bluuebunny/crossref_metadata_2025 huggingface dataset:
Low and asymmetrical hippocampal glutamate levels in healthy older adults
Authors: Roalf David R , Robinson Heather , Kesselring Irena , Jee Joelle , Mordy Arianna , Ruparel Kosha , Meeks Jacqueline , Wolk David A. , Nanga Ravi Prakash Reddy , Gur Ruben C , Reddy Ravinder
Published: December 2022

Background

Glutamate (Glu) is a critical molecule in cellular metabolism and the most abundant excitatory neurotransmitter in the brain. Glutamate dysfunction is common in neurodegenerative disorders—patients with Alzheimer’s disease (AD) have lower hippocampal glutamate—and likely contributes to age‐related declines in cognitive functioning. The extant literature on age‐related changes in brain Glu is small and all studies have employed proton spectroscopy. Thus, in this investigation we use a novel 7T magnetic resonanace imaging technique, Glutamate Chemical Exchange Saturation Transfer (GluCEST), to compare bilateral hippocampal brain Glu in between healthy old and young adults.

Method

Hippocampal GluCEST data were acquired from 14 healthy older adults [HOA; age: 71 (+/‐3)] and 10 young healthy adults [HYA; age: 21 (+/‐3)] using a Siemens 7T Terra. GluCEST data was acquired in axial slice positioned through bilateral hippocampus. Associations between MoCA scores and bilateral hippocampal GluCEST levels were investigated.

Result

Bilateral glutamate levels were 7% higher HYA as compared to HOA. HOA showed significant asymmetry (Left>Right) within the hippocampus while GluCEST in HYA were equivalent across hemisphere (t(22)=2.37, p<0.03). Within HOA, higher left hippocampal GluCEST levels were associated with higher performance on the MoCA [r(13)=0.55, p<0.04].

Conclusion

GluCEST appears to be a marker of aging‐related neurological and cognitive change. The present findings are similar to previous findings in AD (Graff‐Radford et al., 2013) Moreover, the left‐right asymmetry in GluCEST aligns with recent translational studies indicating a left‐right dissociation in long‐term memory function, which may be partially mediated by asymmetries in glutamate receptor content (Shipton et al., 2014). This preliminary study is the first to compare GluCEST levels in young and older adults and is the first step towards elucidate age‐related trajectories of glutamatergic alterations and their relationship to clinical and cognitive phenotypes.
Caregiving Experiences during the COVID‐19 Pandemic
Authors: Ta Kevin , Alto Raquel , Nguyen Krystal , Nguyen Rachel , Tran Duyen , Meyer Oanh L.
Published: December 2022

Background

Caring for a family member with cognitive impairment can be emotionally and physically exhausting. Caregiver challenges have been exacerbated by the COVID‐19 pandemic. This qualitative study examined caregiving experiences during the pandemic, exploring what caregivers perceived as most important in their caregiving experience while navigating through the pandemic.

Method

We enrolled 158 adults (non‐Hispanic White (NHW): 66%; Latino: 16%; Black: 9%; Asian: 8%) caring for a family member with MCI, mild cognitive impairment, (35%) or dementia (65%). Approximately 37% were recruited from an Alzheimer’s Disease Research Center (ADRC) and 63% from the community. Caregivers completed demographic questionnaires and open‐ended questions about their experience during the pandemic. They were asked (1) what was the most important thing to them in terms of providing care; (2) if they felt that they had enough support to help them provide care; (3) how the COVID‐19 pandemic has impacted them and the care they provide; and (4) what strategies have they used to help them provide care. Responses were open‐coded by 2 teams of 2, who met several times with the principal investigator to discuss and refine the themes.

Result

Several themes emerged from the analyses, including (1) caregivers managing their own physical health and safety, or that of their care recipient; (2) changes in relationship dynamics and familial support; (3) fluctuations in availability of formal support; (4) focus on wellness; and (5) employment/financial concerns brought upon by the pandemic.

Conclusion

The pandemic has filled the lives of caregivers with more adversities and struggles, which can exacerbate the stress of caregiving and call attention to the need for more formal support. These findings highlight the urgent need for more online and at‐home caregiving resources that can continue beyond the pandemic.
GWAS of Genetic Resilience to Age‐Related Risk for Alzheimer’s Disease in Admixed African Ancestry Individuals
Authors: Belloy Michael E , Guen Yann Le , Eger Sarah J , Napolioni Valerio , He Zihuai , Mormino Elizabeth C. , Greicius Michael D
Published: December 2022

Background

We sought to identify genetic variants that confer resilience to age‐related Alzheimer’s disease (AD) risk in subjects of admixed African ancestry.

Methods

Participants were ages 60+, of African ancestry (> = 25%), and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed, whole genome sequencing (WGS), or whole exome sequencing (WES). Genome‐wide association studies (GWAS) were performed per data type, split by Hispanic/non‐Hispanic participants (Table‐1), followed by meta‐analysis (Plink v2.0; GWAMA v2.2.2). GWAS performed multiple linear regression on an AD‐age score that models resilience to age‐related risk for AD (Le Guen & Belloy et al. 2021; Figure‐1). Models adjusted for sex, APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Brain amyloid Positron Emission Tomography (PET) qualitative reads together with SNP array data imputed to TOPMed were also available for African American individuals in A4. These data were independent from the primary GWAS and were used to evaluate significant GWAS variants for their association with binarized amyloid outcome (negative/positive), using a consistent model that additionally adjusted for age‐at‐scan.

Results

We found a novel protective genome‐wide significant intergenic variant (rs77450754) ∼200kb downstream of ATXN8OS/KLHL1 (Figure‐2‐3). It has a MAF of 13% in African ancestry samples, but is rare (0.1%) in Europeans and (<2%) Latino/Admixed Americans in gnomAD v.3. The latter may explain why effects appeared less pronounced in the considered Hispanic samples (since linkage to potential causal nearby variants may differ) (Figure‐3). The variant also displayed a protective, non‐significant, association with brain amyloid in African ancestry samples (Table‐2). Interestingly, KLHL1, also known as MRP2, is a member of the superfamily of ATP‐binding cassette (ABC) transporters, and has potential functions related to neurite outgrowth and efflux transport at the blood‐brain barrier, supporting its potential relevance to AD pathogenesis.

Conclusions

Our results provide new insights into genetic resilience to AD across aging and emphasize the importance of including ancestrally‐diverse populations in genetic studies. Our results also highlight the need for the field to compose ancestrally‐diverse multi‐omics and endophenotype data to support further validation analyses of genetic risk loci prioritized from GWAS.
The Effect of Apolipoprotein e4 on Object Mnemonic Discrimination in Healthy Adulthood.
Authors: Lancaster Claire L , Daly Jessica , Berens Samuel , Tabet Naji , Dowell Nicholas , Bakker Arnold , Bird Chris , Rusted Jennifer M
Published: December 2022

Background

Impairment in mnemonic discrimination is a hallmark feature of the very early stages of Alzheimer’s Disease (AD) and is associated with aberrant hippocampal function. Carriers of an Apolipoprotein (APOE) e4 gene, the most well‐established risk factor for AD, show differences in hippocampal function from youth. The cognitive consequences of altered brain activation in this group, however, remain poorly understood.

Methods

An online web‐platform has been developed – the APOE Memory Bank, which presents a collection of in‐depth behavioural tasks targeting hippocampal (object and spatial mnemonic discrimination) and non‐hippocampal cognitive processes (prospective memory, working memory and executive control). Cognitively healthy adults (aged 45–65 years) were invited to take part from the NIHR BioResource database. Selection processes have ensured a well‐matched, equivalent sample of e4 carriers and non‐carriers.

Results

Four hundred and twenty‐one participants have provided data to the APOE Memory bank to date. Ongoing, pre‐registered analyses will test if APOE e4 carriers show alterations in their ability to discriminate objects in memory, and if genotype differences in the cognitive processes supporting successful mnemonic discrimination underpin disparities. The sample is enriched with a high proportion of homozygous e4 carriers, providing a novel examination of gene‐dose effects at scale.

Conclusions

Establishing which cognitive processes are sensitive to the detrimental effects of APOE e4 will advance understanding of how genotype differences in brain development confer vulnerability in this high‐risk group. To date, indices of mnemonic discrimination have been used to discriminate preclinical or prodromal AD. This research provides a novel test of whether, in mid‐life, a web‐based object mnemonic discrimination task can differentiate risk for subsequent cognitive impairment. Identifying non‐invasive, easy‐to‐administer risk markers will advance future avenues of prophylactic, personalised intervention
Infections in people with dementia and mortality: A population‐based cohort study
Authors: Mavrodaris Angelique , Mueller Christoph , Perera Gayan , Brayne Carol , Stewart Robert
Published: December 2022

Background

Infections in older people are a major cause of mortality and morbidity and may be important modifiers of outcomes for people with dementia. There is limited evidence on the role of infections and associated hospital admissions on subsequent outcomes for people living with dementia. We explored mortality in individuals with dementia admitted to hospital for infections from a defined population in comparison to those not admitted and admitted for other reasons.

Method

A retrospective cohort analysis was created using secondary care data from one of Europe’s largest mental health and dementia care providers in South London (UK). People with recorded dementia between January 2008 and March 2017 were linked to national hospitalisation and mortality data and classified as either admitted for infections, admitted for other causes or no admissions around first recorded dementia diagnosis and followed to death or a census date on 31st March 2019. Multivariate Cox proportional hazards regression with date of first dementia diagnosis as index date were applied.

Result

In total 14,375 people diagnosed with dementia were included, of whom 3,480 (24%) were admitted for infections, 3604 (25%) admitted for other causes and 7,291 (51%) not admitted to hospital. Individuals with dementia admitted for infections had lower MMSE scores, higher rates of co‐morbidity and ranked significantly higher on deprivation indices compared to those with no admissions. Adjusted multivariate Cox regression models indicated that people with dementia admitted to hospital for infections had significantly higher mortality rates compared to no admissions (Hazard ratio (HR): 2.3; 95% confidence interval (CI): 2.1 ‐ 2.5) and to admissions for other causes (HR: 1.5; 95% CI: 1.4 ‐ 1.6).

Conclusion

In people with dementia, admissions for infections are critical events associated with substantial increased mortality risk. Addressing care patterns both before and after admission with a focus on infection could improve outcomes and is a key health research area, with optimisation of care a direct priority.
Social health factors and dementia risk – assessing potential pathways in a population‐based cohort study
Authors: Duffner Lukas , Deckers Kay , Cadar Dorina , Steptoe Andrew , de Vugt Marjolein , Köhler Sebastian
Published: December 2022

Background

Epidemiological studies suggest an association between social health factors and dementia risk, but potential pathways between these factors remain largely unexplored. Therefore, the current study assesses the relationship between social isolation, social activity engagement, and dementia risk, including potential effect mediation by level of loneliness.

Method

We used data from 7520 participants of the English Longitudinal Study of Ageing (ELSA), assessed from baseline (Wave 2, 2004/2005) until Wave 9 (2018/2019) for incident dementia. Level of social isolation was defined as the frequency of contact with children, other family and friends in addition to the membership in clubs and organizations. Social activities were inferred by the self‐reported frequency of engagement in activities with a strong social component (e.g. volunteering). Both variables were dichotomized, representing low vs. high social isolation or social activity engagement. Level of loneliness was measured using the short form of the UCLA loneliness scale. Depression diagnoses were assessed through self‐report.

Separate multivariable Cox proportional hazard regression models were fitted, with social isolation and social activities as predictors while controlling for age, sex, education, wealth, cardiovascular risk factors (model 1) and, subsequently, for depression and level of loneliness (model 2).

Result

After a median follow‐up period of 11.8 years (IQR = 5.9 years‐13.9 years), 495 people (67.1 cases per 10,000 person‐years; 95% CI 61.5‐73.3) developed dementia. Higher social isolation (HR = 1.30; 95% CI 1.03‐1.64) and more frequent social activity engagement (HR = 0.74; 95% CI 0.60‐0.92) were related to dementia risk in model 1. Social isolation still predicted dementia risk in model 2 (HR = 1.30; 95% CI 1.02‐1.66), while social activity engagement did not (HR = 0.83; 95% CI 0.65‐1.07). Both depression and loneliness significantly predicted dementia risk in the model including social isolation, while, for the model including social activity engagement, only depression was associated with dementia risk. The change in HR between model 1 and 2 for social activity engagement was mainly due to adding level of loneliness rather than depression to the model.

Conclusion

Lower social isolation and more frequent social activity engagement are associated with lower dementia risk. Part of the association might be explained by level of loneliness and depression.
Associations of AD risk factors with cerebrospinal fluid ATN biomarker profiles in 10,662 persons without dementia from the Amyloid Biomarker Study
Authors: Jansen Willemijn J. , Tijms Betty M. , Janssen Olin , Oomens Julie Elisabeth , Vos Stephanie J. B. , Verhey Frans R.J. , Visser Pieter Jelle ,   the Amyloid Biomarker Study Group
Published: December 2022

Background

The pathophysiology of Alzheimer’s disease (AD) is characterized by amyloid‐β deposition (A), tau tangle formation (T) and neurodegeneration (N). In order to promote the development and implementation of a successful intervention to prevent or delay AD progression, frequency estimates of the evolution of these pathological events across age and its relation with other AD risk factors in the various pre‐dementia stages are essential.

Methods

We selected 4413 participants with normal cognition (NC), 1356 with subjective cognitive decline (SCD) and 4887 with mild cognitive impairment (MCI) from 53 studies that participated in the Amyloid Biomarker Study. We classified participants into 8 ATN biomarker profiles (A‐T‐N‐, A+T‐N‐, A+T‐N+, A+T+N‐, A+T+N+, A‐T+N‐, A‐T‐N+, A‐T+N+) based on CSF amyloid‐β42 (A), phosphorylated tau (T) and total tau (N) abnormality according to data‐driven (A) and center‐specific (TN) cutoffs. Markov‐Chain‐Monte‐Carlo generalized linear mixed models were used to evaluate associations of age, sex, educational level (dichotomized at 14 years) and APOE‐e4 copy number with frequencies of the ATN profiles.

Results

Frequencies of the ATN biomarker profiles strongly depended on age (p<0.001), cognitive status (NC vs. SCD p>0.05; NC/SCD vs. MCI p<0.001) and APOE‐e4 gene dose (p<0.001; Figure 1). In participants with NC and SCD, A+T‐N‐ was most frequent in persons with 2 ε4 alleles, A+T+N+ was most frequent with aging in persons with 1 ε4 allele while A‐T‐N‐ and A‐T+N+ were, depending on age, most frequent in non‐carriers. In MCI, the A+T+N+ biomarker profile was most frequent starting at age 55 for persons with 2 ε4 alleles, at age 60 for persons with 1 ε4 allele and at age 75 for non‐carriers. ATN biomarker profile frequencies were also associated with educational level (p=0.01). Overall, A‐T+N+ was up to 10% more frequent with aging in persons with high educational level, whereas A+T‐N‐ and A+T+N+ were about 5% more frequent across age in persons with low educational level. Sex was unrelated to ATN biomarker profile frequencies.

Conclusions

Frequencies of the ATN biomarker profiles in persons without dementia changed substantially with age, cognitive status, APOE‐ε4 copy number and educational level but not sex. These results may enable a more specific approach to AD prevention.
Neuroprotective role of Syzygium aromaticum on SIRT1 and oxidative balance in Alzheimer’s disease
Authors: Yadav Yudhishthir , Dey Sharmistha , Dey Aparajit Ballav
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory impairment. The holistic approach can be better option to prevent and treat the pathological consequences of neurodegenerative disorders. Recent studies, suggest that Ayurveda may provide a good holistic care and treatment. The accumulation of Reactive oxygen species (ROS) in the brain increases with ageing ultimately to the oxidative stress. Sirtuin1 (SIRT1) is a potential mediator of oxidative balance. Syzygium aromaticum have antioxidant properties, may help in scavenging free radical generation and prevent the diseases. This study determined the role of Syzygium aromaticum on neuroprotection and oxidative balance in amyloid beta (Aβ) induced neurotoxicity by activating SIRT1 protein.

Method

The anti‐oxidative capacity of Syzygium aromaticum was analyzed in Aβ induced neurotoxicity in differentiated SHSY‐5Y cells. The rescue effect of Syzygium aromaticum was performed by MTT assay in time and dose dependent manner. The expression levels of γ‐secretase and SIRT1 were analyzed by western blotting. The neuroprotective effect of Syzygium aromaticum by activating antioxidant enzymes under Aβ induced neurotoxicity was also observed.

Result

Syzygium aromaticum was capable to scavenge ROS and elevated the percentage of anti‐oxidant enzymes. It also activated and elevated the level of SIRT1 and downregulated γ‐secretase level. The cell survival rate of Aβ induced cells was increased by the treatment of Syzygium aromaticum around 60% at 72 h.

Conclusion

This study explored the role of Syzygium aromaticum in prevention of AD like pathology by targeting SIRT1 pathway. This product showed capability of neuroprotection and redox balance for management of oxidative stress.
A digital biomarker for remote self‐assessment of Alzheimer’s Diseases: development and validation
Authors: Butler Joe , Watermeyer Tamlyn J , Matterson Ellie , Harper Emily G , Parra‐Rodriguez Mario A
Published: December 2022

Background

Online data‐collection provide an opportunity for Alzheimer’s Disease research to collect large datasets crucial for understanding important public health concerns. However, the reliability of online tasks as compared to those administered in the lab is poorly examined. Our goal is to validate an online version of the short‐term memory‐binding task (STMBT), a potential digital biomarker sensitive to Alzheimer’s Disease (Parra et al., 2010), to understand if data collected online in two environments, at‐home and in the lab, is comparable.

Method

We created an online version of the STMBT task using Psytoolkit (Stoet 2010; Stoet 2017). Development involved piloting, group and user discussions to explore how such a novel tool could be best presented for self‐assessment. Useful insights led to refinement of the online tool (i.e., instruction videos, images, and text). The validation stage involves test‐retest reliability assessment of cognitively fit participants (aged >40 years) who complete the two conditions of this paradigm (i.e., shape only and binding). Task Environment (home and in the lab) and conditions (shape and binding) were fully counterbalanced. Measures of general cognitive abilities, anxiety and at‐home environment were also taken.

Result

Recruitment is on‐going, but preliminary data (n = 10) has already proved informative. A repeated measures ANOVA looking at task‐accuracy with factors of Environment (home vs. lab) and Condition (shape vs. binding) revealed no significant effects of Environment: F(1, 9) = 0.308, p = .591; Condition: F(1, 9) = 2.202, p = .172); or Interaction: F(1, 9) = 0.308, p = .591). For the shape condition, all participants performed near ceiling regardless of testing environment. In the binding condition, we observed good‐to‐excellent test‐retest reliability between environments using single measures interclass correlation (ICC = 0.954, CI 0.83‐0.99, (F(9, 9) = 39.62, p <.001).

Conclusion

These preliminary results indicate the STMBT can provide reliable data when self‐administered using an online version of the task which has important implications for public health researchers. For our fully powered sample, we will provide summary of other measures.
The heterogeneous amyloid‐positive brain: mapping individualised patterns of atrophy in amyloid‐positive Alzheimer’s disease patients using neuroanatomical normative models
Authors: Verdi Serena , Loreto Flavia , Kia Seyed Mostafa , Duvnjak Aleksandar , Hakeem Haneen , Perry Richard J , Win Zarni , Patel Neva , Schott Jonathan M , Marquand Andre F , Malhotra Paresh A , Cole James H
Published: December 2022

Background

Patterns of atrophy in the brain highly differ between individual Alzheimer’s Disease (AD) patients, however, most clinical research focuses on group‐level differences (Verdi et al., 2021). Here we used a novel technique, neuroanatomical normative modelling, to reveal individual patterns of cortical thickness by quantifying deviations from the normative range. We applied a hierarchical Bayesian regression (HBR) normative model (Kia et al., 2021), to amyloid‐positive AD patients who had clinical amyloid PET imaging at the Imperial Memory Clinic (IMC). Patients had either AD dementia or mild cognitive impairment due to AD. We hypothesised that there would be individual differences in patterns of cortical atrophy in these patients.

Method

Cortical thickness across 148 regions of interest (ROIs) was generated using FreeSurfer from n=130 (102 AD patients and 28 healthy controls) T1‐weighted MRIs acquired from the IMC. A reference HBR normative model was trained on a separate dataset of n=34,490 healthy individuals to index population variability, which predicted cortical thickness at each ROI using age and sex. This generated cortical thickness z‐scores for each ROI, per patient (z‐score < ‐1.96 = outlier).

Result

The patterns of cortical atrophy outliers were highly varied in amyloid‐positive AD patients. For instance, the largest proportion of outliers in a region was 60% within the superior temporal sulci, if atrophy were homogenous we would expect 100% of outliers to be here (Fig.1). This heterogeneity was also seen when comparing how similar outlier patterns were between patients (Fig.2). We also found that the proportions of outliers differ according to disease severity, e.g. the highest percentage of outliers was 70% within superior temporal sulci within the AD dementia subgroup, and 50% in superior temporal sulci in the mild cognitive impairment due to AD subgroup (Fig.3).

Conclusion

Amyloid‐positivity results in heterogenous patterns of cortical atrophy. This is more pronounced in AD dementia, though still present in people with mild cognitive impairment due to AD. Neuroanatomical normative maps have the potential to be individualised markers of disease, and with application to longitudinal data could track individual disease progression.
Principal component analysis of auditory ERPs discriminates mild cognitive impairment and Alzheimer’s disease from normal aging
Authors: Liljander Sara K. , Nieminen Jaakko O. , Keski‐Säntti Petra , Mutanen Tuomas P. , Lehtovirta Maarit , Ilmoniemi Risto J. , Partanen Juhani V.
Published: December 2022

Background

Sensory gating refers to an inhibitory mechanism of the brain that protects higher cortical centers from being flooded with repetitive, redundant sensory inputs. Sensory gating is modulated by cholinergic transmission, the deterioration of which is a prominent neurochemical feature of Alzheimer’s disease (AD), the most common form of dementia in the elderly. The study investigated whether alterations in inhibitory gating, assessed by event‐related potentials (ERPs) in response to repeated auditory stimuli, can discriminate AD and mild cognitive impairment (MCI) from normal aging.

Method

Event‐related electroencephalogram was recorded from 38 AD patients, 37 MCI patients, and 38 elderly cognitively normal control (NC) participants in a conditioning–testing paradigm. ERP waveforms, stimulus‐locked changes in power, and inter‐trial phase clustering (ITPC) were extracted and submitted to a covariance‐based principal component analysis (PCA) to yield data‐driven component measures.

Result

Non‐parametric cluster‐based permutation tests revealed statistically significant differences for ERP waveforms in separating AD, for power in separating AD and MCI, and for ITPC in separating AD, MCI, and NC from the other two groups pooled together.

Conclusion

The study confirms that alterations in auditory sensory gating can discriminate between AD, MCI, and normal aging. Auditory ERPs might serve as an objective, non‐invasive, and cost‐effective method for evaluating cognitive decline suggestive of AD and to monitor disease progression, therapeutic efficacy, or effects of novel drug candidates in clinical trials.
Uncovering single‐nucleus RNA velocity variations in neuropathologic Alzheimer’s disease
Authors: Adewale Quadri , Khan Ahmed F , Bennett David A , Medina Yasser Iturria
Published: December 2022

Background

Differential single‐nucleus (snRNA‐seq) gene expression analyses in Alzheimer’s disease (AD) provide fixed snapshots of cellular alterations, failing to detect the temporal dynamics of genes at individual cells. To overcome this limitation, here we analyze single‐nucleus RNA velocities (RNA‐vel) from the prefrontal cortex to characterize dynamic genetic and cellular differences in neuropathological AD progression. RNA‐vel is the rate of change of gene expression obtained by comparing intronic and exonic sequence counts. Comparison of AD pathology associated gene expression with parallel RNA‐vel differences reveals sets of genes and molecular pathways that underlie the static and putative dynamic regimes of cell type‐specific dysregulations underlying the disease.

Method

We used snRNA‐seq data from the prefrontal cortex of 48 subjects1 with varied levels of AD pathology from ROSMAP2. We then calculated both the expression and RNA‐vel differences between low AD‐pathology and mild‐to‐severe AD‐pathology. These differences were cell‐specific across six major cell types: excitatory neurons, inhibitory neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells.

1. We characterized RNA‐vel differences associated with four AD neuropathology traits: neuritic plaque, neuronal neurofibrillary tangle, overall β‐amyloid load, and PHF tau tangle density.

2. We demonstrated the reproducibility of the RNA‐vel differences in two independent datasets: dorsolateral prefrontal cortex (N = 24) from ROSMAP3 and superior frontal gyrus (N = 6) from GEO4.

Result

Only 10 of 843 (1.2%) genes overlap between the differential RNA expression and velocity analyses, suggesting substantial AD‐pathology related differences between these two RNA descriptors. The genes with only velocity differences relate to cell developmental and synaptic processes. Conversely, the genes with only differential expression are majorly associated with mitochondrial activity and ribosomal processes. Many genes were reproduced in the independent datasets; these overlapping genes are again associated with neural development and synaptic activities across many cell types, as well as vascular‐ and immune‐related processes in astrocytes and microglia, respectively

Conclusion

We use RNA velocity to characterize, for the first time to our knowledge, the dynamical multicellular processes underlying neuropathological AD progression. The results support the validity of the novel RNA‐vel concept for achieving a complementary molecular characterization of AD, which may be obscured by typical analysis of RNA abundance alone.
The Panama Aging Research Initiative: Dementia‐related biomarker research in a low‐resourced setting
Authors: Britton Gabrielle B , Villarreal Alcibiades E , Oviedo Diana C , O'Bryant Sid E. , Edwards Melissa , Carreira Maria B , Rangel Giselle
Published: December 2022

Background

The Panama Aging Research Initiative (PARI) is a two‐cohort study of more than 800 adults aged 60 years and older. PARI has provided the first reports of modifiable and non‐modifiable risk factors of cognitive impairment and dementia, as well as various health conditions common among older adults in Panama, including chronic illnesses, polypharmacy and frailty. Our general objective consists of identifying biomarkers of memory impairment for improving early diagnosis of dementia, and specifically, Alzheimer’s disease (AD). Panama follows the global trend of smartphone use and rapid access to information. Therefore, the implementation of digital phenotyping as clinical tool could be a promising strategy to developing culturally appropriate cost‐ and time‐efficient protocols for early detection of cognitive impairment.

Methods

Our ongoing community‐based cohort has undergone clinical interviews, neuropsychological testing, and assessments of frailty at two time points (14‐29 months apart). Fasting blood draws were obtained for measurements of genetic and blood‐based biological markers. Ongoing studies are evaluating genetic variation both in disease genes and in regulatory factors that modulate onset and progression of AD and other neurodegenerative diseases. In collaboration and with the support of the Davos Alzheimer’s Collaborative (DAC) Global Cohort Development program, we are also introducing the collection of longitudinal AD‐related digital phenotypes.

Results

Blood‐based biomarkers have been shown to be highly accurate in detecting AD and MCI, with promising results for early diagnosis of AD‐related cognitive impairment. We will discuss results of studies examining the combination of blood‐based biomarkers with standard neuropsychological tests to generate molecular profiles that could lead to early and timely MCI and AD diagnosis. We will further present how digital phenotyping will open up new opportunities that will help overcome challenges that arise when trying to apply conventional approaches in low‐resourced settings.

Conclusions

Blood‐based and digital biomarkers could be used as a first screening tool, followed by additional diagnostic testing for those at risk for cognitive impairment. The DAC initiative to leverage existing infrastructures across cohort studies around the world is of particular relevance to refining our assessment processes and dementia risk profiling, and ultimately, developing novel interventions in low‐resource settings.
Mass spectrometry synuclein detection in human plasma
Authors: Lehallier Benoit , Vialaret Jérôme , Pons Marie‐Laure , Mondesert Etienne , Castelnovo Giovanni , Moreau Stéphane , Hirtz Christophe
Published: December 2022

Background

Synucleins (alpha, beta, and gamma) are potential biomarkers for Parkinson’s disease dementia (PDD), Dementia of Lewy body (DLB) and the Multi system atrophy (MSA). Their quantification with Mass spectrometry (MS) represents an interesting approach as it can precisely quantify synuclein proteoforms including mutations, alternative splicing, phosphorylation and other post‐translational modifications.

Methods

We developed an antibody free method starting with 95 µl of plasma. Patient cohort of 155 samples was analyzed with 57% PD, 22% LBD, 6% MSA, and 15% of control (CTRL) patient samples. Briefly, plasma proteins were differentially precipitated, clean‐up on AssayMap BRAVO (Agilent Technologies) and digest with trypsin/lys C. Liquid Chromatography‐Multiple Reaction Monitoring (LC‐MRM, Nexera Mikros – 8060, Shimadzu) method was developed to monitor 14 peptides originated from the alpha, beta and gamma synuclein sequence and one hemoglobin peptide. Method was validated following the EMA guidelines and compare to alpha synuclein immunodetection with Meso Scale Discovery platform (U‐plex human alpha synuclein kit).

Results

Quantitative assay based on LC‐MRM was validated on total alpha (140aa), beta (134aa) and gamma (127aa) synuclein peptides, and 4 alpha synuclein proteoforms (126, 112, 98 and 41) using 3 proteotypic peptides (one for 126/98, one for 112/98 and one for 41). After cohort quantification, alpha and beta synucleins were quantified in plasma with good performances and are able to statistically discriminate CTRL vs PD; CTRL vs LBD; CTRL vs MSA, and MSA vs PD. A slight correlation was found between the quantities obtain between MSD and MS assays.

Conclusion

MS based assay was successfully developed and validated to plasma synuclein proteoforms. Analysis of patient cohort indicate the ability of this assay to discriminate PD, DLB and MSA with a specificity of 81% and a sensitivity of 87%.
Three year longitudinal changes of subcortical volumes in SuperAgers
Authors: Kim Geon Ha , Kim Bori R. , Jeong Jee Hyang
Published: December 2022

Background

“SuperAgers” refer to older adults whose cognitive abilities were comparable to those in middle age or to those of young adults. Given that the volumes of the subcortical structures are the main structures of the frontal‐subcortical circuits that are associated with frontal function, investigating the changes of subcortical volumes in Superagers could help understand the underpinning neural characteristics in SuperAgers. Therefore, the purpose of this study to examine the longitudinal changes of subcortical structures in Superagers compared to typical agers.

Methods

We enrolled a total of 100 elderly (60 years old or older) with normal cognitive functions. The normal cognitive function was defined when participants scored above ‐ 1.SD of population norm on the tests of memory and scored above ‐ 1.5 SD on the tests of language, attention, visuospatial and executive functions. We defined the superagers based on their performance compared to middle‐aged adults (45 year old) on the delayed recall scores in both the Seoul Verbal Learning Test and the Rey Rey‐Osterrieth Complex Figure Test. We followed up cognitive function and brain MRI every year for three years. The T1 images of each subject were processed to obtain the anatomical parcellations of subcortical structures by the FreeSurfer software. Mixed effect model was used to analyze the longitudinal changes of subcortical volumes with age, sex and education years as covariates.

Result

A total of 46 participants were classified as the superagers. At the baseline, SuperAgers demonstrated greater volumes not only in the hippocampus but also in the putamen, thalamus and pallidum. During the three year follow‐up, superagers continued to show greater volumes in the hippocampus, putamen, thalamus and pallidum.

Conclusion

These results indicate that Superagers might be resilient to age‐related structural volume change not only in the hippocampus but also in other subcortical volumes such as putamen, thalamus and pallidum.
Thimet Oligopeptidase is a potential CSF biomarker for Alzheimer’s Disease
Authors: Hok‐A‐Hin Yanaika S. , Bolsewig Katharina , Ruiters Daimy N. , Lleó Alberto , Alcolea Daniel , Lemstra Afina W. , van der Flier Wiesje M. , del Campo Marta , Teunissen Charlotte E.
Published: December 2022

Background

Using antibody‐based Olink proteomics, we recently established that Thimet Oligopeptidase (THOP1) is a potential cerebrospinal fluid (CSF) biomarker for Alzheimer’s Disease (AD). THOP1 is a neuropeptidase able to degradate Aβ peptides. Here, we aimed to develop specific THOP1 immunoassays for further clinical validation and to enable future implementation of this biomarker.

Method

We developed and compared novel immunoassays for CSF THOP1 analysis on automated Ella™ and Simoa™ platforms. After analytical validation, THOP1 levels were measured in a selection of CSF samples from the original discovery study (24 cognitively unimpaired controls, 24 AD and 24 dementia with Lewy bodies (DLB) patients) on both platforms. Passing bablok‐regression analysis showed that platforms were comparable and thus we selected the Ella platform for further validation in two independent cohorts (Amsterdam Dementia cohort (ADC) including 56 controls, 45 mild cognitive impairment with amyloid pathology (MCI‐Aβ+), 55 AD and 55 DLB patients; Sant Pau Initiative on Neurodegeneration (SPIN) cohort including 53 controls, 50 MCI‐Aβ+, 47 AD and 50 DLB patients). Differences in THOP1 levels between diagnostic groups and correlations to the AD CSF biomarkers were tested by ANCOVA (corrected for sex) and Spearman correlation analyses.

Result

THOP1 levels moderately correlated between proteomics analysis and the novel assays (Olink‐Ella: rho=0.720; Olink‐Simoa: rho=0.584; Ella‐Simoa rho=0.713; figure 1). Consistent with results obtained on the Olink proteomics platform, THOP1 levels were significantly increased in AD compared to DLB patients (Ella: 1.6‐fold; Simoa: 1.7‐fold) and controls (Ella: 1.8‐fold; Simoa: p>0.05). We next showed increased THOP1 levels in both MCI‐Aβ+ (ADC: 1.2‐fold, p<0.05; SPIN: 1.4‐fold, p<0.001) and AD patients (ADC: 1.03‐fold, p>0.05; SPIN: 1.4‐fold, p<0.001) compared to controls (Figure 2). THOP1 levels correlated moderately with levels of t‐Tau (ADC: rho=0.644; SPIN: rho=0.721), p‐Tau (ADC: rho=0.480; SPIN: rho=0.712) and Aβ40 (ADC: not available; SPIN: rho=0.625) but not with Aβ42 (ADC: rho=0.110; SPIN: rho=‐0.09).

Conclusion

We show increased CSF THOP1 levels in amyloid positive AD and MCI patients and correlation with CSF Aβ40, which together with literature showing colocalization of THOP1 with Aβ plaques suggests a relationship with Aβ‐production. The association of THOP1 to tau pathologies highlights the potential of this protein as a disease monitoring biomarker.
Plasma biomarkers of brain amyloid‐β and tau pathologies in Down syndrome
Authors: Janelidze Shorena , Christian Bradley T , O'Bryant Sid E. , Price Julie C , Laymon Charles M , Schupf Nicole , Klunk William E , Lott Ira T , Silverman Wayne , Rosas H. Diana , Zaman Shahid , Mapstone Mark , Lai Florence , Ances Beau M , Handen Benjamin L , Hansson Oskar ,   the Alzheimer’s Biomarker Consortium Down Syndrome (ABC‐DS)
Published: December 2022

Background

Plasma tau phosphorylated at threonine 217 (P‐tau217) and glial fibrillary acidic protein (GFAP) are promising diagnostic and prognostic biomarkers of Alzheimer’s disease (AD). We aimed to determine the usefulness of plasma P‐tau217 and GFAP to detect AD‐related pathology in individuals with Down syndrome (DS).

Method

This cross‐sectional study included adults with DS (N=300) and non‐DS sibling controls (N=37) with baseline blood samples enrolled in the Alzheimer’s Biomarker Consortium‐Down Syndrome study. Participants with DS all underwent plasma P‐tau217 and GFAP assessments as well as tau‐PET, β‐amyloid (Aβ)‐PET and cognitive testing. We examined association of plasma P‐tau217 and GFAP with tau‐PET, Aβ‐PET and cognitive measures using regression models and ROC curve analysis and investigated if combining P‐tau217 and GFAP together and with other plasma AD biomarkers (Aβ42/40, neurofilament light [NfL], total tau [T‐tau]) and age could improve their performance for identifying individuals with abnormal tau‐PET or Aβ‐PET.

Result

Plasma levels of P‐tau217 were increased in Aβ‐PET‐positive tau‐PET‐positive (A+T+) DS and A+T– DS compared with A–T– DS while GFAP was only increased in A+T+ DS (Figure 1). Plasma P‐tau217 levels were also higher in A+T+ DS than A+T– DS. In participants with DS, plasma P‐tau217 and GFAP (but not plasma Aβ42/40, t‐tau and NfL) were consistently associated with abnormal tau‐PET and Aβ‐PET status in models covaried for age (ORrange, 1.59‐2.46, p<0.028). A combination of P‐tau217 and age performed best when detecting tau‐PET abnormality in the temporal and neocortical regions (AUCrange, 0.96‐98), whereas the most parsimonious model for Aβ‐PET status included P‐tau217, T‐tau and age (AUC=0.95) (Figure 2). Higher levels of plasma P‐tau217 were associated with worse performance on DS Mental Status Examination and Cued Recall tests in Aβ‐PET positive (βrange, ‐0.231–[‐0.559], p<0.036) but not in Aβ‐PET negative DS.

Conclusion

Plasma p‐tau217 is an accurate biomarker of both tau and Aβ pathological brain changes in DS that could facilitate inclusion of individuals with DS in future AD clinical trials, especially when combined with age as a covariate.
Prospective cohort of elderly patients after hospitalization due to COVID‐19: preliminary results
Authors: Cintra Fabiana Carla Matos da Cunha , Cintra Marco Túlio , Almeida Daniella Cristina Brites , Martins Daniel Messias , Simão Gabriel Rabelo de Barros , Filipin Carolina Sant’anna , Vasconcelos Júlia Cunha , da Cruz Victor Fonseca Alves , da Silva Maria Clara Pereira , Fortini Iza de Faria , Viana Bernardo de Mattos , Bicalho Maria Aparecida Camargos
Published: December 2022

Background

Post Covid‐19 syndrome is recognized as the maintenance of disease symptoms for weeks to months after the disease has healed. It is suspected that the involvement of the ACE enzyme and IL‐6 may trigger an increased risk of dementia.

Method

This is a cohort study that is evaluating over 12 months the functional status and cognition of elderly people after hospital discharge. One group is composed of elderly people admitted to the hospital for Covid‐19 and the other group is composed of elderly people hospitalized for other clinical reasons. The groups are evaluated with The Mattis (DRS), AD8, IQCODE, ADCS‐ADL, PCL‐C, GDS‐15, FIM, COPM, CFS, FSS, mMRC and SARC‐calf. We will describe the preliminary results of the first 15 patients included in the COVID‐19 group on functional status, cognition, mood and quality of life.

Results

Fifteen patients with COVID‐19 were evaluated three months after hospital discharge. One was excluded due to previous mental disorder and another due to a request to be excluded from the study. We found a mean age of 67.7 ± 7.15 years, schooling 8.7 ± 4.7 years, 61.5% female, Charlson Comorbidity Index 1.9 ± 1.4, 69.2% with smoking history had incomplete vaccine protection for COVID‐19. Considering cognition, 15.4% of the sample had no impairment, 53.9% had mild cognitive impairment (MCI) (30.8% amnestic MCI and 23.1% non‐amnesic MCI) and 30.8% had dementia. 23.1% declared their health status and quality of life as fair or poor. Median CFS was 5 (3‐5), mean GDS‐15 was 4.7 ± 2.9, FSS 32.9 ± 18.9, PCL‐c 32.6 ± 12.5, SARC‐calf 3.2 ± 4.2. All had mMRC dyspnea classified between 2 and 4.

Conclusion

There was a high prevalence of mild cognitive impairment and dementia among patients after three months of discharge, with a predominance of mild frailty due to CFS and the presence of fatigue. It is noteworthy that a quarter of the sample reported low quality of life.
GMNC risk alleles in individuals with Alzheimer’s disease are associated with cerebrospinal fluid concentrations of proteins involved in neuronal plasticity and blood brain barrier function
Authors: Visser Pieter Jelle , Reus Lianne M. , Gobom Johan , Teunissen Charlotte E. , Bertram Lars , Zetterberg Henrik , Tijms Betty M.
Published: December 2022

Background

GWAS studies showed that cerebrospinal fluid (CSF) levels of total‐tau in Alzheimer’s disease (AD) are associated with genetic variations in GMNC (Cruchaga,2013). GMNC is involved in neural progenitor cell differentiation and regulates the generation of multiciliated ependymal cells (Kyrousi,2015), but the precise role of GMNC in AD pathophysiology remains unclear. We investigated which processes were associated with GMNC risk alleles by studying its associations with CSF levels of 1705 proteins in AD individuals.

Method

We selected 432 individuals with abnormal CSF amyloid beta 1‐42 levels from the EMIF‐AD multimodality biomarker discovery study and ADNI. We measured 1705 proteins by untargeted mass spectrometry (EMIF‐AD), the Human DiscoveryMAP panel (ADNI) or targeted mass spectroscopy (ADNI). We correlated the number of GMNC rs9877502‐A risk alleles with protein levels in additive models. To characterise proteins associated with GMNC risk alleles, we performed pathway enrichment analyses for Gene Ontology biological processes (GO‐BP) and ChEA transcription factors.

Result

Average age was 71.2 years. At least one GMNC rs9877502‐A risk allele was present in 60% of the AD individuals. Increasing number of GMNC risk alleles was associated with increased total‐tau, as expected, and with increased levels of 591 other proteins (35% of proteins measured). These proteins were associated with neuronal plasticity related processes (table) and SUZ12 and REST transcription factors, which are neuronal transcription repressors (all p‐FDR corrected>6.34e‐18). GMNC risk alleles were further associated with decreased levels of 105 proteins, including 72 proteins associated with blood brain barrier (BBB) permeability.

Conclusion

Within AD individuals, GMNC risk alleles are not only associated with increased total‐tau levels but also with increased levels of neuronal plasticity associated proteins. We also found that GMNC risk allele carriers may have less BBB dysfunction than non‐carriers. Further studies are needed to clarify the association of GMNC with neuronal plasticity and BBB function in AD.

References

Cruchaga, Neuron 2013: 256‐268. Kyrousi, C. , Development 2015: 3661‐3674.