bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive and physical functioning as predictors of everyday functioning
Authors: Chan Michelle L. , Eng Chloe W. , Farias Sarah Tomaszewski , Gilsanz Paola , Whitmer Rachel A.
Published: December 2020

Background

Alzheimer’s disease and associated cognitive impairments are major contributors to functional declines and difficulties with instrumental activities of daily living (IADL); however, it is postulated that functional decline is likely a product of multiple factors. Higher prevalence of cardiovascular conditions has been associated with greater vascular brain injury that can result in greater physical impairments (slower gait speed and reduced grip strength). Thus, physical functioning can also contribute to IADL disability. The current study examined how cognitive and physical functioning contribute to IADL functioning among a diverse ethnoracial sample.

Method

The Kaiser Healthy Aging and Diverse Life Experience (KHANDLE) cohort is comprised of Kaiser Permanente Northern California members who are age ≥65, without a diagnosis of cognitive impairment or dementia, and who participated in Multiphasic Health Checkups between 1964‐1977. At enrollment, participants completed a self‐report measure of IADLs, neuropsychological testing measuring memory and executive functioning, and physical functioning assessment (grip strength and walk speed). Analyses include 1,260 participants (401 Caucasian (32%), 339 African American (27%), 292 Asian (23%), and 228 Latino (18%)).

Result

The sample was comprised of 59.05% females and average baseline age was 75.5 ± 6.8 years. When examined individually, executive functioning (p=0.0466), grip strength (p=0.0005), and walking speed (p<.0001) were significant predictors of IADL functioning after controlling for demographics (age, education, gender, self‐rated health). Memory (p=0.4468) was not a significant predictor. When considering all 4 of these predictors in a combined model, walk speed remained the only significant predictor of IADL performance (p<.000) with slower walking speed being associated with poorer IADL performance. This relationship also differed by race (p=0.0011), with slower walk speed having the greatest negative impact in Asians.

Conclusion

There are limited studies examining how both cognitive and physical functioning predicts everyday functioning, particularly among a diverse ethnoracial sample. Our results indicate that among a cohort of older adults without a formal diagnosis of cognitive impairment or dementia, physical functioning, specifically walking speed, plays an important role in IADL difficulties. Importantly, when considering walking speed, executive functioning was no longer independently associated with IADL performance. Such findings have important implications in terms of screening older persons at risk for IADL disability.
To be alive vs. to live: Filipino elderly, nasogastric tubes, and the issue of artificial feeding in dementia
Authors: Cuadro Carla Krishan A , Herrera Janel Alexis O , Quiros Thomas L
Published: December 2020

Background

Nasogastric tubes (NGTs) are part of the nutritional intervention of patients who present with dysphagia. While NGTs guarantee the unimpeded delivery of nutrients into a body, complaints about its discomfort and aftercare are rife. The provision of continuous nutritional support takes precedence over the NGTs’ infection and aspiration risks. The issue of artificial feeding takes a more urgent turn among individuals with dementia, where frequent pull‐outs and physical resistance are common. Using percutaneous endoscopic gastrostomy (PEG) tubes relieve one of NGT discomfort. However, research had questioned PEG tubes’ ability to improve patients’ nutritional status. For those who do use it, maintenance issues, pull‐outs, and cultural beliefs on ‘holes’ on the abdomen prevail. While most societies equate food intake as supportive of life, risking the use of feeding tubes with those with neurodegenerative conditions remains debatable. There is a paucity of research that investigate the lived experiences of elderly who wore NGTs. Using illness narratives of cognitively‐intact, verbal Filipino elderly, this project interrogated NGT insertion processes, living with the tube, bodily integrity, fullness vs. satiety, and what is amiss such that to be alive is discrepant from to live.

Method

In‐depth episodic interviews were held among 10 older Filipinos aged 60+ years who were using or had used NGTs. These personal narratives were audio‐recorded, transcribed verbatim, and subjected to Burnard’s (1991) qualitative data analysis. The data was coded, categorized, underwent reordering and clustering to identify patterns or recurrent themes.

Result

Themes on NGT as an obstruction but necessary to ‘eat,’ sensation of an NGT in one’s body, and insertion/reinsertion issues dominated these narratives. Recurring themes included NGT feeding as redefining what is gutom (hunger) to the patient, how taste contributed to satiation, and the disparity between napuno (filled up) vs. nabusog (satiated).

Conclusion

Concepts about the NGT as necessary but dissociates fullness from satiation, as being filled up yet never ‘eating’ may be common among older Filipinos on the tube. Understanding these perspectives may guide healthcare professionals on how individuals with dementia understand life on the tube, lending further scholarly insight on the tube‐feeding quality of life of this population.
Boot camp translation of Alzheimer’s disease and the Engaging Communities of Hispanics for Aging Research (ECHAR) Network
Authors: Medina Luis D , Mullen Rebecca , Pressman Peter S , Woods Steven P
Published: December 2020

Background

Hispanics/Latinos (H/Ls), the largest ethnic minority in the U.S., are 50% likelier than non‐Hispanic whites to develop Alzheimer’s disease‐related dementias (ADRD). Despite comprising 18% of the U.S. population, H/Ls represent less than 1% of participants in NIH‐funded clinical trials and less than 8% of NIH AD Research Centers, greatly limiting understanding of underlying causes of disparities. However, health literacy gaps may impact research participation. We introduce here the Engaging Communities of Hispanics for Aging Research (ECHAR) Network. The overall objective of this collaborative, transdisciplinary network is to engage, educate, and motivate H/L community members for participation in ADRD research by addressing ADRD‐related communication through use of a novel community‐based participatory method – Boot Camp Translation (BCT).

Method

BCT is a manualized, robust six‐to‐eight‐month program designed to translate medical jargon into action‐based messages that are more effectively consumed by local communities. It fosters engagement between clinical experts and patients as well as community members with the overarching goal of helping to make medical evidence and guidelines locally relevant and accessible. We completed the first known BCT on ADRD with 15 community stakeholders in the Denver metropolitan area over 6 months.

Result

We had 0% attrition. Group members saw a significant (p<0.05) improvement in both subjective understanding and objective knowledge of ADRD. Four main themes were perceived as most relevant to their community: the importance of brain health, a call for self‐advocacy in medical settings and with providers, the need to learn more through research, and awareness of basic targets of cognitive changes that may be associated with ADRD. These themes were structured into a dissemination plan that included both printed and digital materials in addition to oral presentations shared with community organizations.

Conclusion

The ECHAR Network aims to expand these initial findings. By the end of this project, ECHAR will have: (1) established and trained community advisory committees on ADRD in at least three cities; (2) developed key, culturally‐informed, ADRD‐related materials as well as dissemination and evaluation strategies for H/L recruitment; and (3) developed sustainable research infrastructure to enhance outreach by supporting health disparities investigators and pilot grants.
Resistance to amyloid plaque pathology in the oldest‐old: Results from the 90+ study
Authors: Greenia Dana E , Yan Rui , Paganini‐Hill Annlia , Corrada Maria MM , Kawas Claudia H
Published: December 2020

Background

Although cerebral amyloid deposition is highly associated with age, many elderly individuals show apparent ‘resistance’ to amyloid pathology, with little or none at autopsy. Our objective was to examine factors associated with resistance to amyloid pathology in people 90 years and older.

Method

Participants were 287 deceased individuals who had agreed to brain autopsy as part of The 90+ Study, an ongoing investigation of aging and dementia. We examined demographic factors, ApoE genotype and past medical history reported by participants or, if cognitively impaired, their surrogates. Participants were evaluated every 6 months with neurological examination and neuropsychological testing. Cognitive status (normal, cognitively impaired no dementia [CIND], or dementia) was assigned postmortem during a multidisciplinary case‐conference without knowledge of pathological findings. Amyloid plaque pathology was scored according to CERAD (Consortium to Establish a Registry for Alzheimer’s disease staging) and dichotomized as absent (Stage 0) or present (sparse, moderate, frequent). We used logistic regression with absence of amyloid plaques (CERAD Stage 0) as the outcome of interest. Education was dichotomized as college degree. All analyses adjusted for sex and age at death. We repeated analyses stratifying by cognitive status.

Result

At death, participants’ median age was 97 years (range:90‐108), 72% were women, 50% were college graduates, and 75% had amyloid plaque pathology. Among all participants, the odds for absence of amyloid plaques (resistance) was 75% greater in college graduates compared with those with less education (OR=1,75) (Figure). When stratified by cognitive status, education was related to absence of amyloid plaques in individuals with normal cognition (OR=4.02), but not in those with cognitive impairment. ApoE genotype and medical history variables were not related to absence of amyloid plaques (Table).

Conclusion

In our study of oldest‐old participants, high education (college degree or more) was associated with absence of amyloid plaque pathology in those with normal cognition. Education may contribute to amyloid resistance in late life through a variety of potential biological mechanisms related to cerebral health and neural efficiency, or through associated lifestyle, activities and other factors.
Intracellular signal changes in the anterosuperior medial temporal lobe associated with early cognitive decline
Authors: Crawford Malcolm S. , Cabeen Ryan P. , Toga Arthur W. , Sepehrband Farshid ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Hippocampal degeneration and loss of white matter integrity both play a role in AD pathology. The anterosuperior part of the medial temporal lobe (MTL) acts as a white matter connecting point between the fontal and temporal lobes. Loss of white matter integrity in tracts passing through this region has been associated with AD [1,2]. Our aim was to use diffusion MRI to investigate changes in microstructure of white matter tracts passing through this region corresponding with cognitive impairment.

Method

120 subjects from the ADNI 3 cohort with multi‐shell diffusion MRI were analyzed [3]. Tractography through the anterosuperior MTL (asMTL) tracts were performed using the Quantitative Imaging Toolkit (QIT), using HCP‐derived atlas data [4,5]. Three tracts were selected for analysis including the uncinate and inferior fronto‐occipital fasciculi and the anterior commissure. . Subjects with global clinical dementia rating of 0 (N=71) and 1 (N=39) were grouped as cognitively normal (CN) and mild cognitive impairment (MCI), respectively. Intracellular signal fraction, isotropic signal fraction (free water) were obtained using NODDI [6] and mean diffusivity were obtained using DTI [7] estimated using QIT. The association between cognitive impairment and imaging features were assessed using logistic regression with age, sex, and brain volume as covariates.

Result

The intracellular signal fraction was reduced to a significant extent bilaterally in the uncinate and inferior fronto‐occipital fasciculi and anterior commissure among MCI compared to CN individuals (Figure 2.a). No significant difference in isotropic signal was observed (Figure 2.b). We also observed significantly increased mean diffusivity among MCI bilaterally in the uncinate fasciculi and the anterior commissure and trended towards significance bilaterally in the inferior fronto‐occipital fasciculi (Figure 2.c).

Conclusion

We found significant microstructural alteration in early cognitive decline in tracts passing through the asMTL region. Among these tracts, the left inferior fronto‐occipital fasciculus showed the largest microstructural changes (Cohen’s D=0.525721). Identifying early white matter changes could aid early diagnosis or disease progression monitoring, as it has been suggested that white matter atrophy precede symptom onset [2]. Results suggest that decreased intracellular signal fraction in these tracts passing through the asMTL as a potential driving factor of this increased diffusivity.
Carbonic anhydrase inhibition ameliorates Aβ‐induced neurovascular dysfunction in vivo
Authors: Canepa Elisa , Vazquez‐Torres Rafael , Debure Ludovic , Fossati Silvia
Published: December 2020

Background

Cerebral amyloid angiopathy (CAA) is present in about 90% of Alzheimer's disease (AD) cases and is characterized by the vascular accumulation of amyloid beta (mainly Aβ40), or specific mutated variants (such as the Dutch‐Q22) in familiar forms of the disease. Our laboratory has previously demonstrated that brain vascular amyloidosis triggers mitochondrial dysfunction and caspase‐mediated apoptotic pathways activation in neuronal, glial and endothelial cells, in vitro. We have shown that these pathological processes can be prevented by acetazolamide (ATZ) and metazolamide (MTZ), FDA‐approved carbonic anhydrase inhibitors (CAIs) with a well‐known profile of brain delivery. Carbonic anhydrases (CAs) represent a family of enzymes catalyzing the reaction CO2 + H2O ⇄ HCO3− + H+. Amongst 15 known isoforms in humans, CA‐VA and ‐VB are solely expressed in mitochondria, while CA‐II translocates to the mitochondria from the cytosol in aging and neurodegeneration.

Methods

We fed Tg‐SwDI (APP‐Swedish, Dutch, Iowa) mice, which develop fibrillar amyloid deposits primarily in the cerebral microvasculature starting at 6 months, with a CAI‐diet for 8 months (from 8 to 16 months of age). Following behavioral analysis, brains have been harvested for both biochemical and immunohistochemical analysis.

Results

Brain CA‐VB expression is dramatically increased in Tg animals compared to WT, and the treatment with ATZ and MTZ significantly decreases it. Moreover, CAIs reduce the number of vasculotropic amyloid deposits and GFAP+ astrocytes, main pathological features of the disease. In Tg mice, our preliminary data show that Aβ deposition occurs in both endothelial and glial cells, leading to cell‐specific apoptosis detectable as caspase‐3 cleavage. Interestingly, CAI treatment attenuates brain Aβ load measured by Thioflavin S, as well as endothelial and astrocytic Aβ overload and the resulting caspase activation. Furthermore, the pronounced increase of cerebral CD68+ cells in CAIs‐fed animals suggests a boost of the perivascular phagocytic activity that might explain the observed reduction of Aβ deposition.

Conclusions

This study supports the role of CAs in the endothelial and astrocytic Aβ‐induced cell death and inflammation pathways associated with CAA and AD, indicating CAIs as potential drugs to improve vascular health and provide neuroprotection.
Posterior cortical atrophy in Southeast Asia: Clinical and biomarker profile
Authors: Lim Levinia , Wong Benjamin , Vipin Ashwati , Silva Eveline , Lay Hoon Lim Linda , Vanessa Chua Esther , Yuen Oi Choong Tanya‐Marie , Mei Nyu Mei , Chiew Hui Jin , Hameed Shahul , Seng Ting Simon Kang , Lyn Ng Adeline Su , Ng Kok Pin , Kandiah Nagaendran
Published: December 2020

Background

Posterior Cortical Atrophy (PCA) has been widely studied internationally, but there is limited data on its clinical and biomarker characteristics among Southeast Asians. We aim to describe a case series of PCA patients in this part of the world and explore how the new PCA consensus classification (Crutch et al., 2017) could be applied in this cohort.

Method

A retrospective review of the Singapore Young Onset Dementia (YOD) research database from a tertiary neurology center was performed. Available demographic, clinical and biomarker data of patients with a clinical diagnosis of PCA were extracted.

Result

Of 290 patients with YOD, ten patients (5 males; 5 females) with a clinical diagnosis of PCA were identified. Mean (SD) age of onset was 54.70 (4.11), duration between symptom onset and neurological consultation was 3.90 (1.45) years. All patients reported insidious onset and gradual progression of symptoms.

Upon neurological examination, principle types of cognitive deficits seen were acalculia (80%), finger agnosia (70%), simultagnosia (60.0%) and agraphia (50%).

In another sub‐group with available MRI scans (n=7), all showed biparietal cortical atrophy, five (71.0%) had concomitant bilateral medial temporal lobe atrophy and white matter hyperintensities of varying severity was noted in four (57.0%) patients.

Among patients with known APOE genotyping (n=8), there was one e2e3 six e3e3 and one e4e4. Findings on cerebrospinal Ab‐42 and tau levels was available (n=7), mean (SD) of Ab‐42, phosphor‐tau and total tau levels were 525.1 (195.5)pg/ml, 72.1 (22.9)pg/ml and 611.3 (246.9)pg/ml respectively. Based on the new consensus classification for PCA (Crutch et al., 2017) and incorporating the CSF Ab‐42 criterion cut‐off for AD by Dubois et al. (2014), our series consists of one PCA‐AD (10.0%) and nine PCA‐pure (90.0%) However, if the CSF tau/ Ab‐42 ratio >0.52 (Duits et al., 2014) for biomarker diagnosis of AD is used, there would be seven PCA‐AD (70%) and three PCA‐plus (30%).

Conclusion

PCA patients tend to present late in clinic and greater awareness on the presentation of PCA is needed for earlier diagnosis and timely intervention. Also, the sensitivity of the different CSF criteria for AD in diagnosing PCA‐AD would require further analyses in larger cohorts.
Validity of the severe impairment battery, brief praxis test, and dementia questionnaire for persons with intellectual disabilities in differentiating dementia status in individuals with Down syndrome
Authors: Wallace Elizabeth , Harp Jordan , Pelt Kathryn L. , Koehl Lisa , Caban‐Holt Allison M. , Anderson‐Mooney Amelia J , Robertson William , Lightner Donita , Jicha Gregory A. , Head Elizabeth , Schmitt Frederick A.
Published: December 2020

Background

Individuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer’s disease (AD). However, many measures regularly used for the detection of AD in the general population are not suitable for individuals with DS. Some measures, including the Severe Impairment Battery (SIB), Brief Praxis Test (BPT), and Dementia Questionnaire for Persons with Intellectual Disabilities (DMR), have been used in clinical trials and other research with this population. Validity research is limited, however, particularly regarding identification of predementia symptoms in the DS population. The current project presents baseline cross‐sectional SIB, BPT, and DMR performance in order to characterize their ability to discriminate normal cognition, possible AD, and probable AD in DS.

Method

Baseline SIB, BPT, and DMR performances from 117 individuals were analyzed as part of a large longitudinal cohort of aging individuals with DS. Receiver operating characteristic (ROC) curves were calculated to investigate accuracy in differentiating levels of dementia status.

Result

In comparing no/possible AD vs. probable AD, the SIB and BPT exhibited fair discrimination ability (AUC = .78 and .79, respectively). In comparing no/possible AD vs. probable AD, the DMR exhibited good discrimination ability (AUC = .89), with qualitatively similar performance of the DMR‐Cognitive and DMR‐Social subscales (AUC = .89 and .83, respectively). In comparing no AD vs. possible AD, the SIB and BPT failed to differentiate these groups (AUC = .53 and .55, respectively), whereas the DMR exhibited good differentiation (AUC = .80).

Conclusion

Results suggest that the SIB, BPT, and DMR are able to discriminate between levels of dementia status in individuals with DS, supporting their continued use in the clinical assessment of dementia in DS. Specifically, the DMR, based on informant ratings of social and cognitive behaviors of daily living, outperformed the SIB and BPT, tests of cognitive performance, in discriminating no/possible AD vs. probable AD as well as no AD vs. possible AD. Such findings suggest that the DMR is better equipped to identify symptoms of overt dementia as well as predementia in this population. Findings reinforce the importance of including informant behavior ratings in assessment of this population.
Regulation of amyloid‐beta pathology by CNS amylin receptors in APP/PS1 mice
Authors: Corrigan Rachel , Grizzanti John , Casadesus Gemma
Published: December 2020

Background

Amylin is a pancreatic amyloid protein, known to regulate glucose homeostasis and satiety through its ability to sensitize insulin and leptin. Importantly, the amylin receptor (AMYR) is expressed throughout the brain, including areas important in both cognition and Alzheimer’s disease (AD) pathology, like the hippocampus. We and others have previously shown that an analogue of amylin, Pramlintide (PRAM), reduces Aβ plaque burden and recuses hippocampal‐dependent cognitive decline in AD‐mouse models. However, the mechanisms underlying the therapeutic benefits of PRAM are not known.

Method

APP/PS1 mice were treated with PRAM, or saline, chronically via a subcutaneous pump for eight weeks. Additionally, a second subcutaneous pump connected to an ICV cannula delivered an AMYR antagonist, AC187 or aCSF during the last four weeks of peripheral treatment. Radial Arm Water Maze was performed at the end of study to measure spatial memory. Soluble‐Aβ1‐42 hippocampal levels were measured via ELISA and APP processing enzymes were evaluated by Western Blot.

Result

Preliminary data suggests central blockade of amylin receptors may exacerbate Aβ burden and prevent learning of spatial‐memory tasks; while PRAM treatment showed increased protein expression of certain Aβ degradation enzymes.

Conclusion

Evaluation of AMYR blockade in AD‐modeled mice has supported a deeper knowledge of amylin signaling in the brain.
Hybrid resting state structural connectome reveals disruption of excitation‐inhibition balance in APOE ε4 carriers
Authors: Fortel Igor , Morrissey Zachary , Korthauer Laura E , Zhan Liang , Ajilore Olusola , Driscoll Ira , Schonfeld Dan , Leow Alex
Published: December 2020

Background

Multimodal neuroimaging modalities may improve detection of early brain changes associated with Alzheimer’s disease (AD). We investigated cognitively intact middle‐aged individuals to determine whether male and female APOE‐ε4 carriers demonstrate altered connectivity using a novel multimodal connectomics technique to probe excitation‐inhibition balance.

Method

For 38 cognitively intact APOE‐ε4 carriers aged 40‐60 (μ=50.8) and 38 age (μ=50.9) and sex‐matched (16M/22F) non‐carriers, imaging included: T1‐weighted MRI, resting‐state fMRI and diffusion‐weighted MRI (Korthauer et al, 2018. NeuroImage, 178, 295‐305). Functional connectomes (rs‐FC), constructed with 80 regions of interest (ROIs) used correlation‐based methods on BOLD activity. The hybrid resting state structural connectomes (rs‐SC), constructed using a recently proposed multimodal connectome technique, leverages statistical mechanics to infer connectome‐level excitation‐inhibition balance (Fortel et al, 2019. MICCAI Conference. 503‐511, Springer). Positive edges in this rs‐SC indicate excitatory relationships between ROI pairs, while negative indicate inhibitory relationships. For each ROI, a hyperexcitation indicator (HI) was defined as the percentage of positive edges.

Result

Using rs‐SC and rs‐FC, figure 1 presents a comparison for each sex between group‐averaged HI for ROIs of carriers and non‐carriers. For each sex, we compared carriers and non‐carriers using 2‐sample T‐tests. Functional connectivity shows no significant difference for percentage of positive BOLD correlations for both genders (P > 0.05). By contrast, using rs‐SC, females have a significant increase in HI compared to non‐carriers (P < 0.001), suggesting female APOE‐ε4 carriers have globally disrupted E‐I balance that may confer greater vulnerability to AD neuropathology. Figure 1. Average HI for each ROI computed using the rs‐SC (1A) and rs‐FC (1B). Line x = y is a reference for equal HI between groups. While a strong linear relationship exists between carriers and non‐carriers for both genders using functional connectivity, the HI is comparable. Using rs‐SC, female ε4 carriers show a significant increase in HI compared to non‐carriers.

Conclusion

We demonstrated a global shift towards hyperexcitation in a group of cognitively intact female ε4 carriers, less so in the male carriers. Our findings are consistent with known AD sex differences, suggesting that novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not.
Transforming growth factor β1 differently modulates wild‐type and TgF344‐AD astrocyte cultures' function
Authors: de Souza Débora Guerini , da Rocha Andreia Silva , Salles Giovanna Bortoluzzi , Oliveira Ana Cristina Laydner Joly , Limberger Christian , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Zimmer Eduardo R. , Souza Diogo O.
Published: December 2020

Background

Astrocytes are key players involved in several functional aspects of the brain. They manage extracellular neurotransmitters and ions, regulate blood flow and energy substrates. Additionally, they produce and release growth factors, with autocrine and paracrine reach. Recently, the beneficial effects of Transforming Growth Factor β1 (TGF‐β1) have been shown in some experimental models of neurodegenerative diseases. However, the effects of TGF‐β1 in experimental models of Alzheimer’s Disease (AD) are still a matter of debate and further mechanistic investigation is needed. Here, we used adult astrocyte cultures prepared for the first time from Fischer TgF344‐AD (TG) rats to verify whether exogenous TGF‐β1 would affect astrocyte function.

Method

Cortices of adult (4‐month‐old) Fischer wild‐type (WT) and TG rats were aseptically dissected and digested with trypsin and papain. Cells suspensions were plated in 24‐well plates and cultivated for 3 weeks in DMEM/F12 supplemented with 10‐20% fetal bovine serum (FBS). At confluence, cells were treated with TGF‐β1 10 ng/mL for 1, 4 or 24h in DMEM/F12 1% FBS. Glutamate uptake was measured by radioactive assay and cellular morphology was evaluated with glial fibrillary acidic protein (GFAP) antibody and with rhodamine‐phalloidin for actin staining.

Result

Astrocytes from WT and TG rats take up the same amount of glutamate in basal conditions. WT astrocytes, however, respond to TGF‐β1 treatment increasing the levels of glutamate uptake nearly two‐fold after been treated for 4 or 24h (p<0.05), while TG astrocytes are not affected. GFAP and actin staining of the astrocytes shows extensive expression of the glial marker in the cytoskeleton and typical morphology (Figure 1 ‐ representative of TG astrocytes).

Conclusion

TGF‐β1 enhanced glutamate uptake in WT but not in TG astrocytes. This may be related to an intrinsic lesser ability to fulfill neuroprotective roles and decreased plasticity presented by TG astrocytes. Impaired astrocyte function is thought to be a decisive component of AD and here we show preliminary data that suggests decreased capacity of TG astrocytes to respond to neuroprotective compounds such as TGF‐β1. Whether the decreased response to TGF‐β1 is contributing to neurodegeneration or it is a consequence of neurotoxic stimulus in TG cells remains to be determined.
Genome‐wide profiling of the noncoding regulatory mechanisms in Alzheimer’s disease
Authors: Kleidermacher Lauren , Kuksa Pavel , Lee Chien‐Yueh , Amlie‐Wolf Alexandre , Schellenberg Gerard D. , Wang Li‐San , Leung Yuk Yee
Published: December 2020

Background

Genome‐wide association studies (GWAS) have identified genetic variants associated with Alzheimer’s Disease (AD), but the majority are noncoding and may affect transcriptional regulatory elements such as enhancers. While prior post‐GWAS analyses focused on analyzing only top GWAS signals, this study focuses on a systematic genome‐wide analysis of all significant GWAS signals aimed at identifying a more complete set of causal variants given a complex linkage disequilibrium (LD) genome structures and the regulatory mechanisms, and tissues/cell types.

Method

To perform genome‐wide analysis of GWAS summary statistics (NIAGADS NG00036) from the IGAP study [Lambert et al., 2013], we adopted INFERNO (http://inferno.lisanwanglab.org), a recent method for post‐GWAS analysis of non‐coding variants. INFERNO integrates GWAS data with hundreds of publicly available functional genomics datasets (e.g., ENCODE, FANTOM5, GTEx, HOMER) across 485 tissues and cell types to facilitate identification of the regulatory mechanisms and tissue/cell types affected by noncoding genetic variants.

Results

Genome‐wide INFERNO analysis identified 168 distinct loci by pruning all genome‐wide significant (p‐value < 5e‐8) GWAS variants using LD structure, a significant increase compared to original top‐SNP analysis (19 loci). Across these 168 distinct loci, INFERNO identified 1,358 candidate potentially causal variants in LD. Around 6% of these variants were localized in coding exons, 67% overlapped enhancers in at least one tissue and 57% overlapped transcription factor binding sites. Co‐localization analysis of GWAS and eQTL data (GTEx_v6p) identified tissue‐specific effects of 53 variants on 43 genes across 16 INFERNO tissue categories, with 12 variants affecting expression of 16 genes in the blood (RP11‐1036E20.9, ZNF223, ZNF285B, RP11‐286H15.1, FAM115D, EPHA1‐AS1, TAS2R60, TAS2R62P, PTK2B) and brain (CR1, ABCA7, POLR2E, EML2, PPM1N, RP11‐385F7.1, FAM115C). These INFERNO‐identified genes include both novel and genes previously implicated in AD. E.g. EPHA1‐AS1 activity was confirmed by luciferase reporter assay [Amlie‐Wolf et al., 2019]. Additionally, our analysis found that PTK2B gene, an early marker of Tau pathology [Dourlen et al., 2016], is regulated by rs28834970 that also disrupts binding motif of HLF(bZIP) in blood.

Conclusion

Genome‐wide INFERNO analysis confirmed experimentally validated and discovered additional plausible biological mechanisms related to AD. These can help to inform the development of better AD therapeutic targets.
Circulating metabolites associated with brain MRI markers of Alzheimer’s disease
Authors: Wang Ruiqi , Satizabal Claudia L , Beiser Alexa S , Vasan Ramachandran S , DeCarli Charles , Gerszten Robert Edgardo , Yang Qiong , Seshadri Sudha
Published: December 2020

Background

Prior research has identified metabolites associated with general cognitive function and Alzheimer’s Disease (AD). However, more research is needed to identify additional metabolites related to AD endophenotypes to better understand the earliest pathological processes. We aimed to identify metabolites associated with brain MRI markers of AD, including total brain volume, lateral ventricular volume, and hippocampal volume in the Framingham Heart Study.

Method

About 2,145 participants from the Framingham Heart Study Offspring and Third‐Generation cohorts were used in this project. We used linear mixed effect models to assess the association between metabolites and MRI phenotypes. Brain MRI measures were introduced as the percentage of total intracranial volume to correct for head size. Our primary model was adjusted for age, sex, BMI, and use of lipid‐lowering medications. In secondary analyses, we ran the same model stratifying for APOE4 status subgroups (e4 carriers vs. non‐carriers). Multiple testing corrected significance levels was determined as P < 2.09 × 10‐4 after considering inter‐correlation of the metabolites. Finally metabolite set enrichment analysis (MSEA) was carried out to identify biologically meaningful patterns that are significantly enriched in the top associated metabolites.

Result

We found that higher levels of cotinine, fumarate‐malate‐valine and lactate were associated with lower total brain volumes (P < 8.13 × 10‐5). In subgroup analyses, we observed that higher levels of anthranilate were related to lower brain volumes in APOE‐e4 carriers. Further, only in APOE‐e4 non‐carriers, higher phosphatidylcholine (32:1) levels were related to lower brain volumes (P < 1.52 × 10‐4) and higher levels of urate were related to lower hippocampal volume (P < 1.11 × 10‐4). Valine, leucine and isoleucine biosynthesis, and aminoacyl‐tRNA biosynthesis are significantly overrepresented for hippocampal volume in APOE‐e4 non‐carriers.

Conclusion

Several metabolites were associated with total brain and hippocampal volumes. Remarkably, some of these have been previously related to cognitive function and AD, adding to the consistency of our findings and highlighting the power of endophenotype research. Expansion to include additional brain MRI markers and replication in other neuroCHARGE cohorts, a large international consortium, are currently underway.
Die Young as Late as Possible Project: Trajectory analysis of cognitive aging
Authors: Klinedinst Brandon S. , Obhi Hardeep K. , Pappas Colleen , Shirtcliff Elizabeth , Willette Auriel A.
Published: December 2020

Background

Populations are aging worldwide, average life expectancy in the U.S. has stagnated around 80 years old, and prevalence of Alzheimer’s disease and related dementias are increasing. The Hayflick limit predicts a maximum lifespan of about 120 years among humans, and the oldest observed living human, Jeanne Calment, died after her 122nd birthday. In other words, there appears to be a wide gap between actual and potential human lifespans. Furthermore, the onset age for most health conditions has not increased markedly in many decades. This suggest that increases in lifespan may stem from extensions in the duration of sickness prior to death. Preventing morbidity and increasing healthspan will require better understanding of the different ways individuals can age. Typically, brain aging is accompanied by volumetric changes that negatively impact most cognitive processes. Despite what happens to the majority, or what happens on average, there is a vast range of variation in neurocognitive development in late life. Charting the distinctiveness of developmental trajectories within a population will help identify meaningful subpopulations that could not be uncovered ex ante. In this study we investigated cognitive changes over time and developed typologies of different and unique ways people experienced brain aging.

Method

Fluid intelligence data among 17,016 UK Biobank subjects was sampled three times from 2006 until 2014. Growth curves were used to estimate everyone’s level and rate of change. With these trajectory values, a cluster analysis distinguished several cognitive aging trajectories.

Result

We identified up to seven distinguishable trajectories. Each trajectory component was significant at p<.001. Two trajectories exhibited learning and other cognitive improvements over time, three maintained their cognitive performance, and two experienced cognitive declines over the eight‐year period.

Conclusion

Among longitudinal cohorts, cluster analysis applied to growth curves identified meaningful subpopulations without the need for expert diagnosticians. Including typological information in population models promises to reduce within‐group variance and allow testing for processes that are conditional rather than unanimous across a population. Future works should investigate how trajectories are related to one another and whether more diverse populations demonstrate similar trajectory typologies.
Exercise intervention and promoting physical activity to prevent and delay onset of dementia
Authors: Park Hyuntae , Park Kyung Won , Yang Jakyung , Thapa Ngeemasara , Park Hyejin , Son Haeun , Jang Minwoo , Lee Jihyeon , Kim Hansol
Published: December 2020

Background

This study aimed to investigate the effectiveness of a combined‐exercise intervention program on cognitive and physical functions.

Method

In a randomized controlled trial, we enrolled 167 individuals with mild cognitive impairment (MCI). The definition of MCI was based on medical evaluations through a clinical interview conducted by a dementia specialist. Cognitive assessments were performed by neuropsychologists according to standardized methods, including the MMSE and frontal cognitive function, both at baseline and at 6 months follow‐up. The program comprised physical activity and behavior modification, exercise (aerobic and resistance), and a cognitive and exercise combined intervention program.

Result

Analysis of the subjects for group‐time interactions revealed that the exercise group exhibited a significantly improved attention, working memory, and executive function. Total habitual physical activity levels during intervention were associated with improvements in cognitive function, gait performance and the SPPB score, and the associations were stronger for those who are 75 and older are more likely than for <75, and those who have prefrail than frail individuals.

Conclusion

The 6‐month combined intervention improved cognitive function and physical function in patients with cognitive impairment relative to controls. Encouraging and motivating older adults, particularly old‐older adults and prefrail individual, to improve moderate physical activity under supervision, during ongoing intervention, may be more beneficial to prevent cognitive decline and improve exercise adherence.
Structural‐MRI‐based Alzheimer's disease dementia score using 3D convolutional neural networks to achieve accurate early disease prediction
Authors: Yee Evangeline , Popuri Karteek , Ma Da , Wang Lei , Beg Mirza Faisal
Published: December 2020

Background

In recent years, many convolutional neural networks (CNN) have been proposed for the classification of Alzheimer's Disease (AD). Due to memory constraints, many of the proposed CNNs work at a 2D slice‐level or 3D patch‐level. Other subject‐level 3D CNNs which take a whole brain 3D MRI image as input require a long training time.

Method

Here, we propose a lightweight subject‐level 3D CNN featuring dilated convolutions which allow the receptive field to be increased efficiently through a small number of layers. To comprehensively evaluate the generalizability of our proposed network, we performed four independent tests which includes testing on images from other ADNI individuals at various stages of the dementia, images acquired from other databases/sites (AIBL), images acquired using different protocols (OASIS) and longitudinal images acquired over a short period of time (MIRIAD).

Result

We trained our network on the ADNI data, and we achieved a 5‐fold cross‐validated balanced accuracy of 88% in differentiating stable Dementia of the Alzheimer's type (sDAT) from stable normal controls (sNC). Our network showed 78.5% accuracy in classifying images of mild cognitive impairment (MCI) subjects acquired 2 years prior to conversion to DAT. We achieved an overall specificity of 79.5% and sensitivity 79.7% on the entire set of 7902 independent test images

Conclusion

In this study, we constructed a lightweight 3D CNN network that converts the subject‐level image into a single AD dementia score to represent the disease progression. For estimating the generalization ability of the network to unseen data, independent testing is essential but is often lacking in studies using CNN for DAT classification. This makes it difficult to compare the performances achieved using different architectures. The result of our study highlights the competitive performance of our network and potential promise for generalization.
Genome‐wide association study of tau‐PET: Association of variant near NTNG2 with resistance to tau deposition
Authors: Ramanan Vijay K. , Wang Xuewei K , Przybelski Scott A. , Pillai Sheela Kumari Raghavan , Kosel Matthew L. , Batzler Anthony K. , Knopman David S. , Radford Jonathan Graff , Lowe Val J. , Mielke Michelle M. , Jack Clifford R. , Petersen Ronald C. , Ross Owen A. , Vemuri Prashanthi
Published: December 2020

Background

Tau deposition is a key biological feature of Alzheimer’s disease (AD) that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau accumulation while others are more resistant. The recent availability of tau positron emission tomography (tau‐PET) provides an opportunity to test the hypothesis that genetic factors are associated with differential tau deposition.

Methods

We performed a genome‐wide association study (GWAS) of tau‐PET on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.4% cognitively unimpaired) from the population‐based Mayo Clinic Study of Aging. Following genotyping with the Illumina GSA array and standard quality control, 515,206 single nucleotide polymorphisms (SNPs) were tested for association with entorhinal cortex 18F‐flortaucipir tau‐PET burden using linear regression under an additive genetic model and covarying for age and sex.

Result

A genome‐wide significant association was identified for rs75546066, an intergenic SNP on chromosome 9 between MED27 (mediator complex subunit 27) and NTNG2 (netrin G2), with the minor (A) allele associated with lower tau burden (p=2.85 x 10‐8, β=‐0.48). Linkage disequilibrium and public expression quantitative trait loci (eQTL) data suggested a functional relationship between rs75546066 and NTNG2, the latter of which is highly expressed in the brain. In addition to this novel finding, three SNPs within MAPT (microtubule‐associated protein tau) displayed nominal associations to tau‐PET burden, including rs3785883 (p=0.04, β=0.07) which was previously associated with higher cerebrospinal fluid tau in an independent cohort. No associations with tau‐PET burden were identified for the APOE (apolipoprotein E) ɛ4 or ɛ2 alleles or for genotyped SNPs previously associated with AD in large case‐control studies.

Conclusion

To our knowledge, this study represents the first reported neuroimaging GWAS of tau pathology. Our findings confirm the association of MAPT with tau burden and nominate the rs75546066‐NTNG2 locus as a novel potential protective influence against tau pathology which warrants further functional characterization. Our data also supports the inference that tau accumulation may have a genetic architecture distinct from APOE and other known AD susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting models.
Detection of misfolded protein aggregated in HIV‐infected people
Authors: Calderon Olivia , Ruiz Nazaret Gamez , Moreno‐Gonzalez Ines , Gelman Benjamin B. , Rocha Natalia P. , Soto Claudio
Published: December 2020

Background

Many people living with HIV (PLWH) develop dementia and cognitive dysfunction often referred as HIV‐associated neurocognitive disorder (HAND). The prevalence of HAND increases with age and considering that the number of PLWH aged 55 and older is increasing in the United States, it is expected that this number will also increase in the near future. The cellular and molecular mechanisms responsible for HAND are not well defined but evidence suggests many commonalities with Alzheimer’s disease and related neurodegenerative disorders.

Method

In the present study, we analyzed by histological analysis the presence of misfolded protein aggregates of amyloid‐β (Aβ) and Tau in the brain of 22 PLWH (67.41±1.48 y/o) and 15 controls (HIV negative, 73.87±2.93 y/o).

Result

We found a higher prevalence of Tau deposits in the brain of PLWH (N=9/22; 41%) in comparison with HIV‐negative controls (N=3/15; 20%). However, the co‐occurrence of Aβ and Tau pathology was more prevalent in controls (N=8/15; 53%) than in PLWH (N=7/22; 32%) samples.

Conclusion

This result may be due to the fact that the control group was significant older than the HIV‐infected group. More analyses with age‐matched groups are needed to clarify this finding. Our preliminary results suggest some differentiation between the groups with a higher prevalence of Aβ‐independent Tau pathology in HIV.
External validation of a proprietary delirium superimposed on dementia risk score using claims data and predictive analytics
Authors: Rao Anitha , Miller Benjamin , Kulman Tanzila , Pinho Paulo , Aggarwal Neelum T
Published: December 2020

Background

Delirium is an acute change in mental status, attention, and cognition that develops over a short period of time and can fluctuate in course. When delirium occurs in patients with underlying dementia, it is known as dementia superimposed on delirium (DSD). The prevalence of DSD is high in all care settings and patients with DSD have a 15‐fold increase in walking dependence, 5‐fold increase in nursing home placement, and 2‐fold increase in mortality according to published studies.

Method

Cognitive claims from long term care insurance (LTCI) were processed using proprietary predictive analytics from Neurocern Inc, a neuroinformatics and data analytics company. The insurance third party administrator (TPA) who processes claims was blinded to the results from the predictive analytics. Claims data including carrier approval and denial decisions were provided. A DSD risk score was given to cognitive claims that met clinical criteria for delirium. A third party neurology task force validated Neurocern’s proprietary analytics and DSD score.

Result

A total of 67 claims (F=41, M=26) were assessed by the third party task force, the proprietary DSD score had a sensitivity of 94.7% and a specificity of 100%. Inter‐rater reliability was high. Females had a higher incidence of DSD than males. Delirium was missed on 28% of approved claims by both the insurance carrier and the TPA.

Conclusion

Claims flagged with a DSD score should be medically assessed before any severity of dementia or benefit eligibility workup is performed. The high number of delirium cases missed by the insurance carrier and TPA represent claims where the patient’s condition may have improved with appropriate medical management and support. DSD claims represent high cost and high mortality claims that require appropriate financial reserving from insurance carriers.