bluuebunny/crossref_metadata_2025 huggingface dataset:
An extensive plasmid library for preparing tau variants and studying their functional biochemistry
Authors: Karikari Thomas K. , Rodríguez‐Lantero Juan , Olsson Maria , Hill Emily , Moffat Kevin G. , Zetterberg Henrik , Blennow Kaj
Published: December 2020

Background

While tau supports axonal transport by modulating microtubule stability, pathologically it can form neurofibrillary tangles, a key hallmark of Alzheimer’s disease and other tauopathies. Significantly, familial mutations and specific truncations regulate the biochemical processes involved in tau pathology. With the complexity and limited supply of human brain samples for research purposes, recombinant protein technology has become vital for studying tau structure and function. However, open‐source and well‐characterized plasmids and methods for expressing and purifying tau variants are lacking.

Method

We generated 58 plasmids, encoding different tau variants and verified their identities by DNA sequencing. Purification of E. coli‐expressed constructs was achieved by immobilized metal affinity chromatography followed by size exclusion chromatography. Subsequently, tau monomers were utilized to prepare oligomers and paired helical filaments (PHFs), characterized by circular dichroism (CD), transmission electron microscopy and dot blotting. Cellular uptake and cytotoxicity of stabilized oligomers were studied in neuroblastoma cells and stem cell‐derived neurons.

Result

Two sets of plasmids were generated: (i) tau fragments (14 plasmids; Figure 1), including disease‐associated fragments identified directly from human brain samples. The constructs include full‐length (FL) tau‐441 (Uniprot#P10636‐8) as well as FL tau‐441 truncated at 224, 368, 391 and 421, and their respective control fragments, and (ii) tau mutation variants (44 plasmids; Figure 2), including those encoding FL tau‐441, its four‐repeat microtubule‐binding (K18) fragment, and their respective selected familial pathological variants (N279K, V337M, P301L, C291R and S356T). Since cysteine content and locations can affect biochemical properties of tau, plasmids for expressing single (C291A), double (C291A/C322A) and triple (C291A/C322A/I260C) cysteine‐modified variants were also generated. Dot blotting with specific anti‐tau antibodies were used to verify purified fragments. Beta‐sheets in purified monomers increased with aggregation. Oligomers were granular‐shaped and reacted strongly with the anti‐oligomer antibody T22. PHFs had paired‐helical structures. Oligomer stabilization was achieved by cysteine‐labelling with fluorescent/non‐fluorescent maleimide derivatives. Fluorescent‐stabilized oligomers were internalized by neurons and co‐localized with endogenous tau.

Conclusion

We anticipate that the plasmid library and the associated purification and characterization methods will facilitate future studies including microtubule‐binding assays, aggregation, cellular uptake, intra‐cellular toxicity, and extracellular release. Plasmids can be requested at: shorturl.at/ABDM3
Perceived control attenuates the relationship between experiences of discrimination and left amygdala volume in older adults
Authors: Rosario Michael A , Ayoub Amara , Alotaibi Razan , Clark Uraina S , Schon Karin
Published: December 2020

Background

The medial temporal lobes (MTLs), which exhibit neuropathology in Alzheimer’s disease (AD), are modulated by experience. Animal models of environmental enrichment and chronic stress have shown structural plasticity in the amygdalae and hippocampi. Experiences of discrimination (EoD; e.g., sexism, racism, ageism) are salient chronic psychosocial stressors that affect physical and mental health. Perceived control, one’s perception of environmental and psychological control, may attenuate the impact of EoD by increasing resilience. Although aberrant amygdala activity has been implicated in relation to EoD, research has yet to investigate the structural correlates of EoD.

Methods

Data from 36 participants (58% female, 55‐86 years, 31% African American) were used to investigate the moderating effect of perceived control on EoD and MTL volume. T1‐weighted MR images were captured on a 3T Philips Achieva scanner and analyzed using FreeSurfer's automatic segmentation protocol. Models were adjusted for age, sex, education, and intracranial volume.

Results

Multiple regression models showed an association between left (t(30) = ‐4.073, p < 0.001) and right (t(30) = ‐2.116, p < 0.05) amygdala, but not hippocampal, volume and EoD scores. Additionally, perceived control significantly interacted with EoD for the left (b = 10.66, t(28) = 2.776, p < 0.01), but not right (b = 2.096, t(28) = 0.514, p > 0.05), amygdala. At lower levels of perceived control, higher EoD (b = ‐108.57, t(28) = ‐4.509, p < 0.001) predicted smaller left amygdala volume. However, EoD (b = ‐11.77, t(28) = ‐0.562, p = 0.58) did not predict left amygdala volume at higher levels of perceived control.

Conclusion

This cross‐sectional study of cognitively healthy, older adults, provided evidence that greater EoD was associated with smaller amygdala volumes bilaterally. Further, participants with lower perceived control at higher levels of EoD showed a greater reduction in left, but not right, amygdala volume. This suggests that the interaction between chronic stress and resilience might contribute to neuropathology or reserve of AD‐sensitive regions, specifically in populations that face higher discriminatory experiences. Future studies are needed to examine whether interventions that increase perceived control (resilience) have beneficial effects on neural structure and function.
Nativity differences in lifecourse socioeconomic position and late‐life cognition among KHANDLE participants
Authors: Peterson Rachel , George Kristen M , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , DeCarli Charles , Whitmer Rachel A
Published: December 2020

Background

Socioeconomic position (SEP) in childhood and adulthood is associated with late‐life cognition. Less is known about how SEP changes may be associated with late‐life cognition in diverse cohorts.

Methods

The Kaiser Healthy Aging and Diverse Life Experiences Study (KHANDLE) is a cohort of community‐dwelling Kaiser Permanente members who reside in the San Francisco Bay area and Sacramento valley (n=1,708; Asians (24%), Blacks (26%), Latinos (20%) and Whites (30%)). KHANDLE aims to evaluate how lifecourse and sociocultural factors influence late‐life brain health and cognitive decline and contribute to race/ethnic disparities. We used linear regression to test the association between lifecourse SEP trajectories and late‐life cognition and tested if these associations differed by US vs. foreign nativity. Childhood SEP is a composite of parents’ education (≥HS vs. <HS), childhood hunger, and self‐reported family financial status. Adult SEP included participants’ education (≥HS vs. <HS), late‐life low income status (e.g. qualified for low‐income welfare programs), and self‐reported social status. Participants were classified as having consistently high SEP (HH), low childhood/high adult SEP (LH), high childhood/low adult SEP (HL), or consistently low SEP (LL). Executive function, semantic memory and verbal episodic memory measured with the Spanish and English Neuropsychological Assessment Scales (SENAS) were z‐standardized and averaged for overall cognition. Pooled analyses adjusted for age, race/ethnicity, gender, and foreign nativity.

Results

Overall, participants classified as LH did not differ from HH (ref.) in any cognitive domain, while those classified as HL and LL had lower cognition than HH in all domains (see table). We observed a significant interaction of US vs. foreign birth and lifecourse SES trajectory for semantic memory (p=0.01), but no other domain. Stratified analyses demonstrated a similar pattern to pooled. However, foreign‐born participants HL participants had significantly lower overall cognition (p=0.03), and verbal memory (p=0.02) than US‐born HL participants. By contrast, foreign‐born LH participants performed significantly better than US‐born LH in semantic memory (p=0.01).

Conclusions

Those with high Adult SEP had the best cognitive function, regardless of childhood SEP or nativity. In some measures of cognition, foreign‐born HL participants performed worse than US‐born, while foreign‐born LH performed better.
African and European local ancestry surrounding Apolipoprotein E has a differential biological effect upon acute amyloid beta exposure in iPSC‐differentiated astrocytes
Authors: Oron Oded , Maddy Krisna S. , Celis Katrina , Cukier Holly N. , Pericak‐Vance Margaret A. , Young Juan , Blurton‐Jones Mathew , Griswold Anthony J. , Vance Jeffery M. , Dykxhoorn Derek M.
Published: December 2020

Background

Studies have shown that the lower risk associated with the ε4 allele for African ancestry is associated with the local ancestry (LA) surrounding the ApoE gene. Previous studies have shown differences between ApoE3 and ApoE4 alleles in isogenic induced pluripotent stem cell (iPSC) models when exposed to Aβ. We hypothesized that ApoE4 individuals with African LA would respond differently to Aβ compared to European ApoE3 and European ApoE4 LA lines. However, as we cannot produce isogenic lines to test LA, we used RNA expression changes to Aβ exposure to increase our sensitivity to potential differences.

Method

We differentiated European LA ε4/ε4 and African LA ε4/ε4 allele astrocytes from iPSC lines. Astrocytes were exposed to exogenous Aβ and RNA was obtained at 0 and 24 hours. We performed bioinformatic analyses with the STAR algorithm and differential expression calculation using linear models implemented in edgeR. Pathway enrichment analysis for Gene Ontology Biological Processes, KEGG and Reactome pathways was performed using Metascape.

Result

Twenty‐four hours following Aβ exposure, 524 and 671 genes were deferentially expressed from baseline in African and European LA lines respectively. Analysis of the unregulated genes in the two different ancestries revealed markedly different pathways. The unregulated genes in African LA astrocytes were enriched for Ribosome Biogenesis and RNA modification processes while the upregulated genes in the European LA astrocytes were enriched for Cell Cycle and DNA modification processes. In the European LA astrocytes, downregulated genes were enriched for Synaptic Assembly and Kainate Receptor Activity while in the African LA astrocytes downregulated genes enriched for Extracellular Matrix‐related processes.

Conclusion

Our initial results suggest that the two ancestries respond differently to Aβ exposure. Whether this is due to global or local ancestry differences is unclear. Further studies including astrocytes bearing African LA ε3/ε3 are needed to clarify that question. Both ribosomal dysfunction and astrocyte‐neuronal and astrocyte‐microglia synaptic assembly have been implicated in Aβ clearance and/or AD. A potential link between LA and the regulation of these processes due to Aβ exposure could pave the path to a better understanding of LOAD pathology.
Evaluation of amyloid and tau PET quantitation methods using a 3D‐printed anatomically accurate brain phantom
Authors: Minhas Davneet S , Ghodadra Anish , Yu Zheming , Royse Sarah K , Aizenstein Howard J , Cohen Ann , Tudorascu Dana L , Lopresti Brian J , Mathis Chester , Klunk William E , Laymon Charles M
Published: December 2020

Background

A potential source of error in quantifying longitudinal changes in amyloid and tau imaging is the spatial resolution of PET. Partial volume correction (PVC) methods have been developed to account for this, but there remains a lack of consensus in the Alzheimer’s field on their use due to a lack of method evaluation relative to ground truth. The aim of this work was to evaluate various reconstruction and image‐based PVC techniques using an anatomically accurate 3D‐printed PET phantom with physiologically relevant radiotracer distributions.

Methods

A lateral temporal phantom (Figure 1) with six fillable, thin‐walled (1.0 mm) chambers corresponding to inferior, middle, and superior temporal gray matter (GM) and white matter (WM) regions was constructed via 3D‐printing (Formlabs Form 3) using the FreeSurfer v5.3 segmented sample subject “bert” as a pattern. Inferior and superior temporal GM regions were filled with a 3.0 kBq/cc concentration of F‐18 solution and WM regions with 1.5 kBq/cc, simulating a high amyloid‐burden subject with a GM‐to‐WM radioactivity ratio of 2:1. The phantom was scanned on a Siemens Biograph mCT and reconstructed using three techniques: FBP; OSEM; and TrueX, an iterative method with system matrix modeling using a spatially variant point spread function. Image‐based geometric transfer matrix (GTM) PVC was applied to the FBP and OSEM images. Regional uncorrected and PVC radioactivity concentrations were compared to known ground truth.

Results

FBP, OSEM, and TrueX PET images are presented in Figure 2. Inferior and superior temporal GM and WM radioactivity concentrations for each of the reconstructions, uncorrected and PVC, are presented in Figure 3.

Conclusion

GTM PVC resulted in more accurate regional quantification relative to uncorrected data, regardless of reconstruction method. TrueX, which accounts for the system resolution during reconstruction, did not result in improved quantitative accuracy despite apparent differences in image quality. Optimization of TrueX parameters may result in improved quantitation accuracy. This study adhered to one fundamental assumption of the GTM technique: radioactivity uniformity within a region. This assumption may be violated in human imaging. Future studies will address this and will examine varying levels of amyloid and tau burden and cortical atrophy.
Rationally designed antibodies selective for pathogenic tau aggregates
Authors: Roman Andrei , Hsueh Shawn Ching‐Chung , Kaplan Johanne , Gibbs Ebrima , Adekunle Aina , Plotkin Steven S. , Cashman Neil R.
Published: December 2020

Background

Tauopathies are neurodegenerative disorders characterized by the abnormal aggregation of tau protein in the brain. Soluble toxic tau aggregates have the ability to transfer from cell‐to‐cell and to induce newly formed aggregates in recipient cells, thereby propagating tau pathology across the brain in a prion‐like manner. We used computational modeling to identify conformational “disease‐specific” epitopes predicted to become exposed on misfolded tau aggregates. Selectivity of antibodies for tau pathogenic species, as opposed to pan‐tau reactivity, is needed both in order to preserve normal tau function and to minimize the diversion of active antibody from the target through unproductive binding to more abundant non‐toxic forms of the protein.

Method

The ability of predicted disease‐associated conformational peptide epitopes to induce tau aggregation on their own was tested in a Thioflavin‐T fluorescence(ThT)‐based seeding assay. Mouse monoclonal antibodies raised against selected epitopes were screened by surface plasmon resonance (SPR) for binding to synthetic tau monomers, toxic oligomers, and soluble pre‐formed fibrils (PFFs). Recognition of naturally occurring tau species in Alzheimer’s disease (AD) brain was also confirmed by SPR. The ability of selected antibodies to inhibit induction of tau aggregation by AD brain seeds was assessed in a seeding assay using TauRD P301S FRET Biosensor Cells expressing tau constructs with different fluorescent labels producing a FRET signal when aggregated.

Result

Predicted conformational peptide epitopes capable of seeding activity in the ThT assay were used to immunize mice. SPR screening of hybridoma supernatants was used to identify antibody clones with the desired profile of preferential binding to a preparation of toxic tau oligomers vs non‐toxic tau monomers. A majority of these antibodies also bound soluble tau PFFs, a species believed to play a role in propagation of disease. Antibodies selected for further testing were found to recognize tau from AD brain extract by SPR and to inhibit seeding activity in a FRET assay.

Conclusion

Computational modeling for identification of predicted disease‐associated epitopes together with in vitro screening methods allowed for the generation of monoclonal antibodies with selectivity and activity against pathogenic, aggregated species of tau.
Therapeutic potential of oxytocin receptor signaling in vascular dementia
Authors: Counts Scott E. , Manfredsson Fredric P. , Sandoval Ivette , Paulson Henry L. , Lieberman Andrew P. , McKay Erin C.
Published: December 2020

Background

We recently demonstrated a de novo upregulation of the oxytocin receptor (OXTR) in astrocytes located in the peri‐infarct regions of subjects who died with vascular dementia (multi‐infarct subtype). OXTR activation has been linked to antioxidant, anti‐inflammatory, and angiogenic signaling, suggesting that OXTR upregulation is a novel protective target for vascular dementia, mixed dementias, and perhaps even cerebrovascular accidents. To test this hypothesis, we modeled OXTR upregulation in a novel rat model of vascular dementia.

Method

Four month‐old spontaneously hypertensive, stroke prone rats are being randomized to receive cortical injections of adeno‐associated virus (AAV, serotype 6) bearing either OXTR or green fluorescent protein (GFP) cDNA under control of the astroglial‐specific GFAP promoter, followed by randomization to receive cortical injections of the vasoconstrictor endothelin‐1 (ET‐1) or saline vehicle (n = 16/group, balanced for sex). Following behavioral testing, rats are being analyzed postmortem for infarction lesion size, cerebrovascular pathology, and several mechanistic indices including markers for cell death, inflammation, and oxidative stress.

Result

Preliminary results (n = 6‐8/group) showed that rats receiving AAV‐OXTR and ET‐1 displayed a nonsignificant 40% reduction in mean latency time to target on the Barnes maze compared to rats receiving AAV‐GFP and ET‐1 (p = 0.7). Similarly, OXTR/ET‐1‐treated rats showed a 110% increase in the mean ratio of time spent exploring novel vs. familiar objects on the Novel Object Task compared to GFP/ET‐1‐treated rats (p = 0.08). Postmortem histological analysis revealed a nonsignificant 60% reduction in infarct size in OXTR/ET‐1 compared to GFP/ET‐1 rats (p = 0.08).

Conclusion

Preliminary data are trending to support the concept that astrocytic OXTR signaling may have a therapeutic benefit for dementia resulting from cerebrovascular accidents.
Development and validation of composite scores for language and visuospatial functioning in ADNI
Authors: Choi Seo‐Eun , Mukherjee Shubhabrata , Gibbons Laura E , Sanders R. Elizabeth , Jones Richard N. , Tommet Douglas , Mez Jesse , Trittschuh Emily H , Saykin Andrew J. , Lamar Melissa , Rabin Laura , Foldi Nancy , Sikkes Sietske A.M. , Jutten Roos J. , Grandoit Evan , MacDonald Christine , Risacher Shannon L. , Groot Colin , Ossenkoppele Rik , Crane Paul K. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Composite scores may be useful to summarize overall language or visuospatial functioning. We generated composite scores for these domains from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and evaluated their validity.

Method

We used item response theory to derive composite measures for language (ADNI‐Lan) and visuospatial functioning (ADNI‐VS). We performed multiple validation analyses comparing ADNI‐Lan and ADNI‐VS to individual test and global scores among participants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). We evaluated ability to detect change, strength of association with a priori selected structural brain imaging findings, association with risk of AD conversion for people with MCI, and differences in intercepts and slopes for people with MCI with vs. without the CSF AD biomarker signature.

Result

There were 1,913 people with imaging data and age ³60. Single factor IRT models fit the data well for both composites. ADNI‐Lan outperformed MMSE language items, ADAS‐Cog language items, the Boston Naming Test (BNT), and fluency items in detecting change for MCI and AD. The clock score was modestly better than ADNI‐VS at detecting change for MCI and AD. ADNI Lan was the best at predicting MCI to AD conversion, while the clock score did slightly better than ADNI‐VS. Strength of association of language scores with structural MRI findings are shown in Table 1. ADNI‐Lan and the BNT had stronger associations than other scores for MCI in ADNI1, and also in ADNI2/ADNIGO except for BNT/temporal pole. For AD, ADNI‐Lan had strong associations with each region, similar to other scores except MMSE. Strength of association of visuospatial scores with structural MRI findings are shown in Table 2. ADNI‐VS and the clock had similar strong associations for most regions. People with MCI with the CSF AD biomarker signature had lower language intercepts, captured best by ADNI‐Lan, and more rapid decline, also captured best by ADNI‐Lan. Intercepts were not different for either visuospatial score, and ADNI‐VS and the clock score had similar slope terms.

Conclusion

ADNI‐Lang and ADNI‐VS had good evidence of validity and may be useful composites for language and visuospatial functioning in ADNI.
Heart rate and blood pressure decreases after a motor task in pre‐symptomatic AD
Authors: Rochart Roger , Liu Quanying , Doyle John C , Arechavala Rebecca Johnson , Kloner Robert , Kleinman Michael T , Harrington Michael G , Arakaki Xianghong
Published: December 2020

Background

Understanding how cardiovascular health affects the early Alzheimer’s disease (AD) pathology is challenging because several variables can contribute to significant changes in blood pressure (BP) and heart rate (HR). Previous studies have suggested an association between Alzheimer's disease and HR. Little association is known about pre‐symptomatic AD. We aim to explore the HR and BP changes before and after a motor task in a cognitive healthy population.

Method

Participants (age ranged 61‐95 years old) were recruited from the local community, including cognitively healthy (CH) individuals who were further subdivided based on cerebrospinal fluid (CSF) classification: those with a normal amyloid/tau ratio (CH‐NAT, n = 11) or a pathological amyloid/tau ratio (CH‐PAT, n = 8). Two groups were age, gender, BMI, and education matched. Participants were asked to use a steering wheel to follow a moving line presented on the monitor. Practice session were followed by three task‐identical sessions, 90 seconds per session. Each session consisted of 3 repeated blocks, 30 seconds per block: bump, trail, and bump & trail. Systolic pressure (SP), diastolic pressure (DP), pulse pressure (PP), and HR were measured before and after completing the whole task.

Result

No differences in BP and HR were found between CH‐NATs and CH‐PATs. We found a significant decrease in SP for both CH‐NATs (pre‐task 135.2±24.2, post‐task 127.2±18.8, reduced by 8±9.7, p = 0.0208) and CH‐PATs (pre‐task: 146.1±20.6, post‐task: 134.8±19.6, reduced by 11.3±5.2, p = 0.0004). Furthermore, CH‐PATs have a significant drop in HR (pre‐task: 71.4±10.7, post‐task: 66.3±8.2, reduced by 5.1±4.1 beats, p = 0.0098) compared to CH‐NATs (pre‐task: 70.8±11.8, post‐task: 69.2±13.3, reduced by 1.5±6.2 beats, p = 0.4302). CH‐PATs has decreased HR*SP (pre‐task: 10464±2375.6, post‐task: 8941.1±1843.1, reduced by 1522.9±775.8, p = 0.0009), compared to CH‐NATs (pre‐task: 9537.2±2098.3, post‐task: 8765.2±1769.2, reduced by 772.0±1153.5, p=0.0507). No significant change was found in DP for either CH‐NATs or CH‐PATs.

Conclusion

Pre‐symptomatic AD participants have a significant drop of HR, SP, and SP*HR compared to CH‐NATs, indicating reduced sympathetic responses after motor task. These changes in HR and SP may provide evidence of compromised cardiovascular health and autonomic regulation in pre‐symptomatic AD.
Lifetime brain structural trajectories in TAUPS2APP mouse model of Alzheimer's disease
Authors: Blūma Marina , Micotti Edoardo , Devenyi Gabriel A. , Tolomeo Daniele , Cupo Lani , Forloni Gianluigi , Chakravarty M. Mallar , Babiloni Claudio
Published: December 2020

Background

The TAUPS2APP Alzheimer’s disease (AD) mouse model expresses mutant APPSWE, PSEN2N141I and TAUP301L mutations and displays age‐dependent accumulation of Aβ plaques and neurofibrillary tangles. In humans, abnormal protein accumulation and spreading are related to neurodegenerative processes, most stereotypically in the hippocampus and medial temporal lobe. Prior reports in different AD models have demonstrated various brain structural phenotypes (Grandjean et al.,2016). Here we assess neuroanatomical trajectories in the TAUPS2APP model of AD using longitudinal MRIs.

Method

Thirteen C67BL/6 (11f/2m) and seventeen TAUPS2APP (10f/7m) mice underwent T2‐weighted MRI (voxel size 117x147x147 μm, matrix 256x102x120, FoV 3x1.5x1.5 cm, TR=2500 ms TE=50 ms) at 4,9,13,18, and 24 months of age. Data were analyzed following two‐level deformation‐based morphometry pipeline that uses ANTs SyN nonlinear registration. At the first level within subjects’ minimum deformation averages are created and estimates of volume change are computed (log Jacobian determinants). Next, a second level average is created out of unbiased within‐subject averages and the Jacobians are resampled into the common space

Result

A linear mixed‐effect model with subject as random effect (second order spline fit, sex as a covariate) revealed significant differences in interaction between age and genotype in neuroanatomical trajectory (absolute Jacobian) of bilateral hippocampus, lateral septal area (LSA) and isocortical areas (at False Discovery Rate of 5%, fig.1). TAUPS2APP showed an accelerated overgrowth of hippocampus at young age but larger volumetric decline with age in comparison to non‐TG animals (fig.2a). A similar pattern was observed in LSA (fig.2b). On the contrary in the isocortex, where non‐TG declined with age, TAUPS2APP mice showed volume enlargement (fig. 3c).

Conclusion

These data suggest that TAUPS2APP model is characterized by abnormal neuroanatomical trajectory throughout its lifespan relative to controls. While hippocampal atrophy recapitulates clinical markers of late‐onset AD, enlarged cortex that had been reported earlier in some AD mouse models (TgCRND8, APP/J20 and PSAPP) does not. It was suggested that elevated APP levels may affect the rate of local region growth in adult mice ‐ due to space occupancy by amyloidosis and astrogliosis. In line with this Maheswaran et al. had reported a link between transgene expression, age, and volume increase over time (Maheswaran et al., 2009).
Retinal amyloid deposits found in association with Alzheimer’s disease compared with those in age‐related macular degeneration
Authors: Neathway Peter A.C. , Campbell Melanie C.W. , Redekop Rachel , Kitor Monika , Hirsch‐Reinshagen Veronica , Hsiung Ging‐Yuek Robin , Mackenzie Ian R.
Published: December 2020

Background

Alzheimer’s disease (AD) and age‐related macular degeneration (AMD), both associated with ageing, share common underlying pathology, in that both have been shown to be associated with retinal amyloid deposits. However, amyloid in association with AD has been found in more anterior retinal layers, while amyloid in AMD is typically found in association with drusen, in posterior retinal layers. Here, we compare amyloid deposits found in anterior and posterior layers of the retina.

Method

Eyes were obtained from donors, including those with an intermediate (n=2) or high likelihood of AD (n=10). The severity of AD was assessed from brain pathology. Retinas were stained with 0.1% Thioflavin‐S, counter‐stained with DAPI and flat mounted. Retinal deposits were imaged using a fluorescence microscope fitted with a polarimeter. For each deposit, retinal layer was recorded (anterior, n=264; posterior, n=65). From 16 polarimetric images, interactions with polarized light were derived and image texture was assessed via multifractal analysis (MFA). 15 MFA properties were calculated. Using principal component analysis, the polarimetric and MFA variables which explain most of the variance within each group of deposits (anterior and posterior) were determined. These variables were then input into a non‐parametric discriminatory analysis to separate and classify deposits by retinal location (anterior or posterior).

Result

Following principal component analysis, 12 polarimetric and 7 MFA properties were retained. Using the 5 nearest neighbours, a non‐parametric discriminate analysis was able to discriminate between deposits found in the anterior and posterior of the retina with success rate of 76% (+/‐3%) using 4‐fold cross‐validation.

Conclusion

In conclusion, a combination of polarimetric properties and textural features of retinal amyloid deposits can be used to discriminate between anterior and posterior deposits. This suggests that the properties of deposits found in AD (expected in anterior layers) and AMD (expected in posterior layers) can be differentiated. Furthermore, an ability to distinguish these two types of retinal amyloid deposits in live‐eye imaging would assist their differential classification as associated with AD or AMD pathology. This could improve specificity of diagnosis in each of these conditions.
A systematic review on the potential role of APOE genotype as a moderator in the relationship between physical activity, brain health and dementia risk
Authors: de Frutos Jaisalmer , Rodriguez Juan Manuel Serrano , Maestú Fernando , Laws Simon M , Brown Belinda M
Published: December 2020

Background

Physical activity (PA) has been associated with decreased dementia risk, reduced Alzheimer’s disease (AD) neuropathological burden, and cognitive decline. On the other hand, the strongest genetic risk factor for AD is the Apolipoprotein E (APOE) ε4 allele, which increases AD‐risk in a dose‐dependent manner. Over the past two decades, researchers around the world have tried to unveil whether APOE ε4 carriage moderates the relationship between PA, brain health and dementia risk (Figure 1). Nevertheless, at present, this findings within this field remain inconsistent.

Method

Pubmed and Web of Science were searched for entries following the criteria specified in Table 1. The PRISMA guidelines for systematic reviews were followed throughout the process. A final set of 33 studies were considered after abstracts and full‐text articles were screened by two independent researchers. These included studies addressing the protective effect of PA on dementia risk (19 publications) and different markers of brain pathology (14 publications, see Figure 2).

Result

Studies with shorter follow‐up periods found PA reduced dementia risk generally found that in both genotype groups; however, studies with longer follow‐ups showed varying results. Midlife PA seems to exert a greater impact on ε4 non‐carriers. Conversely, in neuroimaging studies, mainly ε4 carriers or both groups showed benefits, particularly when group sizes were large. Additionally, the association between PA and amyloid burden is stronger among ε4 carriers.

Conclusion

Although available data appears inconclusive, a close‐up look into the different study designs, methodologies and outcomes utilized can clarify the relationship between dementia and PA. More randomized clinical trials as well as longitudinal neuroimaging studies are need in order to fully elucidate relationship between PA, brain health and dementia risk.
Genetic drivers of longevity provide protection against Alzheimer's disease pathology
Authors: Riedel Brandalyn C. , Dumitrescu Logan , Hohman Timothy J. , Saykin Andrew J.
Published: December 2020

Background

Genome‐wide association studies (GWAS) have consistently found human longevity correlations within the APOE gene cluster (APOE, APOC1, TOMM40, PVRL2). Many variants in this cluster show inverse effects between longevity and Alzheimer’s disease (AD). This suggests genetic pleiotropy between AD and longevity, e.g., the APOE ε2 allele is associated with both protection from AD and increased longevity. Recent evidence supports the idea that certain aged individuals do not have significant AD pathology, exhibiting AD resistance. Here we sought to determine whether a genetic signal of AD resistance could be identified by leveraging previous GWAS of longevity and AD pathology.

Method

We used a large meta‐analysis of longevity, defined as reaching the 90th age percentile for a birth cohort compared to those who reach the 60th. Following p‐value informed LD‐clumping (r2 ≥ 0.1), we used random‐effects regression to meta‐analyze three GWAS on AD phenotypes: cerebrospinal fluid levels of amyloid, and phosphorylated tau, as well as amyloid PET imaging. Subsequent methods are shown in Figure 1 and involved mapping variants to genes and determining gene scores and pathway enrichment using PASCAL.

Results

Variants showing discordant effects between AD pathology and longevity (increased pathology/decreased longevity or decreased pathology/increased longevity) included APOE and others across the genome. The top Reactome pathways (p < 0.05) included those involved in axon growth and guidance (Signal transduction and recycling by L1, signalling of NGF, Neurotrophin signalling), cell survival and apoptosis (MAPK pathway, ERK/MAPK targets, NFKB/MAPK activation by TLR4), lipid metabolism (chylomicron‐mediated and HDL‐mediated lipid transport), and the immune system (innate and adaptive).

Conclusion

Significant pleiotropy exists between longevity and AD pathology, implying that focus on discordant effects may yield novel insights relevant to AD resistance. Ongoing work seeks to map results from our discordance analysis to an AD‐specific transcriptional regulatory network created from the Harvard Brain Tissue Resource Center data, with hubs of known transcription factors. This will allow identification of functional modules via eQTL enrichment, will help to further characterize these effects, and may prove useful for downstream drug repurposing analyses.
A case report of a patient with mild cognitive impairment preceded by transient global amnesia with hypometabolism on FDG‐PET
Authors: Yu Justine Megan F. , Dominguez Jacqueline C
Published: December 2020

Background

This is the case of a 61‐year‐old Filipino female who presented with two episodes of transient global amnesia at the ages of 56 and 57.

Method

The patient underwent serial cranial MRI, cranial FDG‐PET/CT scan, and cognitive assessments over a period of five years.

Result

Cranial MRI at the time of the first episode in 2014 showed foci of restricted diffusion abnormality in the left hippocampus. Baseline cognitive assessment was negative for any impairment. On recurrence of TGA in 2015, brain FDG‐PET/CT scan was done which showed mild hypometabolism in the temporal and parietal cortices and hypometabolism in the posterior cingulate cortex. A second comprehensive cognitive assessment was negative for any impairment. Three years after the first episode (2017), she developed subtle changes in memory and thinking and had mild impairment in categorical fluency on neuropsychologic examination. Follow‐up cranial MRI (2017) showed slight decrease in hippocampal volumetry from the 43rd percentile to the 41st normative percentile. Follow‐up cranial FDG‐PET (2019) showed small mildly hypometabolic areas in the frontal, parietal and temporal lobes. The clinical assessment for the patient at this time is very mild cognitive impairment, non‐amnestic, probably secondary to a neurodegenerative process.

Conclusion

This case study shows that transient global amnesia can recur and it may be a risk for cognitive impairment. It also illustrates that existing brain pathology related to a neurodegenerative process can be evident on neuroimaging despite very subtle clinical and neuropsychological cognitive changes. These findings also support aggressive preventive measures of delaying cognitive impairment.
Increased white matter MRI T1 hypointensity volume in young‐onset Alzheimer’s disease patients is not accounted for by age or cardiovascular risk factors
Authors: Flaherty Ryn , Ezzo Rania , Collins Jessica A. , Krivensky Samantha , Eckbo Ryan , Vemuri Prashanthi , Borowski Bret J. , Iaccarino Leonardo , La Joie Renaud , Lesman‐Segev Orit H. , Bourakova Viktoriya , Eloyan Ani , Aisen Paul S. , Fagan Anne , Foroud Tatiana M. , Gatsonis Constantine , Jack Clifford R. , Kramer Joel H. , Koeppe Robert A. , Saykin Andrew J. , Toga Arthur W. , Day Gregory S , Graff‐Radford Neill R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Salloway Stephen P. , Wolk David A. , Wingo Thomas S. , Carrillo Maria C. , Apostolova Liana G. , Rabinovici Gil D. , Dickerson Brad C.
Published: December 2020

Background

White matter (WM) hypointensity volume in T1 MRI correlates strongly with T2 hyperintensities and both are typically associated with advancing age and vascular brain injury (VBI). Recent research has suggested that Alzheimer’s Disease (AD) neuropathologic changes (ADNC) also increases WM hypointensity volume. Sporadic early onset AD (EOAD) patients provide a unique model to examine the relationship between ADNC biomarkers and WM hypointensity volume in the absence of advanced age, cardiovascular injury, or autosomal dominant genetic mutations.

Method

Included in the analysis were sporadic EOAD patients (n = 75) and cognitively normal controls (n = 39) from the Longitudinal Alzheimer’s Disease Study (LEADS) for whom full demographic and health information were available. WM hypointensity volume in T1 MRI was segmented by Freesurfer and corrected for total white matter volume. Multiple‐factor ANOVA models with logarithmic transformations were used to determine the effects of age, cohort, and presence of cardiovascular conditions on WM hypointensity volume. Further multiple‐factor ANOVA models assessed whether the addition of covariates improved the model fit.

Result

In a reproduction of prior research, WM hypointensity volume was correlated with age for controls (p < 0.05), but not for EOAD patients. We additionally found an effect of cohort, such that EOAD patients had a higher mean WM hypointensity volume than controls when accounting for age (p < 0.05). No difference in the presence or number of cardiovascular conditions was found between groups. Additionally, no correlation was found between WM hypointensity volume and the presence or number of cardiovascular conditions. Including cardiovascular condition as a covariate failed to improve the model fit, even when accounting for interaction effects.

Conclusion

These results support the hypothesis that patients with ADNC have higher WM hypointensity volume beyond what would be expected based on aging or cardiovascular risk factors. Further research is needed to assess the co‐localization of WM hypointensities with cortical degradation, amyloid pathology, and tau pathology.
Collection of genetic data in population‐based studies across urban and rural areas: The challenges of the Mexican Health and Aging Study
Authors: Reyes‐Dumeyer Dolly , Samper‐Ternent Rafael , Obregon Alejandra Michaels , Arango Silvia Mejia , Mayeux Richard , Tosto Giuseppe , Barral Sandra , Wong Rebeca
Published: December 2020

Background

The Mexican Health and Aging Study is a longitudinal study aimed to evaluate the impact of age‐related diseases among adults 50 years and older in both urban and rural areas of Mexico. Over a 20‐year follow‐up period the study has collected data on cognitive function, health and socio‐economic factors among the study participants. In addition, blood and saliva samples are available from 2,800 and 7,862 participants respectively. The DNA extracted from blood and saliva samples will be used to conduct downstream genetic analyses.

Method

The saliva collection cohort consisted of participants aged 60 and older from the Mexican Health and Aging Study willing and able to provide a sample. Interviewers across Mexico were trained to collect and ship the saliva samples to the headquarters of the National Institute of Statistics (INEGI) in Aguascalientes, Mexico. Saliva samples passing quality control process were sent to the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) in Indiana, for DNA extraction and storage. DNA samples were distributed to different institutions for genetic analysis: APOE genotyping was conducted at LGC Genomics and genome wide genotyping at the Children’s Hospital of Philadelphia. A subset of the samples were subject to whole genome sequencing conducted by the Uniformed Services University of the Health Sciences.

Result

A total of 8,156 saliva samples were collected of which 279 failed customs clearance for shipment from Mexico to the USA. 0.23% samples were dropped at extraction and 0.23% failed DNA quality standards for genotyping. A total of 7,832 samples were used for APOE, genome‐wide genotyping and whole genome sequencing.

Conclusion

Sample collection for genetic studies in remote rural areas of developing countries such as Mexico present important logistical challenges. The use of saliva as a main source of DNA provides a non‐invasive, low cost, effective and feasible alternative to blood sample collection. Our results suggest that similar protocols can take place in other under‐represented populations of Latin America. Future work will aim to augment the analytical power of the cohort by collecting saliva samples from additional subjects of the MHAS cohort.
A network‐based, multi‐omics atlas for target identification and prioritization in Alzheimer’s disease
Authors: Wörheide Maria , Krumsiek Jan , Nho Kwangsik , Huynh Kevin , Meikle Peter J. , Saykin Andrew J. , Kaddurah‐Daouk Rima F. , Kastenmüller Gabi , Arnold Matthias
Published: December 2020

Background

Alzheimer’s disease (AD) is an untreatable neurodegenerative disorder that represents a major global health burden. Large investments in the generation and analysis of increasing amounts of multi‐omics data have provided us with multi‐layered molecular imprints of pathogenic processes in AD. To identify the most promising targets for translating these readouts into development of novel therapies, it is crucial to take into account the complex biology underlying this heterogeneous disease via evaluating potential targets utilizing the entirety of multi‐omics evidences. However, integrated cross‐omics analyses are complicated and often lack intuitive and interpretable representation.

Method

We propose a network‐based, multi‐omics framework that allows for large‐scale analysis of data on biological entities across omics, as well as their associations with AD and related biomarker changes. Using Neo4j, a graph database, we store and interconnect these diverse biological domains in accessible network structures. Known biological relationships available in public databases such as gene‐transcript‐protein relations and pathway annotations constitute the backbone of this multi‐layered network. Large‐scale quantitative data from population‐based studies are included to establish data‐driven relationships within and across omics as a reference. To identify entities within this network that are relevant to AD pathomechanisms, the framework is finally overlaid with a comprehensive set of association data from multi‐omics screens in large AD cohorts generated through the AMP‐AD initiative.

Result

The resulting heterogeneous meta‐network is comprised of protein‐coding genes annotated with differential abundance in AD, readouts on more than 1000 metabolites and a large set of AD biomarkers and related phenotypes. Genes, proteins, metabolites, and AD phenotypes are interconnected by more than one million statistical links, including genetic and phenotype associations as well as gene/metabolite coexpression and co‐regulation data. We provide access to this comprehensive resource through an intuitive web‐interface, along with interactive visualizations and query and analysis tools of phenotype‐associated multi‐omics subnetworks.

Conclusion

The AD Atlas is a comprehensive and intuitive framework that facilitates the integration, exploration, and exploitation of large‐scale multi‐omics data. Applications of this resource include the network‐based identification of multi‐omics modules centrally linked to AD pathogenesis, followed by the prioritization of identified potential therapeutic targets for AD.
Circulating cell‐free DNA of mitochondrial origin connects cognitive and physical decline in aging and is associated with increased mortality
Authors: Nidadavolu Lolita S. , Feger Danielle M. , Gross Alden L. , Bennett David A. , Walston Jeremy , Abadir Peter , Oh Esther S.
Published: December 2020

Background

Mitochondrial dysfunction and subsequently impaired energetics triggering cell death have been observed in both dementia and frailty. Cell death releases circulating cell‐free DNA (ccf‐DNA) from mitochondrial (ccf‐mtDNA) and nuclear (ccf‐nDNA) sources. Size and relative abundance of ccf‐mtDNA fragments is suggestive of mechanism of cell death; long ccf‐mtDNA fragments originate from cell necrosis and short ccf‐mtDNA fragments from apoptosis. Our hypothesis is that in aging there is common pathophysiology contributing to development of physical and cognitive decline and that ccf‐mtDNA are potential mediators of these changes.

Method

Using ultra‐sensitive digital PCR, mitochondrial and nuclear ccf‐DNA was measured in serum from community‐dwelling individuals from the Rush Alzheimer’s Disease Center Religious Orders Study/Rush Memory and Aging Project (median age 80.4, N = 670). Multiple regression analysis, adjusting for age, sex, race and education, associated ccf‐DNA with cognitive and physical measures, including neuropsychological testing and frailty including hand grip strength.

Result

Higher levels of short ccf‐mtDNA fragments were associated with lower global cognitive scores, with a 0.09 decrease in global cognitive score per one copy increase in short fragment (p < 0.05). Higher levels of short ccf‐mtDNA normalized to serum ccf‐nDNA (ccf‐mtDNA/ccf‐nDNA) was associated with increased mortality (hazard ratio HR = 1.11) Longitudinal analysis demonstrated higher levels of long ccf‐mtDNA fragments at baseline was associated with greater frailty over time, with frailty score increasing 0.21 per year for every one copy increase in long fragment (p< 0.05). Cross‐sectional analysis demonstrated higher integrity ratio, defined as long ccf‐mtDNA relative to short ccf‐mtDNA, associated with increased handgrip strength (β= 0.14; 95% CI 0.01 – 0.26; p<0.05). Integrity ratio was associated with 0.14 increase in global cognition and 0.12 decrease in frailty score per increase in integrity ratio.

Conclusion

Mitochondrial dysfunction is a primary theory of aging and we demonstrate that quantity and relative size of ccf‐mtDNA are associated with cognitive and physical trajectories over time. This study highlights the utility of ccf‐mtDNA fragments in identifying and risk stratifying older patients who are more likely to develop frailty and dementia. Further directions include identifying mechanisms by which ccf‐mtDNA fragments are generated and regulate downstream pathways.