bluuebunny/crossref_metadata_2025 huggingface dataset:
Thinking outside of the box through adaptive reuse of closed malls for dementia programs and services: Community workshop outcomes
Authors: Roberts Emily
Published: December 2021

Background

It is estimated that 5.4 million Americans have some form of dementia and these numbers are expected to rise in the coming decades, leading to an unprecedented demand for memory care housing and services. In searching for innovative options to create more autonomy and better quality of life in dementia care settings, repurposing existing structures, in particular vacant urban malls, may be one option for the large sites needed for the European model of dementia villages. These settings may become sustainable Dementia Friendly City Centers (DFCC), because in the case of enclosed mall construction, the internal infrastructure is in place for lighting, HVAC, with varied spatial configuration of public spaces. This presentation describes the community engagement research being conducted by a research team at a Midwestern university, laying groundwork for the DFCC model for centralized dementia programs, services and attached housing. An online community workshop was held with 50 participants from multiple stakeholder groups including architect, urban planners, landscape architects, memory care administrators, medical doctors, family caregivers, university professors and students and public health employees. 5 breakout sessions were held after the initiative was introduced to the participants with topics covered which included the themes of community revitalization, building sustainability, urban regreening, onsite housing and medical care and innovation and culture change in dementia care This presentation provides the qualitative data collected through the recorded breakout sessions and the participants agreed that the DFCC model is one opportunity to make life better not only for those with needs associated with dementia now, but also for ourselves in the future. Others saw education of future stakeholders about the value of this model of care as critical in transforming current hurdles into future opportunities.
MoCA Test: Validation of a five‐minute telephone version
Authors: Nasreddine Ziad S
Published: December 2021

Importance

This study validates the use of a telephone version of the MoCA Test, which helps health professionals assess patients remotely.

Objectives

This is a validation study for a 5 minute telephone version of the MoCA.

Study design

The subjects’ performances were compared to results obtained from the full version of the MoCA test, at an average of 50.8 days, prior to having completed the 5 Min Telephone MoCA.

Participants

84 consecutive subjects were approached to participate in the study. Subjects had to be over 50, male or female, an education level of 6 years.

Settings

Subjects were recruited in a memory clinic setting.

Outcomes and Measures

Correct classification and correlation between the Telephone MoCA and full MoCA was evaluated, with area under the curve (AUC) analysis, and Pearson Coefficient respectively.

Results

81 subjects were recruited, and 3 subjects declined participation. The average age of the subjects was 69 (Range 47‐92) with a sex distribution of 42 females and 41 males. The average education level for the subjects was 12.6 years. The 5 Min Telephone MoCA results correlated well with the full version of the MoCA, with an area under the curve of 0.864 and a strong Pearson Coefficient of 0.74.

Conclusion and Relevance

The 5 Min Telephone MoCA is feasible, practical, and reliable, when compared to the full, in‐clinic, MoCA. Clinicians are already familiar with the use of the full MoCA Test, and this new 5 min telephone version, can help them reliably assess patients who cannot make to an in clinic evaluation.
Establishing a relationship between semantic clustering and language performance
Authors: Mae de la Cruz Raelynn , Jeffers Sharlene L , Miller Justin B ,   Cleveland Clinic Lou Ruvo Center for Brain Health
Published: December 2021

Background

Semantic clustering (SC) is an implicit learning strategy commonly utilized on verbal list‐learning tasks. While research has examined SC and executive functioning and memory, little has been done relating SC and language. In the present study, we calculated a SC score on a common list‐learning task and explored relationships with language performance. We predicted weaker SC in individuals with MCI compared cognitively normal individuals, which could potentially be used as an additional measure to help identify MCI and Alzheimer’s disease.

Method

Archival test data from an outpatient neurology clinic were extracted (N=355), including the Hopkins Verbal Learning Test – Revised, Boston Naming Test, WAIS‐IV Similarities, D‐KEFS Verbal Fluency Letter Fluency (FAS) and Category Fluency (CF) tests, and Wide Range Achievement Test‐Reading (WRAT). Diagnostic subgroups of MCI and CN were created using actuarial diagnostic criteria. SC was calculated as the sum of novel consecutive recalls belonging to the same category, without repeats or semantically‐related intrusions. A chi‐square test was conducted to assess differences between demographic factors. ANCOVA was used to compare performance of SC and selected language measures between the MCI and CN groups using age and WRAT‐Reading as covariates; SC and language measure raw scores were treated as dependent variables and diagnostic grouping as the independent variable.

Result

Differences in age(X2
=36.39,p<0.01), education(X2
=21.44,p<0.05), and WRAT‐Reading SS(X2
=45.43,p<0.01) were found. ANOVA found significant differences between the groups’ SC scores, as well as performance on language measures (p<0.05). The CN group showed a trend of being stronger than the MCI group across all measures, including SC. Generally, language measures were significantly positively correlated with SC scores for both groups (p<0.05), including BNT and CF, and FAS for the CN group.

Conclusion

Overall, findings support our hypothesis that both SC and language scores vary as a function of clinical diagnosis with the CN group having stronger abilities than those with MCI. As such, SC scores derived from verbal learning tests may be able to contribute to knowledge of one’s language skills. Further research should aim to help establish this relationship. SC scores could assist in screening for MCI or cognitive deficiencies resulting from AD.
Phase 1b study of XPro1595 in Alzheimer's patients with biomarkers of inflammation
Authors: Barnum Christopher , Tesi Raymond , Malberg Jessica
Published: December 2021

Background

XPro1595 is currently being tested in a proof of biology Phase 1b study in Alzheimer’s patients with biomarkers of inflammation.

Method

Inflammatory and neurodegeneration protein and imaging biomarkers were measured 3 months after weekly treatment with multiple doses of XPro1595.

Result

XPro1595 dose‐dependently reduced All CSF inflammatory protein levels and neuroimaging inflammatory markers (free water white matter). Moreover, we observed a strong correlation between MRI inflammation (Free water white matter) and CSF inflammation was observed (R2 =0.761). In addition to the reduction in neuroinflammation, XPro1595 reduced biomarkers of neural injury and synaptic dysfunction as assessed by CSF protein and neuroimaging. Additional data on novel MRI metrics to assess neuroinflammation and white/gray matter quality will be presented.

Conclusion

XPro1595 achieved its primary goal of reduced markers of neuroinflammation, neural injury, synaptic dysfunction across multiple measures and assays. Data support advancement to Phase 2.
Cell‐type specific variations of within pathway interaction in AD using covariance regression
Authors: Lu Xiaoyu , Zhang Chi , Zhao Yi , Cao Sha
Published: December 2021

Background

Alzheimer’s disease (AD) and related dementias are among the greatest public health challenges in the United States. A deeper understanding of the disease pathology on a molecular and cellular level is critical to devise treatments to slow down the disease progression and better understand the mechanisms behind AD. Recent advancement in single‐cell technology provides new avenues for molecular profiling of AD at the single‐cell resolution, which improves the omics studies by making greater precision and granularity possible.

Method

We here present a statistical framework for extracting the variability of gene‐gene interaction in a disease‐, sex‐ and cell type‐ specific manner, to identify AD‐associated markers and pathways and to articulate disease mechanisms on cellular and molecular levels. We applied our method to the Religious Orders Study and Memory and Aging Project (ROS/MAP) single nucleus dataset, with single cells of five cell types including astrocyte, microglial, neuron, oligodendrocyte, and oligodendrocyte progenitor cell (OPC).

Result

Existing methods for AD gene and biomarker detection mainly focus on comparative and univariate analysis, with the lack of adequate statistical power in detecting abnormal gene‐gene interaction structure in the same pathway. Our covariance regression based analytical pipeline represents a statistically solid tool to investigate the abnormalities in genetic interaction on pathway‐level using single‐cell RNA sequencing data, and to make inference on key covariates. Importantly, such a pathway‐level analysis is robust to the severe drop out events in single cell RNA‐Seq data. Compared with enrichment‐based pathway analysis, our method has much higher statistical power in detecting significant differentially co‐expressed pathways in comparing AD vs healthy control cells in a sex and cell type specific manner.

Conclusion

Majority of the pathways tend to have lower co‐expression strength among its genes in AD cells than healthy cells for female subjects in astrocyte, neuron and microglial. While not much pathways are differentially co‐expressed in male AD vs healthy subjects, neuron and astrocyte are the two major cell types with the largest number of alternatively co‐expressed pathways in female subjects, with 3972 and 4218 pathways. These altered pathways belong to known pathway categories, such as synapse, neuronal development, lipid metabolism, calcium transport, etc.
Changes in alkaline phosphate and calcium levels during early mild cognitive impairment, indicating a role for bone in the progression of Alzheimer’s disease
Authors: Suryadevara Vidyani , Monte Willis S.
Published: December 2021

Background

Over 50 million people worldwide have dementia, one of its most common form being Alzheimer’s disease. It’s one of the top ten leading causes of death attributing to the extraneuronal effects in the bone, skeletal muscle, liver, kidney, and heart. Falls and fractures are one of the predominant causes of mortality in AD patients, indicating the cross talk between the bone and brain during AD. Women with lower femoral BMD were two times more risk‐prone to develop AD than women with higher BMD and this was found to be independent of other risk factors of AD. In this study, we are investigating the changes in the bone markers during early stages of the AD.

Method

The Alzheimer’s Disease Neuroimaging Initiative(ADNI) is a multisite, longitudinal study of normal cognitive aging, early Mild cognitive impairment(EMCI), late MCI and AD individuals, wherein specific recruitment methods are used to recruit participants. We analyzed data from the ADNI‐1, ADNIGO and ADNI‐1 focusing on the relationships between the severity of dementia (mini‐mental state scores), the clinical musculoskeletal findings, and the laboratory data from these participants, which included fluid biomarkers. A total of 1765 patients were included, 57% male and 43% female.

Result

We observed in females that there was robust decrease in the alkaline phosphate levels in EMCI group compared to normal cognitive group, whereas a significant increase in alkaline phosphate levels between EMCI and AD groups. The higher alkaline phosphate levels at EMCI indicates the activity of bone cells and thus bone remodeling. In males, there was a significant reduction in the alkaline phosphate levels during EMCI when compared to cognitive normal groups; however, alkaline phosphate levels were significantly increased both in LMCI and AD groups when compared to EMCI group. Also, in males, there was significant decrease in the calcium levels from cognitive normal group to EMCI group, which was further significantly reduced in the AD groups. However, there was no change in calcium across the groups in the females.

Conclusion

Detecting changes in the bone biomarkers early on, will help in better management of AD, thereby improving the quality of life in these patients.
Feasibility and evaluation of the Dementia Engagement Modelling Program (DEMP): a novel model of aged care during COVID‐19
Authors: Atee Mustafa , Morris Thomas , Cunningham Colm
Published: December 2021

Background

The COVID‐19 pandemic has a significant impact on the quality of life of aged care residents living with dementia (RLWD). Lockdown measures necessary to protect RLWD and caring staff from COVID‐19 have resulted in increased social isolation, loneliness, and behaviors and psychological symptoms of dementia (BPSD). In response, the Australian Government funded a pilot program, the Dementia Engagement Modelling Program (DEMP) as part of the Aged Care COVID‐19 Grief and Trauma support package for RLWD, their families and aged care staff. Operated by the Dementia Centre of HammondCare, the DEMP provides first‐line multimodal external support for RLWD at a greater risk of developing BPSD due to COVID‐19 restrictions. This study aims to describe the DEMP and evaluate its feasibility and outcomes for Australian RLWD.

Methods

A team of 10 trained DEMP consultants was involved in delivering a consultancy service that modelled best practice and person‐centred activities of engagement to support staff in providing residents with meaningful purpose, comfort, and reassurance. Consultants also provided coaching and development opportunities for staff to enhance their knowledge regarding communication and engagement. Outcome measures included the regular administration of the Engagement in Preferred ActivitieS Scale (EPASS; ≥4‐9 moderate‐to‐high engagement). A phone evaluation survey for supported residential aged care homes (RACHs) was conducted to determine the feasibility of DEMP.

Results

A total of 60 residents (86.0 ± 7.8 y; 68% female) across 10 RACHs from three Australian states (VIC, NSW, QLD) was supported by DEMP between May and July 2021. More than half of the residents had Alzheimer’s disease (n = 24, 40%) and vascular dementia (n = 7, 12%). Completed EPASS assessments (n = 389) demonstrated that the vast majority (64%‐72%) of residents scored moderate‐to‐high engagement. All supported RACHs highly recommended the DEMP to other colleagues and rated the program highly for implementation feasibility including the recommended engagement activities/brokered items.

Conclusions

The DEMP is a novel, feasible and effective dementia‐specific engagement modelling program for Australian RLWD in the era of COVID‐19 pandemic.
Investigating isoform‐specific functions of Tau under healthy and pathological conditions using Tau‐deficient hiPSC‐derived cortical neurons
Authors: Bachmann Sarah , Bell Michael , Kabbani Mhd. Aghyad Al , Klimek Jennifer , Zempel Hans
Published: December 2021

Background

One hallmark of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is the formation of neurofibrillary tangles by hyperphosphorylated Tau in the brain, resulting in neuronal death and cognitive decline. In the adult human brain, six Tau isoforms are expressed, originating from alternative splicing of exons 2, 3, and 10 of the MAPT gene. The isoforms differ in the number of N‐terminal inserts (0, 1, or 2N) and the C‐terminal repeat number (3 or 4R). Mutations affecting splicing of the MAPT gene can alter the Tau isoform ratio and ultimately cause neurodegeneration. Recent results from murine neurons highlight that the six human‐specific isoforms are differentially localized within neurons and influence microtubule dynamics in an isoform‐specific manner.

Method

To further investigate the Tau isoforms in a human neuronal model, we generated three Tau KO iPSC cell lines derived from Ngn2‐WTC11 cells using CRISPR/Cas9.

Result

Basic characterization of the Tau KO cell lines showed no difference in the morphology or pluripotency of iPSCs, the capability of neuronal differentiation or neuronal morphology compared to WT iPSCs and induced neurons. Initial results from re‐expressed TAU isoforms in Tau KO human neurons support the differential localization of the isoforms observed previously. Further experiments will investigate the isoform‐specific role of Tau regarding microtubule dynamics, axonal branching, and synapse formation under basal and pathological conditions.

Conclusion

Expected results will provide a major understanding of basic biological functions of Tau and help to identify potential therapeutic targets for the treatment of AD and related neurodegenerative diseases.
Associations between iron deposition in the brain and grey matter volumes in cognitively unimpaired adults
Authors: Stankeviciute Laura , Falcon Carles , Operto Grégory , Rojas Santiago , Grau‐Rivera Oriol , Garcia Marina , Minguillón Carolina , Fauria Karine , Molinuevo Jose , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Cacciaglia Raffaele , Gispert Juan Domingo
Published: December 2021

Background

Iron dyshomeostasis is involved in the pathophysiology of Alzheimer’s disease (AD). Magnetic resonance imaging (MRI) is sensitive to iron in the brain as its concentration decreases the intensity of T2‐weighted images. However, there is little evidence on how iron affects structural changes in the brain of cognitively unimpaired individuals at the inception of the Alzheimer’s continuum. This research aimed to investigate the relationship between T2 MR hypointensities, as a proxy for iron content, and grey matter volume (GMv) in middle‐aged cognitively unimpaired (CU) individuals.

Methods

This cross‐sectional study included 302 CU adults from the ALFA+ cohort who underwent MRI, cerebrospinal fluid sampling (CSF) and neuropsychological assessment (Table 1). T2‐weighted images were used to calculate mean hypointensity values in a set of 18 subcortical nuclei (http://nist.mni.mcgill.ca/?p=1209). T1w scans were entered into voxel‐based morphometry (VBM) analysis to evaluate the relationship between regional T2 intensities and GM volumes. Due to the strong correlations between the T2 intensity of the subcortical regions, we performed principal component analysis (PCA) to reduce the dimensionality (Table 2). We created a general linear model where GMv was the dependent variable, the first principal component (PC1) was the independent variable and age, sex, APOE‐ε4 status, education level and total intracranial volume (TIV) were the covariates. In an additional model, CSF levels of amyloid‐beta (Aβ) ratio (CSF Aβ42/40) and phosphorylated tau (p‐tau) were entered as covariates. Statistical significance was set at p<0.001 uncorrected for multiple comparisons with a cluster‐level threshold of 100.

Results

PC1 explained 47.64% of the variance, and it was significantly and negatively associated with grey matter volumes in a highly symmetrical pattern which included the parahippocampal cortex (Table 3. Figure 1). These results remained largely unchanged when entering CSF AD biomarkers in the model.

Conclusions

Our results indicate that, in cognitively unimpaired individuals, a higher content of iron deposition, as expressed by lower T2‐weighted MR intensities in subcortical regions, are associated with higher grey matter volumes in parahippocampus, independently of CSF AD biomarkers. These preliminary results may suggest that iron accumulation might be associated with neuroinflammatory mechanisms and render the brain more vulnerable to early AD pathology.
Assessing neuroinflammation and inflammasome activity in mouse models of Down syndrome
Authors: Farrell Clíona , Mumford Paige , Salih Dervis , Toomey Christina , Fisher Elizabeth , Wiseman Frances K
Published: December 2021

Background

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer’s disease. Neuroinflammation is altered in the post‐mortem brain of people with DS, with altered microglial morphology and upregulated proinflammatory cytokines, including IL‐1β. IL‐1β is produced by inflammasome activity activating caspase‐1 which cleaves and releases active IL‐1β. We hypothesize that IL‐1β levels are raised in the DS brain via upregulation of inflammasome activity, which persists when people with DS develop AD.

Method

Levels of 10 cytokines IL‐1β, TNFα, IFNγ, IL‐6, IL‐2, IL‐4, IL‐5, IL‐10, IL‐12p70 and KC/GRO were measured (MSD) in the 3‐month hippocampus of a panel of segmental duplication models of DS, Dp1Tyb, Dp2Tyb, Dp3Tyb, Dp9Tyb and Dp17Yey. These models have a duplication on one chromosome of a number of orthologues for Hsa21 genes.

Result

Raised IL‐1β abundance was identified in the hippocampus of the Dp1Tyb mouse, which has an additional copy of 148 mouse orthologues for Hsa21 genes. No difference in IL‐1β or any other cytokines measured were identified in the Dp3Tyb (39 genes duplicated), Dp9Tyb models (76 genes duplicated), Dp2Tyb (33 genes duplicated) or Dp17Yey (19 genes duplicated).

Conclusion

Raised IL‐1β in the Dp1Tyb brain is a multigenic phenotype, caused by having 3 copies of more than one gene/region of Hsa21. Next, we will prepare organotypic hippocampal slice cultures from the Dp1Tyb model and stimulate these with LPS, nigericin and amyloid‐β to understand how having three copies of Hsa21 orthologues modulates the neuroinflammatory and inflammasome response.
Brain regional volume analysis to differentiate Alzheimer’s disease (AD) and vascular dementia (VD) from healthy control (HC): Machine learning approach
Authors: Cheung Eva YW , Chiu Patrick Ka‐Chun , Kwan Joseph SK , Shea Yat Fung , Mak Henry
Published: December 2021

Background

In previous decades, structural MRI has been widely adopted in the diagnosis of AD, MCI and other forms of dementia[1]. Through quantitative measurement of volume of regions‐of‐interest (ROI), it is suggested that hippocampal volume reduction and the rate of reduction can be use in dementia diagnosis and predict the disease progression[2]. However, there is no such application to VD.

Method

81 participants (25 HC, 16AD, 28MCI, 12VD) were recruited to undergo structural MRI scanning. T1W Images MRI images were acquired using a Philips Achieva 3T. Volume of brain structures were assessed using Freesurfer (v. 7.1). MANCOVA test was adopted to determine the significant difference between diseased groups and HC, with GM volume, age and gender as covariates. R decision tree was adopted to identify major parameter and its threshold to classified AD, MCI, VD from HC.

Results

In brain structural volume analysis, AD demonstrated significant atrophy in thalamus, hippocampus, amygdala, accumbens areas when compared to HC. VD showed similar results as AD, with ventral diencephalon as an addition region of atrophy when compared to HC group. For MCI, less severe atrophy was observed when compare to AD and VD toward HC. Furthermore, VD showed significantly enlarged in lateral ventricle, third ventricle, fourth ventricle, CSF, choroid plexus and white matter hypointenisty (WMH). While AD showed significantly enlarged lateral ventricle, inferior lateral ventricle and CSF when compared to HC. There is no statistically significant difference for MCI. In the decision tree model, WMH volume > 5826cm3 was used to classify VD from the rest. The left hippocampus volume < 3287cm3 was used to classify AD from HC. However, the MCI group could not be accurately identified. The accuracy of the model to predict AD, VD, HC from others were 87.5%, 99% and 96% respectively.

Conclusion

The findings demonstrated that AD and VD had significant reduction in brain regional volume when compared to HC, but not MCI. The WMH and left hippocampus volume were included in the decision tree model as predictive parameters to classify AD and VD from HC. Though the sample size is small, further validation may be required.
HCN channelopathy couples disease‐associated tau to synaptic dysfunction
Authors: Goniotaki Despoina , Tamagnini Francesco , Biasetti Luca , Rumpf Svenja‐Lotta , Troakes Claire , Pollack Saskia J , Ukwesa Shalom , Sun Haoyue , Serpell Louise , Noble Wendy , Staras Kevin , Hanger Diane P
Published: December 2021

Background

Deficits in synaptic function and neurite connectivity are early correlates of tauopathies. Altered tau processing and mis‐localization coincide with reductions in synapse density and synaptic function, suggesting a causal role for tau in disease pathogenesis. In parallel, altered activity of hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, involved in synaptic integration, is implicated in disease progression in animal models of tauopathy. However, the mechanisms underlying these pathological events are not fully understood.

Methods

We performed histological and biochemical analyses of hippocampal tissues from Alzheimer’s disease (AD), age‐matched controls and Tau35 mice, in which a human tauopathy‐associated tau fragment is minimally expressed. Image analysis and quantification were performed on antibody‐labelled human and mouse hippocampal sections (Visiopharm). Brain tissue from Tau35 and wild‐type (WT) mice was also examined on western blots, by Golgi‐Cox staining and transmission electron microscopy. Primary hippocampal neurons from Tau35 and WT mice were transfected with a plasmid expressing enhanced green fluorescent protein (eGFP) and imaged up to 14 days in vitro. Three‐dimensional digital reconstruction of dendrites and spines enabled morphological analysis of eGFP‐expressing neurons. In parallel, patch‐clamp recordings were performed to assess functional changes and HCN channel activity in Tau35 neurons.

Results

Here we show that HCN channels are functionally linked to tau abnormalities. Alterations in HCN channel expression are detected in both Tau35 mouse and human post‐mortem AD brain. Tau35 neurons exhibit altered synaptic cytoarchitecture, including progressive reductions in dendritic branching, pre‐synaptic vesicles, spine density and synaptic markers, along with the development of tau pathology. These changes are accompanied by functional abnormalities in network activity, including increased HCN‐dependent sag voltage, reduced frequency and slower kinetics of spontaneous excitatory postsynaptic currents.

Conclusions

Our findings are consistent with the hypothesis that disease‐associated tau species impact on HCN channels to drive network‐wide structural and functional synaptic deficits, with significant therapeutic relevance for tauopathies.
Identification of cis‐regulatory elements associated with MAPT expression in human induced pluripotent stem cell derived neural cells
Authors: Rogers Brianne B. , Lauzon Shelby N. , Davis M. Natalie , Rizzardi Lindsay F. , Cooper Sara J. , Myers Richard M. , Cochran J. Nicholas
Published: December 2021

Background

Tau is encoded by MAPT and abnormal aggregates of tau are a hallmark of many neurodegenerative diseases. MAPT is highly expressed in neurons but much more lowly expressed in other cell types, including neural precursor cells (NPCs), suggesting that its expression may be controlled by neuron‐specific transcription factors and cis‐regulatory elements. Tau reduction, even of endogenous tau, is a current therapeutic strategy in both model systems and humans; therefore, understanding MAPT regulation may point to new strategies to achieve tau reduction. Additionally, genome sequencing studies continue to identify disease‐associated variants in non‐coding regions of the genome. These variants are likely located in regulatory regions and affect the expression of target genes whose function contributes to neurodegeneration. Therefore, an additional benefit of this study is that high confidence regulatory regions for MAPT may provide a way to identify important non‐coding variants associated with disease.

Methods

Three‐dimensional chromatin conformation capture (Capture‐C), single‐cell multiomics (RNAseq + ATACseq), and chromatin marks including H3K27ac, H3K4me1, and DNase hypersensitivity were used to identify candidate enhancers of MAPT in human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures (all lines were H1/H1). Approaches included nomination of elements with signals specific to neurons or neuronal subtypes. The nominated regions were then assessed using luciferase assays to test sufficiency for regulatory activity as well as CRISPR‐dCas9‐KRAB to assess the effect of nominated elements on MAPT expression.

Results

We identified both proximal and distal regulatory elements for MAPT with function confirmed by up to four orthogonal approaches (chromatin capture, single cell multiomics, a reporter assay, and element inhibition using dCas9‐KRAB). Several of these elements were specific to neurons. One particularly important region was centromeric to MAPT beyond the H2 inversion breakpoint.

Conclusions

Overall, these results indicate that MAPT regulation is likely controlled by neuron‐specific cis‐regulatory elements, including both proximal and distal elements. Next steps include study of the effect of trans‐regulatory elements (i.e., transcription factors) that may control recruitment of these cis‐regulatory elements for expression of MAPT and assessment of the effects of the disease‐associated genetic variation on cis‐regulatory element function and expression of MAPT.
DNA methylation "GrimAge" acceleration mediates sex differences in verbal learning and memory: Findings from the health and retirement study
Authors: O'Shea Deirdre , Tremont Geoffrey , Drake Jonathan D
Published: December 2021

Background

Evidence from cognitive science support sex differences in verbal memory, that tend to favor women. Epigenetic research has also shown slower rates of biological aging in women compared to men. The aim of the current study examined whether sex differences in biological aging mediate sex differences in verbal learning/memory in older adults.

Method

Data was obtained from the Harmonized Cognitive Assessment Protocol and the 2016 Venous Blood Study, sub‐studies of the 2016 wave of the Health and Retirement Study (HRS). Thirteen epigenetic “clocks” were constructed from these data and made publicly available by HRS staff. DNA methylation “GrimAge” clock was used as the indicator of biological aging, given evidence relating it to cognition in prior studies. A sample of 1,505 participants (mean age =75, SD= 6.8, male= 42%, White= 81%, Black=13%, Hispanic= 6%), with full data were included in the analyses. The residual from age adjusted GrimAge (AgeAccelGrim) was used as the measure of age acceleration. Cognitive composites were constructed from the learning and delayed recall trials of the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Task and the Wechsler Memory Scale‐IV, Logical Memory subtest and used as the outcome measures. Mediation analysis tested whether AgeAccelGrim mediated (5,000 resamples) the association between sex and learning/recall composites. Chronological age, years of education, smoking status, white blood cell count, and race/ethnicity were included as covariates.

Result

Mediation analyses revealed a total direct effect of sex on learning (β=.32, 95% CI [.26, .37]), with a significant indirect effect of AgeAccelGrim, that explained 12.5% of the total effect of sex (CI [.02, .06]). A similar pattern was revealed for delayed recall (total effect of sex β= .26, 95% CI [.20, .32]), with AgeAccelGrim accounting for 11.5% of the total effect (95% CI [.01, .04]).

Conclusion

Women performed better on verbal learning/recall measures compared to men, and this association was partially explained by slower biological aging in women. These findings demonstrate the potential for epigenetic markers of aging to increase understanding of sex differences in verbal learning and memory in older adults.
White matter lesion burden correlates with the free water distribution surrounding the lateral ventricle
Authors: Zhou Liangdong , Nguyen Thanh D , Li Yi
Published: December 2021

Background

The clearance function is considered playing significant role in the neurodegeneration and neuroinflammation diseases, such as Alzheimer's disease (AD), Parkinson disease (PD) and multiple sclerosis (MS), etc. The enlarged perivascular space (EPVS) is believed to be a main pathway for the clearance of metabolic wastes. The free water in the PVS helps to clear the waste. The dysfunction of clearance function may accelerate the progression of diseases. We propose to use a T2 relaxometry based free water mapping to investigate the free water distribution in MS subjects. We call the free water mapping as cerebrospinal fluid water fraction (CSFF).

Method

Multi‐echo T2 image was acquired with 7 echoes (TE = 0, 7.5, 17.5, 67.5, 147.5, 307.5, 1000 ms). Then the T2 data was fitted to three‐compartment water model (myelin water, intro‐extracellular water, and free water) by the T2 relaxometry of different tissue type. The CSFF in the white matter region is extracted from the FreeSurfer processed white matter mask. For each subject, the extracted WM CSFF was organized into a column vector and then fed in the k‐means algorithm. The number of categories is set to k = 8, which is sufficient to categorize the WM CSFF pattern into detailed tissue structure. We are interested in the distribution pattern of smallest CSFF values in WM, i.e., the category that has smallest mean CSFF.

We then check the correspondence between the smallest CSFF pattern with the anatomic structure. If the distribution of the smallest CSFF is continuous region near the posterior of ventricle CSF, then we call the subject CSFF‐negative (Fig. 1a), otherwise it’s CSF‐positive (Fig. 1b).

Result

The distribution of the smallest WM CSFF in the MS cohort is significantly related to the severity of the disease. CSFF‐positive subjects have light MS lesion load, while the CSFF‐negative subjects have heavy MS lesion load (Fig.2).

Conclusion

The results show that the T2 relaxometry based free water mapping could be treated as a biomarker of MS load. This finding might be helpful for the understanding of development of MS disease.
Mitochondrial changes caused by LDL in hippocampal neurons
Authors: Farias Hemelin Resende , Martins Leo , Beber Lílian Corrêa Costa , Rodrigues Matheus Scarpatto , Guma Fátima , de Oliveira Jade
Published: December 2021

Background

Familial hypercholesterolemia (FH) is characterized by high plasma accumulation of low‐density lipoproteins (LDL) due to mutations in the LDL receptor gene (Hobbs et al., Hum. Mutat., 1: 445‐466, 1992). Furthermore, FH patients present a high incidence of cognitive impairments (Zambón et al., Am J ed, 123:267‐274, 2010; Ariza et al., Eur J Intern Med., 34:e29‐e31, 2016). Experimental studies also demonstrated that FH leads to an increase in blood‐brain‐barrier permeability (De Oliveira et al., J Alzheimers Dis, 78:97‐115, 2020), which could allow the LDL to pass from the peripheral system to the central nervous system. Importantly, the cellular mechanisms responsible for neurotoxicity induced by LDL are unclear. Herein, we aimed to investigate whether LDL causes mitochondrial alterations in neurons.

Method

We exposed HT‐22 cells (Mouse Hippocampal Neuronal Cell) to human isolated LDL (50 and 300 ug/mL) for 24 hours. Furthermore, mass and potential mitochondrial were evaluated by Mitotracker green (MTG) and red (MTR), respectively, and the reactive species generation was evaluated by DCF.

Result

Notably, when HT‐22 cells were incubated with LDL (50 ug/mL), MTR fluorescence was decreased compared with control cells. The ratio between MTG and MTR fluorescence showed increased mitochondria mass compared to their activity, suggesting an increase of swollen and non‐functional mitochondria. We observed in HT‐22 cells exposed to LDL (300 ug/mL) that both MTG, MTR, and ratio MTR/MTG were decreased, suggesting mitochondrial dysfunction. It is known that mitochondrial dysfunction leads to the excessive production of reactive species, and this may cause damage to essential cell components. In this regard, next, we evaluated the reactive species formation using DCF. The reactive species formation was significantly increased in cells exposed to both concentrations of LDL (50 and 300 ug/mL) in two times of exposure (1 and 24 hours) compared with the control cells.

Conclusion

These findings indicate that LDL causes mitochondrial dysfunction, which appears to be a relevant event in hypercholesterolemia‐induced cerebral dysfunction.
Association of life‐course traumatic brain injury with the risk of dementia: a nationwide twin study
Authors: Zhang Lulu , Yang Wenzhe , Li Xuerui , Dove Abigail , Qi Xiuying , Xu Weili
Published: December 2021

Background

Traumatic brain injury (TBI) has been related to dementia, but the impact of life‐course TBI on dementia remains unclear. We aimed to examine the association between lifespan TBI and dementia, and to explore whether genetic and early‐life environmental factors contribute to this association.

Method

Within the Swedish Twin Registry,35,312 dementia‐free twins (mean age 62.78 years) were followed for up to 18 years.Life‐course TBI was assessed based on information from the SwedishNational Patient Registry (NPR) and participants were divided into five groups according to age at TBI occurrence (≤39, 40‐49, 50‐59, 60‐69, and ≥70 years). Dementia and cardiovascular disease (CVD, including heart disease and stroke) diagnoses were ascertained based on medical records in the NPR and the SwedishCause of Death Register. Data were analyzed using generalized estimating equation (GEE) and conditional logistic regression.

Result

In multi‐adjustedGEE model, the odds ratios (ORs, 95% confidence intervals [CIs]) of dementia were 1.29 (1.05–1.60) for TBI at any age, 1.01 (0.54–1.89)for TBI at ≤39 years, 1.11 (0.65–1.88) for TBI at 40‐49 years, 1.66 (1.13–2.45) for TBI at 50‐59 years, 1.84 (1.24–2.74) for TBI at 60‐69 years, and 0.86 (0.55–1.34) for TBI at ≥70 years, respectively. In the conditional logistic regression, the OR (95% CI) of dementia for TBI at any age was 1.59 (1.04–2.45). The difference in ORs from the two models was not statistically significant (P =0.40). In joint exposure analysis, the multi‐adjusted OR (95% CI) of dementia was 1.46 (1.04–2.04) for participants with TBI but no CVD and 2.64 (1.63–4.29) for those with both TBI and CVD (reference: absence of both TBI and CVD). There was significant additive (attributable proportion0.48, 95% CI 0.17–0.78) and multiplicative interactions (OR1.98, 95% CI 1.09–3.60) betweenTBI at 50‐69 years and CVD on dementia.

Conclusion

TBI, especially occurring at age 50‐69 years, is associated with increased risk of dementia, and the risk becomes greater in people with CVD.Genetic and early‐life environmental factors may not account for the TBI‐dementia association.
Food Dietary Choices Predict Brain Volume and Neurovascular Lesion Load 10 Years Later
Authors: Klinedinst Brandon S , Kharate Mihir , Willette Auriel A
Published: December 2021

Background

The population age structure in the U.S. is advancing, as to is the prevalence of Alzheimer’s disease and related dementias despite life expectancy stagnating in recent years. Decline in neural parameters like brain volume and lesion density are expected with advanced age, but rate and severity of loss and function vary widely. Here, we examined how 149 variables representing the total diet could predict or explain variation in total brain volume and lesion density.

Methods

Among 10,938 adults aged 45 to 80 from the UK Biobank, food choices for 149 items were measured using the 24‐hour Dietary Recall questionnaire and collected up to 5 times over the course of a year. Our outcomes of interest were total brain volume and white matter hyperintensity load, which were derived from a structural Magnetic Resonance Imaging scan conducted 10 years after baseline. Structural equation models of correlated outcomes, using a Backwards selection method (p<.05), were used to identify the most significant food choice predictors.

Results

Over a period of 10 years, more total brain volume was related to consuming more calories in general, water, various coffee preparations, and teas, hard cheeses, whole grain products, pomme fruits like apples and pears, and to some degree various desserts. Conversely, less total brain volume was seen with consuming more red and rose wine, certain vegetables and mushrooms, potatoes, crackers, and beef. For white matter hyperintensities, less lesion load was seen with consuming more mangoes, apiaceae vegetables like carrots and celery, allium vegetables like onions and leeks, spinach, sweet potatoes, and cow’s milk of any fat percentage. Conversely, greater lesion load was seen with consuming refined chocolates, processed meats and shellfish, fried potatoes, beets, eggs, mushrooms, and vitamin B6 or calcium supplements.

Conclusion

Maintaining brain health was generally related to consuming more water, fruits and vegetables, complex vs. simple carbohydrates, certain sweets, and dairy products while avoiding processed meats, eggs, and mushrooms. Future work will elucidate how whole food choices are related to functional brain imaging outcomes.
Effect of COVID‐19 on BPSD severity and caregiver distress: Trend data from national dementia‐specific behavior support programs in Australia
Authors: Whiting Daniel , Atee Mustafa , Morris Thomas , Cunningham Colm
Published: December 2021

Background

Globally, Coronavirus disease 2019 (COVID‐19) caused a significant disruption to the physical and mental well‐being of all individuals, including those living with dementia. Social restrictions and lockdown measures due to COVID‐19 have worsened the feelings of loneliness and behaviours and psychological symptoms of dementia (BPSD). National BPSD support programs in Australia are offered by Dementia Support Australia (DSA) through the Dementia Behavior Management Advisory Service (DBMAS) and the Severe Behavior Response Teams (SBRT). This study aims to investigate the impact of COVID‐19 on BPSD severity and related caregiver distress among referrals to DSA programs.

Methods

A retrospective comparative analysis was conducted on the intake data of referrals to DSA between two periods: Pre‐COVID‐19 Period (January 2018‐Decmeber 2019) and COVID‐19 Period (January 2020‐July 2021). Referrals were compared on demographic characteristics (e.g., age), and BPSD severity (i.e., neuropsychiatric symptoms such as agitation) and caregiver distress as measured by the Neuropsychiatric Inventory (NPI). NPI scores were compared on a month‐to‐month basis between the specified periods.

Results

Across the two periods, there were a total of 23,180 referrals eligible for the analysis. While no differences were noted in age, sex, or dementia subtype, there were elevated levels of NPI severity and caregiver distress scores during COVID‐19 Period compared to the Pre‐COVID‐19 Period. The month‐to‐month trends of these differences (Figure 1, Figure 2) reflect the timing of outbreaks across Australia. Specifically, there were no significant differences at the start of 2020 prior to the declaration of the pandemic, with an initial rise in NPI severity and distress through April after initial measures were implemented nationally in March 2020. These levels of severity and distress continued to rise through the remainder of 2020, alongside outbreaks in specific regions within Australia, such as Victoria (June‐October), and New South Wales (December/January). NPI severity and caregiver distress then began to return to Pre‐COVID levels from February‐May before elevating again with the outbreak of the Delta variant in Australia.

Conclusions

COVID‐19 has a significant impact on the severity levels of BPSD and related caregiver distress.
Pain intensity characteristics of referrals to national dementia behavior support programs in Australia
Authors: Atee Mustafa , Lloyd Rebecca Victoria , Morris Thomas , Cunningham Colm
Published: December 2021

Background

Recognizing pain in people with advanced dementia who cannot effectively communicate is difficult. As such, pain is underdetected and undermanaged in this group and can lead to behaviors and psychological symptoms of dementia, impaired quality of life, and significant caregiver distress. Further, little is known about the clinical experience of pain intensity in dementia. This study aims to describe the pain intensity characteristics of referrals to Dementia Support Australia, a national dementia‐specific behavior support program in Australia.

Methods

Pain in a sample of referrals (period: January‐November 2020) was evaluated during various activities (rest vs movement) using PainChek®, a medical device application (app)(Figure 1) linked to a web admin portal (WAP)(Figure 2) for non‐verbal adults including those living with dementia. PainChek® consists of six domains (Face, Voice, Movement, Behavior, Activity, and Body) that have collectively a total of 42 items. The PainChek® app uses artificial intelligence to detect pain‐indicative facial action units (e.g., brow lowering) in combination with a digital checklist of non‐facial indicators to produce a pain intensity score as follows: 0‐6 (no pain), 7‐11 (mild pain), 12‐15 (moderate pain), ≥16 (severe pain). The difference in pain scores according to the activity status (rest vs movement) was computed using Cohen’s d values (e.g., 0.01‐ <0.50: very small‐to‐small).

Results

A sample of 75 referrals (84.2 ± 8.7 y, 50.6% male) from residential aged care homes were included in this study. A total of 79 pain assessments (rest n = 31, post‐movement n = 44, not assigned n = 4) were completed for the sample. Most referrals had a diagnosis of Alzheimer’s disease (n = 40, 50.6%), vascular dementia (n = 7, 8.9%) and mixed dementia (n = 8, 10.3%). Over one‐third (n = 29, 36.7%) of the sample had mild pain whilst one‐third (n = 26, 33%) had moderate‐severe pain. Across the sample, four out of six domain scores (Face, Voice, Movement, Activity) were higher after movement compared to rest e.g., Voice (d = 0.34) and Behavior (d = 0.38).

Conclusion

Higher pain intensities are prevalent in referrals with dementia, particularly after movement‐based activities, warranting the need for analgesic treatments.