 1.73±0.49 years) of 117 Ab‐ Cognitively Normal elderly (CN), 65 Ab+ CN, 148 Ab+ MCI and 19 Ab+ AD individuals from ADNI were included. Annualized atrophy rates of PRC and PHC were estimated with an unbiased deformation‐based morphometry method. Whole‐brain cortical thickness annualized atrophy rates were estimated using ANTs. Voxel‐wise correlations between MTL measures and whole‐brain maps were performed to highlight structural covariance patterns [Pcluster(corr)<0.05, Pvoxel(uncorr)<0.01]. Functional connectivity analyses (seed‐based) were employed to define the AT and PM networks [Pcluster(corr)<0.05, Pvoxel(uncorr)<0.01] in an independent sample of 68 CN older adults. The overlap between structural covariance patterns and the AT and PM networks was visually inspected. T‐maps from the voxel‐wise correlations were used to calculate goodness of fit (GOF) indices with the AT and PM networks (GOF=tinside‐toutside).

Result

Functional connectivity analyses revealed two distinct networks: the AT network encompasses the amygdala and the temporopolar cortex extending posteriorly to inferior and middle temporal gyri while the PM network encompasses the posterior cingulate cortex, the precuneus, the cuneus, the angular and occipital gyri and the right insula (Figure 1‐a). PRC structurally covaried with the amygdala and the left temporopolar cortex, overlapping with the AT network (Figure 1‐b,c). In contrast, PHC covaried with the posterior cingulate cortex, the precuneus, the cuneus and the angular and occipital gyri, overlapping with the PM network (Figure 1‐b,d). PRC covariance showed best GOF with the AT system (1.10 vs ‐0.50 for PM) and PHC covariance showed best GOF with the PM system (0.92 vs ‐0.33 for AT).

Conclusion

Overall, MTL atrophy propagates within two distinct networks over time, recapitulating the typical atrophy pattern in AD.
PENSA study: Study design, recruitment profiles and participant inclusion in multimodal intervention studies
Authors: Fauria Karine , Forcano Laura , Knezevic Iva , Minguillón Carolina , Menezes‐Cabral Sofia , Gispert Juan Domingo , Sánchez‐Benavides Gonzalo , Soldevila‐Domenech Natalia , Boronat Anna , Cuenca Aida , Puig‐Pijoan Albert , Mateus Julian , de la Torre Rafael , Molinuevo Jose Luis ,   PENSA Study Group
Published: December 2020

Background

A large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that primary prevention studies focusing on risk reduction and lifestyle modification may offer benefits. The PENSA Study is a clinical trial aiming at preventing cognitive decline in APOE‐ɛ4 carriers with subjective cognitive decline (SCD). The proposed clinical trial design will evaluate the efficacy of epigallocatechin‐3‐gallate (EGCG) in the context of a personalized medicine approach including a multimodal intervention looking at improving person‐centered outcomes in this population.

Method

We have established a randomized, double‐blind, multimodal personalized clinical trial with 200 participants (60‐80 years; APOE‐ε4 allele carriers; fulfilling SCD criteria with 2 additional SCD plus supportive features) with 4 arms of 50 participants each (Fig 1). Recruitment is primarily achieved through web‐based forms capturing information about participants’ subjective cognitive status. Those participants a priori eligible will be tested for APOE status, and carriers of the APOE‐ε4 allele will be invited to the study. The intervention lasts for 12 months and the multimodal lifestyle approach will include physical activity, dietary, and mental health promotion interventions.

Result

The trial’s primary efficacy outcome is a modified ADCS‐PACC score. The secondary efficacy outcome will be evaluated by Functional neuronal connectivity (fcMRI) and structural connectivity (MRI). Exploratory outcomes include Microbiota composition, Dietary patterns (metabolomics), additional cognitive performance scores and plasma AD biomarkers assessment.

Conclusion

The multimodal intervention approach of PENSA is expected to slow down cognitive decline and improve brain connectivity in a population of APOE‐e4 participants with SCD. The study also intends to evaluate several underlying mechanisms that could explain the efficacy of the intervention in slowing down cognitive decline such changes in brain connectivity, gut microbiota composition, AD biomarkers and biological ageing predictors. Further, this trial will give us information regarding participants’ retention and compliance, and therefore feasibility of this kind of high‐demanding engagement prevention studies.