bluuebunny/crossref_metadata_2025 huggingface dataset:
Chaperone interventional therapy restores proteostasis, improves cognition and increases ADAM10 in young and aged APP knockin mice
Authors: Hafycz Jennifer , Strus Ewa , Naidoo Nirinjini
Published: December 2023

Background

Two distinct phenotypes of Alzheimer’s disease are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant Aβ production. The UPR is a signal transduction pathway activated in the endoplasmic reticulum (ER) at the onset of proteostatic stress. With age the UPR is less efficient and the expression of the key regulator, the chaperone BiP / Hspa5, also declines. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock‐in mouse model of AD and several small molecule chaperone supplementation paradigms, including an early and late‐stage intervention.

Method

Transgenic APP knock‐in mice were used as a model for AD. Two groups of mice and their wildtype littermates, (treatment starting early at 1‐2 mos old and late at 12 mos old) were administered the chemical chaperone 4‐phenyl butyrate (PBA) by weekly I.P. for 10 weeks. Controls were given I.P. injections of sterile saline. After 10 weeks of PBA or saline treatment, mice were subjected to the Spatial Object Recognition (SOR) cognitive tasks. A third group of APP knock‐in mice and wildtype littermates were given stereotaxic local hippocampal AAV‐BiP overexpression or AAV‐mCherry control injections. Following recovery and viral expression, mice were subjected to the SOR test. All mice were perfused, and tissue was collected for both immunohistochemistry and biochemical analyses.

Result

PBA treatment improved performance in the SOR test both with early and late‐stage PBA interventions. AAV‐BiP overexpression recapitulated those results. Histological data indicates that chaperone treatment, both with PBA injections and AAV‐BiP overexpression, reduced hippocampal ER stress and was correlated with increased pCREB. Chronic PERK activation which leads to inhibition of protein translation was reduced, while XBP1s levels were increased with chaperone treatment. This was coupled with increased ADAM10, which is associated with non‐amyloidogenic cleavage of APP

Conclusion

Reducing proteostatic stress even at a late age improves cognition in a mouse model of Alzheimer’s disease. The implications of these results could have an impact on the development of therapies to inform the development of potential treatments for Alzheimer’s disease.
Therapeutic Modulation of WASH Complex‐Retromer Interactions is a Novel Target for Alzheimer’s Disease (AD)
Authors: Yilmaz Gokhan Nathan
Published: December 2023

Background

Alzheimer’s Disease (AD), the most common form of dementia among the elderly, is characterized by the progressive decline of cognitive function. Although production and accumulation of amyloid beta (Aβ), particularly soluble Aβ oligomers, is central to the pathogenesis of AD, monoclonal antibodies targeted against the Aβ oligomers have failed to modify the disease progression clinically despite confirmed target engagement. Here we present, characterization of 3xTg‐AD mouse model treated with an engineered recombinant tandem protein consisting of a WASH complex member FAM21 linked with Retromer complex member VSP35 in order to stabilize these intrinsically disordered proteins. In addition, we present complete rescue of autophagic flux deficiencies and lipid accumulation phenotypes seen in iPSCs (from non‐familial AD patients)‐derived neurons and microglia with this therapeutic tandem protein. We will discuss our findings as a novel disease modifying treatment for Alzheimer’s Disease.

Method

By using proteomics, biochemical analysis and iPSCs‐derived neurons and microglia, we have characterized a recombinantly produced fusion protein’s (FAM21/VPS35) utility in reduction of the accumulation of soluble amyloid β oligomers; resolution of autophagic flux deficiencies and misfolded protein burden and neural degeneration in vitro and 3xTg‐AD in vivo model of AD.

Result

Treatment of 3xTg‐AD mice and iPSCs‐derived neurons and glial cells with a novel recombinant therapeutic protein resulted in a statistically significant reduction of accumulation of soluble amyloid Aβ oligomers and neural degeneration; reversal of autophagic flux and lipid deregulation.

Conclusion

Therapeutic modulation of WASH Complex‐Retromer interactions merits further analysis especially in early AD & mild cognitive impairment for its potential neuroprotective and disease modifying effects.
CSF SNAP‐25 Correlations with Synaptic Density by [11C]‐UCB‐J‐PET Imaging and AD Biomarkers
Authors: Wilson Rachael E , Jonaitis Erin M. , Langhough Rebecca E , Betthauser Tobey J , DiFilippo Alexandra H , Christian Bradley T. , Okonkwo Ozioma , Bendlin Barbara B , Chin Nathaniel A. , Carlsson Cynthia M , Asthana Sanjay , Johnson Sterling C , Zetterberg Henrik
Published: December 2023

Background

Synaptic dysfunction occurs prior to neuronal loss in the early stages of AD. A biomarker reflective of these changes could indicate AD before clinical manifestations. SNAP‐25 is a potential candidate, but the relationship between SNAP‐25 and established AD biomarkers is unclear. Further investigation is needed to determine the utility of this biomarker during the pre‐clinical phase.

Method

SNAP‐25 was measured using the Quanterix Single molecule array platform. A partial validation was conducted to evaluate assay performance in CSF and EDTA plasma. A cross‐sectional pilot study was then performed by measuring SNAP‐25 in CSF from 54 participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Research Center (WI‐ADRC) cohorts. SV2A synaptic density was measured in each participant using [11C]‐UCB‐J‐PET. Amyloid and tau status was determined in a subset of the group using [11C]‐PiB (N = 52) and [18F]‐MK6240‐PET (N = 44), respectively. Additional CSF biomarkers (Aß42, pTau‐181, and tTau) were measured using the Roche Cobas e601 Elecsys platform. A confirmatory study was performed with 80 additional WRAP and WI‐ADRC participants (53A+, 27 A‐). These participants did not have [11C]‐UCB‐J‐PET imaging.

Result

The SNAP‐25 assay demonstrated excellent precision (<5% CV), recovery (96‐101%), and linearity in CSF. Plasma SNAP‐25 levels were detectable but inconsistent, suggesting matrix interference. In the pilot study, SNAP‐25 was highly correlated with CSF pTau‐181 and tTau (Figures 1A, 1B). SNAP‐25 was not correlated with CSF Aß42 (Figure 1C). A modest but significant correlation was observed with amyloid PET in the pilot study (Figure 2A) but not in the confirmatory study (Figure 3). SNAP‐25 did not correlate with SV2A density (Figure 2B) or fibrillary tau (Figure 2A). Mean SNAP‐25 levels were significantly different between amyloid‐ and tau‐positive groups compared to biomarker negative controls (p < 0.001 for amyloid, p < 0.05 for tau). Similar trends were observed in the confirmatory study (Figure 3).

Conclusion

These results demonstrate a close relationship between SNAP‐25 and soluble tau in CSF, suggesting that CSF SNAP‐25 reflects early Aß‐induced neuronal impairment in a way that correlates with tau pathophysiology. This indicates that SNAP‐25 could be a useful biomarker of early neurodegeneration in pre‐clinical AD.
Impaired ability to smile in Alzheimer’s disease is associated with reduced brain volume of nucleus accumbens and pallidum, revealed by artificial intelligence
Authors: Iizuka Tomomichi , Kameyama Yumi Umeda , Fukasawa Makoto , Akishita Masahiro , Kameyama Masashi
Published: December 2023

Background

Patients tend to lose the ability to smile during the clinical course of dementia. However, details of such impairment remain obscure presumably due to difficulty of quantifying facial expression. Feature extraction is now automated as a result of recent developments in artificial intelligence (AI). The authors applied a model to quantify impaired smile expression in patients with Alzheimer disease (AD). The relationship between the expression of a smile and subcortical volumes was also investigated.

Method

This study included 280 and 190 participants with AD and with normal cognition (NC), respectively. The faces of the participants were photographed as they smiled or maintained a neutral expression. Subcortical brain volume was assessed in 210 and 90 of those with AD and NC, respectively, using MRI and the FSL‐FIRST algorithm. Datasets of the photographs were prepared with combinations of smiling and neutral expression in NC and AD, smiling in AD and NC, and neutral expression in AD and NC, then binary discrimination proceeded using the VGG‐Face convolutional neural network (CNN).

Result

The accuracy of discriminating a smile from a neutral expression was of 92.3% in NC, and 61.2% in AD, indicating that a considerable proportion of patients with AD have difficulties forming a natural smile. 48.5% of smile AD were classified as negative in NC dataset. The smile/neutral‐NC scores for AD were robustly associated with the volume of the bilateral nucleus accumbens (right, r = 0.51, p = 2.59 × 10−15; left, r = 0.493, p = 2.89 × 10−14) and the bilateral pallidum (right, r = 0.266, p = 0.0000981; left, r = 0.256, p = 0.000174). The accuracy of discriminating between AD and NC was 95.2% with smile and 90.1% with a neutral expression, respectively (p = 0.0045). The neutral‐AD/NC score inversely correlated with the results of the MMSE (p = 1.62 × 10−7), but not with smile/neutral‐NC or smile‐AD/NC scores.

Conclusion

The ability to form smile was impaired in AD and associated with nucleus accumbens and pallidum shrinkage. Such impairment enhanced the accuracy of facial discrimination between AD and NC, whereas a neutral expression was associated with cognitive function.
Amyloid‐β precursor protein facilitates spreading of tau pathology in Alzheimer models
Authors: van Eersel Janet , Przybyla Magdalena , Genoud Sian , Fath Thomas , Ke Yazi D. , Ittner Lars M.
Published: December 2023

Background

Spreading of tau pathology between connected brain regions correlates with disease progression in Alzheimer’s disease (AD) and gives rise to distinct neuropathological stages. While seeding and spreading of tau pathology has been reproduced in cell and animal models, the understanding of the molecular pathways mediating tau spread remains limited. Binding of tau fibrils to the extracellular region of the Amyloid Precursor Protein (APP) was reported to result in the uptake of tau in a cell culture model. This raised the question whether APP may function as a tau fibril receptor during the trans‐neuronal spread of tau pathology in vivo, thereby contributing to disease progression.

Method

To study the effect of APP expression on tau spread we (1) injected APP KO mice with human AD brain extracts and analysed induction of tau pathology; (2) expressed an AAV‐based reporter construct in APP KO and KI mice and analyse tau spread; (3) cultured APP KO primary neurons in microfluidic devices and analysed tau spread (4) stimulated brain slices and primary neurons from APP KO and KI mice and analysed tau release.

Result

(1) AD brain extracts failed to induce tau pathology in APP KO mice; (2) APP KO mice showed reduced spreading of AAV‐dependent expression of human tau, whereas mutant human APP mice showed increased spread of tau; (3) spread of tau between connected neurons was reduced in microfluidic devices containing APP KO neurons compared to wild type neurons; (4) brain slices and primary neurons from APP KO mice showed reduced tau release after neuronal stimulation, whereas tissue from mutant human APP mice showed increase release of tau.

Conclusion

APP facilitates neuronal release and spreading of tau. This process is augmented by pathogenic APP mutations and increased APP levels, and reduced in the absence of APP. Our data suggest APP as an integral part of spreading of tau pathology and delineates a novel role for pathogenic APP mutations in AD.
Childhood dementia: the collective impact and opportunities for intervention
Authors: Elvidge Kristina L , Christodoulou John , Farrar Michelle A , Tilden Dominic , Maack Megan , Valeri Madeline , Ellis Magda , Smith Nicholas JC ,   Childhood Dementia Working Group
Published: December 2023

Background

Childhood dementia is a devastating and under‐recognised group of conditions with a high level of unmet need. Typically monogenic in origin, this collective of neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in infancy, childhood or adolescence.

Method

We undertook a scoping review and burden of illness study to understand the spectrum of childhood dementia conditions and their impact. A literature review identified conditions that met the case definition and an expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective incidence, prevalence and life expectancy were modelled.

Result

Over 140 individual genetic conditions were identified that can be consistently defined as childhood dementia with the largest proportion of births belonging to the lysosomal disease and mitochondrial disease categories. Collectively the incidence is surprisingly high at 1 in 2,900 births and the life expectancy is low, with most affected children not surviving into adulthood. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/).

Conclusion

This scoping review highlights the importance of grouping these conditions as a phenotypic syndrome, rather than individually rare diseases, in keeping with the approach to adult dementia. Opportunities exist to address overlapping disease mechanisms and utilise therapeutic platforms for multiple childhood dementia conditions to tap into significant economies of scale. Collaboration with adult dementia researchers on common disease attributes is also expected to be mutually beneficial.

By unifying these conditions, we have highlighted the many unmet needs of this significantly disadvantaged group of children and young people and the data presented here will enable advocacy for systemic change in treatment, care, and support for them and their families.
Human Herpes Simplex Virus‐1 Encoded ICP27 Promotes the Alternative Splicing of MAPT Resulting in increased 4R Ratios within Cells of Neuronal Origin
Authors: Miller Michael , Czajka Timothy , Ijezie Emmanuel , D'Brant Lianna , Jarvis Ava , Butler David , Murphy Eain Anthony
Published: December 2023

Background

Familial linked Alzheimer’s Disease (AD) accounts for a small percentage of current cases, with the remaining caused by unknown etiologies. Independent of causation, AD is defined by three common characteristics: inflammation, extracellular b‐amyloid aggregation and intracellular Tau accumulation. Human herpes simplex virus 1 (HSV‐1), a neurotropic virus found in ∼50% of the population, was recently linked to AD progression in clinical samples and animal models. HSV‐1 infections induce inflammation and APP cleavage producing Ab42, but a role for viral‐mediated Tau accumulation has not been defined. In healthy brains, alternative splicing of MAPT, the gene encoding Tau, results in equimolar ratios of 3R and 4R isoforms of Tau protein. However, in AD tissues, unequal ratios of either 3R or 4R results in Tau microtubule disassociation, hyperphosphorylation and aggregation. Host factors that regulate MAPT alternative splicing include SRPK1. Interestingly, HSV‐1 encodes a protein, ICP27, that impedes the SRPK1 functions. Thus, we hypothesized that
HSV‐1 infections alter MAPT neuronal splicing resulting in altered 3R/4R Tau ratios in an ICP27 dependent fashion
.

Method

We used infection with WT and mutant HSV‐1 and ectopic ICP27 expression to monitor MAPT splicing in iPSC‐derived 3D cortical organoids and 2D neuronal models.

Results

We observed that 3D cortical organoids infected with HSV‐1 accumulate phospho‐Tau and increase MAPT 4R mRNA splicing. HSV‐1 infection of neuronal SHSY‐5Y cells, results in a significant increase in 4R isoform relative to 3R, which we did not observe when we infected these cells a virus that lacks ICP27 expression, suggesting that this viral protein is
necessary
for the altered splicing. Further, using lentiviruses that express either wild‐type ICP27 or a mutant ICP27 that lacks the SRPK1 interaction domain, we observed increased 4R splicing only with the wild‐type protein, revealing that ICP27 is
sufficient
for modulating Tau isoforms and that the SRPK1 domain is required. Finally, we found that levels of 4R splicing was increased within infected astrocytes, thus underscoring the impact HSV‐1 imparts on cells of both neuronal and non‐neuronal origin.

Conclusion

In sum, our findings reveal the remaining critical third link in how neurotropic human herpesviruses can impact and influence AD progression.
The association between microbiome and white matter integrity in the elderly with youthful memory in superaging
Authors: Kim Bori.R. , Kim Geon Ha , Jeong Jee Hyang
Published: December 2023

Background

Aging‐related cognitive decline has been regarded as a normal consequence of aging. However, previous research on ‘SuperAgers’ suggests that such decline is not inevitable. The purpose of this study was to investigate the relationship between the microbiome and white matter integrity in SuperAgers, which may help us understand the mechanism that preserves memory function in these individuals.

Method

We enrolled a total of 115 elderly individuals aged 60 years or older with normal cognitive function, which was defined as scoring one standard deviation or more above the population norm on tests of memory, attention, language, visuospatial ability, and frontal function in the Seoul Neuropsychological Screening Battery. SuperAgers were defined based on their delayed recall scores compared to middle‐aged adults (45 years old) in both the Seoul Verbal Learning Test and the Rey‐Osterrieth Complex Figure Test. Diffusion tensor images were analyzed using tract‐based spatial statistics (TBSS). Parameters related to diffusion tensors were calculated at the voxel level to generate fractional anisotropy (FA) images using the DTIFit. FA values, a diffusion tensor parameter reflecting white matter fiber tract integrity, were measured and compared between SuperAgers and typical agers using the FSL randomise program. For microbiome analysis, EZ biocloud was used to perform alpha diversity, taxonomic hierarchy, and taxonomic composition analysis for each subject analysis. Group analysis was also conducted using the taxonomic composition values, and further group analysis was carried out using ACE, Chao1, and Jacknife, which are indicators of species richness. Statistical analyses were conducted using Statistical Package for Social Science 19.

Result

Compared to typical agers, superagers showed a higher number of Firmicutes and Actinobacteria, which have been associated with higher cognitive function. However, there was no significant difference between superagers and typical agers. Additionally, an analysis of the association between p_firmicutes, c_mollicutes, o_lactobacilales and f_erysipelotrichaceae with white matter integrity showed no significant association.

Conclusion

Based on these results, it can be inferred that superagers may have a correlation with microbiome strains that are closely related to cognitive function, as well as white matter in the brain
Iron homeostasis alters neuro inflammation response during AD white matter degeneration: A HFE + APOE4 genetic study
Authors: Pang Ran
Published: December 2023

Background

The HFE gene involves regulation of iron metabolism that directly participates in white matter (WM) myelination and neuroinflammations processes, while ApoE4 mutation are known to affect normal myelination through disruptions of iron and lipid metabolisms. Taken together, it is important to investigate the collective effects of HFE and the ApoE4 mutations, focusing on iron metabolism and neuronal inflammation during AD WM degeneration.

Method

Diffusion tensor imaging (DTI) MRI, cognitive and CSF biomarkers (sTREM2, Tau, Abete42) data were collected from ADNI database in the AD cohorts of ApoE4 carriers with and without HFEH63D polymorphism. Multivariate analysis with AMOS in SPSS software was used to establish and validate directed correlations using structural equation models (SEM).[1]

Result

Prominent WM degeneration in AD is significantly attenuated in HFEH63D carriers (Fig.1). The negative and indirect correlation between HFEH63D genotype and CDR‐cog (Fig. 2) suggests a protective role by HFEH63D mutation on WM degeneration and cognitive decline in AD ApoE4 carriers. As indicated by the negative and direct correlation between sTREM2 and CDR‐cog, such a protective role during AD aging is likely due to the reduced neuroinflammation in the HFE polymorphism cohorts.

Conclusion

Unified multivariate analysis with SEM allowed us to establish directed/causative relationships between genotyping and AD neurodegeneration‐to‐cognitive‐decline within the ATN framework. Our SEM analysis demonstrated that the protective role in ADApoE4 carriers may involve in attenuated neuroinflammation by the altered iron management by HFEH63D polymorphism.

Ref.

[1]. Bagozzi, R. and Yi, Y. (1988) On the Evaluation of Structural Equation Models. Journal of the Academy of Marketing Sciences, 16, 74‐94. https://doi.org/10.1007/BF02723327
Calcineurin inhibition prevents hippocampal synaptic plasticity impairment induced by brain‐derived tau oligomers via modulation of the transcriptome
Authors: Scaduto Pietro , Kayed Rakez , Taglialatela Giulio
Published: December 2023

Background

Cognitive decline in Alzheimer’s disease (AD) strongly correlates with tau protein accumulation, with the most toxic species being in form of oligomers [1,2]. Due to the polymorphism of tau oligomers, isolating and testing brain‐derived tau oligomers (BDTO) directly from AD patients could provide new insights into tau toxicity. BDTO are potent inhibitors of long‐term potentiation (LTP) in hippocampal brain slices [3], however the involved mechanism is still not fully understood. We previously reported significantly reduced incidence of AD in aging humans chronically treated with a FDA‐approved calcineurin inhibitor, FK506, used as immunosuppressant after solid organ transplant [4]. Here we show that impairment of the synaptic functionality driven by BDTO is restored by calcineurin inhibition using FK506 via selective transcriptomic changes.

Method

Combination of electrophysiological and RNA‐seq techniques were used. Ex‐vivo slices from 8‐12 weeks old C67BL/6J mice were treated with aCSF (Ctrl), BDTO (100nM) or BDTO+FK506. Field excitatory post‐synaptic potentials (fEPSPs) recordings were performed by stimulating the Schaffer collateral pathway, and recording electrode was located at the junction of the alveus and cornu ammonius 1 (CA1). After electrophysiological recordings, the hippocampus was isolated from the brain slice, snap frozen and processed for RNA‐seq.

Result

FK506 treatment significantly ameliorated the BDTO‐induced attenuation of fEPSP. One‐way ANOVA followed by Tukey’s test, showed that BDTO caused reduction of fEPSP compared to Ctrl (p = 0.068). fEPSP was re‐established at physiological levels in the group BDTO+FK506 (vs Ctrl p = 0.603; vs BDTO p = 0.0163). A similar trend was observed when we analyzed the paired‐pulse ratio. Analysis of the transcriptome showed that FK506 modulates key synaptic transcripts impaired after BDTO treatment.

Conclusion

Our study provides evidence that FK506 has the potential to block the BDTO toxic effect on synaptic plasticity. These results suggest that FK506 may represent a promising therapeutic strategy for the treatment of AD. Further research is needed to elucidate the precise molecular mechanisms underlying FK506‐mediated neuroprotection and to explore its potential in in vivo models of AD.

References: [1] PMID: 27105663, [2] PMID: 28420982, [3] PMID: 23050084, [4] PMID: 26401556

Founding: NIH/NIA R01‐AG060718
Referral Patterns From Primary Care Clinicians to Specialists Among People With Cognitive Impairment Disorders, including Alzheimer’s Disease
Authors: Mearns Elizabeth S , Patel Anisha M , Jinnett Kimberly , Gaur Abhishek , Cobb Bryan R , Macaluso Christine J , Weiss Jonathan , Seleri Sheila , Win Nikki
Published: December 2023

Background

A timely and accurate diagnosis of Alzheimer’s disease (AD) can optimize treatment outcomes; however, few people are referred to a specialist for reasons that are not well understood. The objective of this study was to evaluate referral to a specialist by a primary care clinician (PCC) or other healthcare provider (HCP) among people diagnosed with cognitive impairment disorders, including AD (CIDiAD).

Method

This retrospective cohort study analyzed claims data from the Optum de‐identified Normative Health Information database between 1/1/2016‐31/12/2021 (study period). Adults were required to have ≥2 ICD‐9/10‐CM diagnosis codes for AD from any provider during the study period. The index event was defined as the first CIDiAD diagnosis (Table 1) from a PCC or other HCP before or on the date of their diagnosis during the identification period (1/1/2017‐31/12/2020) (Table 2). Continuous medical enrollment was required in the pre‐ and postindex periods. No diagnoses of CIDiAD in the pre‐index period were allowed. People with a post‐index diagnosis of AD from a specialist comprised the referral cohort. Time to specialist referral was assessed, and characteristics of people who were or were not referred were summarized.

Result

A total of 48,525 people with a CIDiAD diagnosis from a PCC or other HCP were included; of these, 13,074 (26.9%) were referred to a specialist. The overall median (IQR) time to first specialist visit was 10.0 (3.2‐20.7) months. Time to first specialist visit was longer for referrals from PCCs compared with those from other HCPs (10.8 [3.8‐21.6] vs 9.2 [2.8‐19.9] months, respectively; P<0.0001). No notable differences in sex, age, race and ethnicity, or geographic region were observed between people who were referred and those who were not (Table 3).

Conclusion

The majority of people with CIDiAD were not referred to a specialist. Among people who were referred to a specialist, time to first visit was long. Approval of disease‐modifying therapies may accelerate referral to a specialist and shorten referral times as early diagnosis of AD becomes more important. Further analyses will inform geographic differences in specialist referral patterns.
FTIR analysis of neuronal‐like cells upon Aβ exposure
Authors: Vaz Margarida , Martins Tânia Soares , da Cruz e Silva Odete , Nunes Alexandra , Henriques Ana Gabriela
Published: December 2023

Background

The Aβ peptide is a key player in Alzheimer´s disease (AD) pathogenesis, tending to aggregate into oligomers and fibrils, and finally senile plaques; a major hallmark in AD brains. This peptide is extremely toxic to neurons, triggering several mechanisms, that ultimately inducing neuronal death. Brain metabolic alterations are also closely linked to disease pathogenesis. In this work, the effect of Aβ in the spectroscopic profile of distinct neuronal‐like cell lines was analyzed using Fourier Transform Infrared (FTIR) spectroscopy.

Method

Two neuroblastoma cell lines, human derived SH‐SY5Y and mouse derived N2a, were treated with 10 µM of Aβ25‐35 peptide for 48 h. After treatment, cells were detached, samples containing 1×105 cells were prepared and immediately frozen until FTIR analysis. Prior to analysis, cells were resuspended in PBS and FTIR spectra was acquired. Data was analyzed by partial least squares (PLS) multivariate analysis or using univariate approaches for the calculation of peak areas associated with the fingerprint region (1200‐900 cm−1). This corresponds to a spectral region assigned mostly to carbohydrates and nucleic acids.

Result

PLS analysis of the fingerprint region showed a clear discrimination between the spectra of control and Aβ‐treated cells. The univariate analysis for the peak areas of this spectral region also presented significant differences between the two groups, for both cell lines.

Conclusion

The spectroscopic profile of the two neuronal‐like cell lines was altered in response to Aβ treatment, particularly in the fingerprint region, supporting the contribution of this peptide to metabolic changes that can potential underly AD pathogenesis.

This work was funded by Instituto de Biomedicine (iBiMED) under Grant UIDB/04501/2020 and UIDP/04501/2020; MV is supported by the individual PhD grant UI/BD/151354/2021.
Brain vasculature influences local tau accumulation in the human inferior temporal gyrus
Authors: Hoglund Zachary T , Zwang Theodore J , Woost Benjamin , Bailey Joshua J , Hyman Bradley T. , Bennett Rachel E
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disease that involves the accumulation of pathological tau protein. While the mechanisms behind tau accumulation are not well understood, they are pivotal to understanding the pathogenesis of AD. Because protein clearance in the brain is mediated in part by vasculature, we hypothesize that vasculature may direct the accumulation and distribution of tau pathology. In this study, we analyzed the spatial relationship between tau distribution and vasculature to elucidate vasculature’s role in tau clearance.

Method

Post‐mortem human tissue samples (∼1 cm3) from the inferior temporal gyrus of 6 AD and 6 control donors were sliced at thicknesses of 500 µm to 1 mm. Tissue slices were prepared with tissue clearing. Cleared samples were stained with antibodies for tau (AT8), vasculature (GLUT1), nuclei (DAPI), and neurons (HUD). Images were collected using confocal fluorescence microscopy. A virtual reality tracing method was developed to segment individual blood vessels across large tissue volumes and 12‐21 individual vessels were isolated in each sample. Novel MATLAB scripts were developed to calculate the intensity of tau as a function of distance from the blood vessels’ surfaces.

Result

In AD samples, tau intensity varied along the length of the blood vessel and with distance from the blood vessel surface. Regions with high tau accumulation on the blood vessel surface exhibited elevated tau accumulation in the surrounding tissue. In regions with low tau accumulation on the blood vessel surface, tau intensity was observed to decrease near the vessel. The influence of blood vessels on tau intensity dissipated as distance from the vessel surface increased, where tau intensity approached the bulk value (average tau intensity across the entire image). Compared to AD samples, control tissue showed little AT8+ tau labeling and the relationship between tau and distance from blood vessels was not apparent.

Conclusion

These results indicate that pathological tau accumulation is spatially related to blood vessels in AD. In addition, these data imply that blood vessels contribute to tau clearance and that vascular tau clearance is disrupted in regions with high tau accumulation.
Early identification of Alzheimer’s risk using anatomically interpretable estimation of brain age
Authors: Imms Phoebe , Kawamura Jaron , Yin Chenzhong , Amgalan Anar , Chowdhury Nahian F , Chaudhari Nikhil N , Irimia Andrei
Published: December 2023

Background

Neuroanatomical aging patterns can be revealed by examining the discrepancy between brain age (BA) and chronological age (CA) – also known as age gaps (AGs). Older than expected BAs, as estimated using deep learning of magnetic resonance images (MRIs), are observed in patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) (Tseng et al., 2022). Our 3‐dimensional convolutional neural network (3D‐CNN) enhances the accuracy of BA estimation and employs saliency mapping to explore structural patterns of aging between persons with and without CI.

Methods

MRIs and neurocognitive measures for 6,561 participants (5,851 cognitively normal ‘CN’, 351 MCI, 359 AD) were collated across online repositories (Downey & Peakman, 2008; Petersen et al., 2010; Van Essen et al., 2012). We constructed a deep learning regression model using a 3D‐CNN whose inputs are pre‐processed MRIs (Fischl, 2012) and whose outputs are estimated BAs and saliency maps (Yin et al., 2023). Spearman rank correlations between neurocognitive measures and BA and CA were calculated, then compared using Fisher’s z‐test. The ability of AGs to predict conversion from MCI to AD was examined using logistic regression.

Results

In participants with CI, older BA (but not CA) is significantly correlated with worse neurocognitive function across all measures except delayed verbal recall and logical memory (Table 1, Fig 1). AGs are positively associated with MCI participants’ probability of conversion to AD (β = 1.417, t
343 = 2.240, p = 0.025). Saliency maps reveal that, in CI participants, the 3D‐CNN relies more on features of the cerebral white matter, the brainstem, medial aspects of the temporal lobes, and the caudal portions of the anterior cingulate when estimating age according to cognitive status (Fig 2).

Conclusions

Compared to CA, our BAs are significantly more strongly associated with early signs of Alzheimer’s disease, possibly reflecting disease‐related structural alterations. Saliency maps conveying the importance of each brain region for estimating BA reveal differences in patterns of neurological aging between persons with and without CI. Our BA estimation tool enhances the interpretability of such models, potentially improving the ability to stratify people according to risk of CI.
Genetics and diet explain sex differences in glucose metabolism and cognitive function
Authors: Litkowski Elizabeth M , Dai Miko , Dunn Amy R , Bridges Dave , O'Connell Kristen MS , Kaczorowski Catherine C.
Published: December 2023

Background

Diabetes and cognitive impairment occur together more often than would be expected by chance [1–6]. Individuals diagnosed with type 2 diabetes have a 1.4–2.2‐fold higher risk of dementia than those without diabetes [2,6,7]. Epidemiological research has demonstrated shared risk factors, metabolic disorders, and comorbidities[5,8], shared genetics[9], and evidence of causality assessing glycemic traits [4,10–12]. We set out to determine how glucose metabolism modifies normal aging‐related cognitive decline in comparison to Alzheimer’s Disease (AD)‐related decline, given genetic diversity and controlled diet (GxD).

Method

We studied an innovative, genetically diverse mouse population (AD‐BXDs, Fig. 1) to determine GxD effects on metabolic function and the transition to cognitive impairment [13]. The data were collected longitudinally from a cohort of ∼650 AD‐BXD mice (39 unique strains) fed either a low‐fat chow diet or a high‐fat, high sucrose diet (HFD:45% fat,17.5% sucrose). Glucose metabolism was assessed by measuring the area under the curve of an intraperitoneal glucose tolerance test (IPGTT). In general, faster clearance of glucose (smaller area under the curve) reflects better glycemic control. Contextual fear memory (CFM) at 6 and 14 months of age was the measure of cognitive function. We used multivariable linear regression to model the relationship between overall CFM and an IPGTT by strain effect.

Result

We found that there was heterogeneity in IPGTT by sex, strain, and diet, accounting for more than 50% of the variation explained (Fig. 2). Females generally exhibit faster glucose metabolism than males (Fig.2, left), while the magnitude of the effect of sex and diet on IPGTT differs by strain (Fig. 2, x‐axis). For our research question of how glucose metabolism affects cognitive function, we identified strains that exhibited resilience to cognitive dysfunction as predicted by their glucose metabolism, with a broad‐sense heritability of 0.81 (Fig. 3). These early findings establish a foundation to identify quantitative trait loci (QTLs) and GxD‐type QTLS based on glucose tolerance and cognitive function associations.

Conclusion

By examining the effect of diet on AD‐BXD strains and incorporating metabolic measures associated with diabetes, we will be able to evaluate and validate cause in these relationships for the first time.
Vascular contribution to the relationship between cerebrovascular reactivity and cognition
Authors: Kim Donghoon , Hong Sarah Y. , Hughes Timothy M. , Lipford Megan E. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D , Whitlow Christopher T , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina , Bobinski Matthew , Jung Youngkyoo
Published: December 2023

Background

Brain vascular health is closely related to cognitive performance, and cerebrovascular reactivity (CVR), an indicator of cerebral blood flow (CBF) compensatory capacity in response to vasoactive stimuli, may help elucidate this relationship. Arterial spin labeling (ASL) and blood‐oxygen‐level‐dependent (BOLD) are two representative methods for measuring CVR, although BOLD is a complex combination of CBF, cerebral volume, and cerebral metabolic rate of oxygen. This study aimed to investigate the relationship between cognition and two different CVR methods.

Method

Seventy‐nine subjects (age: 68.7±7.2 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including both dynamic pseudo‐continuous ASL (PCASL) under a hypercapnic respiratory challenge and multi‐TI PCASL for resting CBF and ATT mapping. The dynamic PCASL with a longer TE (20ms) provided simultaneous acquisition of ASL and BOLD. CVR was obtained by calculating CBF or BOLD signal changes during a hypercapnic period. Voxel‐wise multiple linear regression analyses were performed to examine the relationship between CVR and mild cognitive impairment (MCI), adjusting for age, sex, glycemic status, APOE e4 allele, hypertensive status, and years of education. False positive cluster thresholding was applied for each modality. Additional statistical analyses were conducted to investigate differences in baseline CBF and ATT between cognitively healthy and MCI groups within the voxel clusters that showed significantly different CVR values.

Result

In the BOLD‐based CVR analysis, two voxel clusters in the white matter (WM) of superior temporal and parietal lobes showed lower CVR in the MCI group compared to the cognitively healthy group (Figure 1). Additionally, reduced CBF and prolonged ATT were observed within the clusters (Figure 2 and 3).

Conclusion

Subjects with MCI exhibited lower BOLD‐based CVR in WM, while no association was found between ASL‐based CVR and MCI. BOLD‐based CVR may be a more sensitive measure than ASL‐based CVR in association with cognition, particularly in WM where optimization of ASL acquisition is challenging. The impaired CVR in the MCI group may be due to cerebrovascular impairments, such as reduced CBF and prolonged ATT.
Novel characterization of Alzheimer’s disease genetic loci using long‐read sequencing
Authors: Talozzi Lia , Chemparathy Augustine , Jensen Tanner D. , Gorzynski John , Belloy Michael E , Guen Yann Le , Kasireddy Nandita , Dailey Maddie , Stewart Ilaria , Ashley Euan , Greicius Michael D
Published: December 2023

Background

Alzheimer’s disease (AD) is up to 60‐80% heritable, but less than ∼20% is explained by studies analyzing single nucleotide variants (SNVs). One limitation of short‐read whole‐genome sequencing (SRS) is the standard read length of 150 base pairs, which does not enable the detection of longer structural variants (SVs). Here we sequenced individuals using long‐read sequencing (LRS), which can sequence reads with an average length of ∼20 kilobases, allowing us to identify SVs previously uncaptured.

Method

All participants underwent whole‐genome LRS (∼15x coverage) and a subgroup (84%) underwent SRS. Out of 576 participants (47% males, age = 70.6±7.9 y.o.), 115 were diagnosed with AD or mild cognitive impairment, 365 were healthy controls, and 96 were diagnosed with a synucleinopathy (either Parkinson or Lewy Body disease). Eighty‐three index SNVs from loci associated with AD risk through GWAS (Bellenguez et al., Nature Genetics 2022) were genotyped with 30x coverage SRS, in addition to APOE2‐4. A 1Mbp window was defined around these SNVs to construct the discovery range for SVs (Sniffles2 population mode). Linkage disequilibrium (LD) was assessed between SNVs and SVs (CubeX).

Result

A total of 14854 SVs were found across the AD risk loci (Figure1). After LD calculation, N = 197 SVs had a R2>0.1 (Figure2). The SVs with the highest LD (R2>0.7) are reported in Table1, among which there is a 322 bp deletion in the 3’ UTR region of the TMEM106B in high LD (R2 = 0.918) with the intronic SNV rs13237518. This TMEM106B locus has been previously associated with the risk of frontotemporal lobar dementia with TDP‐43 pathology in addition to AD, but the causative SNV has not been identified yet. This large deletion may mediate TMEM106B’s risk‐modulating role in AD and FTLD‐TDP (Chemparathy et al. medRxiv 2023). At the complex MAPT locus, three SVs showed a high LD with rs199515.

Conclusion

Insights into the role of SVs in neurodegenerative disorders have been hampered due to limitations with SRS. Using LRS in a large AD‐related sample, we characterized for the first time the genetic variation of SVs in known AD risk loci and provide a roadmap to identify potential causal SVs driving the AD association signal.
Hypertension predicts lower cerebral blood flow and fluid cognitive scores after a lipid challenge in older adults
Authors: Ashford Nathanial K , Miglani Jasroop K , Farris Kristen M , Levendovszky Swati Rane , Hanson Angela J
Published: December 2023

Background

Hypertension (HTN) is a modifiable risk factor for AD. We previously reported an association with high systolic blood pressure (SBP) and lower cerebral blood flow (CBF) using ASL MRI at AAIC 2022. Here we reproduce and expand on those findings in a new cohort of participants.

Method

After fasting, 29 older adults (age = 66.9±7.3, 20 females) underwent ASL MRI two hours after ingestion of 1/2 cup heavy cream to mimic an oral triglyceride tolerance test (OTTT). At three hours, participants underwent a cognitive assessment using the NIH Toolbox as well as several blood pressure assessments. We used 3D pCASL MRI with background suppression to measure CBF in ml/100g/min using label duration = 1.8 s, post‐labeling delay = 2 s, labeling offset = 25‐30 mm, slices = 30, resolution = 2×2×4 mm3, SENSE‐factor = 2, TR/TE = 5000/18 ms. Finally, we acquired a reference scan (M0, 1 minute) identical to the above scan but with TR = 10,000 ms and no labeling or background suppression. CBF was measured in AD‐vulnerable regions (posterior cingulate, temporal cortex, angular gyrus, and hippocampus). Statistical analyses included Pearson correlation using SAS Studio.

Result

Overall, SBP tended to drop at one hour following lipid drink and returned to baseline around 2‐3 hours; around 30% of participants had a higher SBP at 2 or 3 hours compared to fasting levels. Systolic but not diastolic blood pressure negatively correlated with global CBF as well as CBF in all four prespecified regions of interest, with strongest correlations at the 3‐hour time point. When the group was split into those with and without HTN (≥130), those with HTN scored lower on fluency composite of NIH Toolbox (110.5±4.3 vs 98.8±3.2, p = 0.037) whereas no differences were noted for the crystallized composite (125.3±4.6 vs 122±3.5, p = 0.58) or MoCA at screening visit (27.9±1 vs 26.7±0.8, p = 0.37).

Conclusion

Building on our pilot work, we continue to find a strong negative correlation between SBP and CBF. Individuals that met criteria for HTN after ingestion of lipids had lower fluid composite scores on NIH Toolbox, suggesting that maintaining a normal blood pressure helps prevent cognitive decline.
Comparative analysis of types according to activities and social participation of the Oldest‐old
Authors: Lim Young Myoung , Kim Ah‐Ram , Lim Seungju , Park Ji‐Hyuk
Published: December 2023

Background

Using the Korean Longitudinal Study of Ageing(KLoSA), we tried to classify the clusters according to the activity and social participation of the oldest‐old and analyze the differences in characteristics between the clusters.

Method

Data from 682 people aged 85 years or older were included in the analysis using the KLoSA cross‐sectional data. Data extracted factors related to demographic characteristics, activities of daily living, social participation, lifestyle‐related factors, and successful aging. Cluster analysis was conducted focusing on activity and social participation variables. A chi‐square test was performed to determine the differences between demographic characteristics and variables for successful aging between clusters. In addition, ANOVA and Welch’s robust were performed according to the homogeneity of variance, and Scheffe and Dunnett T3 were performed for post hoc analysis.

Result

As a result of Cluster analysis, ‘Active participation’ (4%), ‘Dependent daily life’ (27.1%), and ‘Passive participation’ (68.9%) were clustered. Differences in demographic characteristics between clusters showed high rates in all clusters for women, the level of education below elementary school, and the number of household members of 2∼4. For related‐factors to successful aging, cognitive, perceived health status, depression, and satisfaction of life all showed differences between cluster, and the active participation group showed the most positive results in the post‐hoc analysis.

Conclusion

The cluster according to the activities and social participation of the oldest‐olds confirmed the difference in the factors related to successful aging. This is significant in that it was an empirical analysis focused on successful aging for the older aged 85 years and over, and it can be used as a useful basic data for access to health promotion for the super‐aged society in Korea.