bluuebunny/crossref_metadata_2025 huggingface dataset:
AD Biological Domains—an evolving computational resource for big data classification in AD from the TREAT‐AD Consortium
Authors: Wiley Jesse C , Cary Gregory A. , Ganesh Sruthi , Levey Allan I. , Carter Gregory W , Greenwood Anna K
Published: December 2023

Background

Alzheimer’s disease (AD) is a highly heterogenous disease with a multitude of subtypes and interacting biological systems emerging in a complex pattern of pathology, neurodegeneration and cognitive decline. In order to help organize large scale data analysis in AD in an unbiased manner, we developed a computational model of endophenotypes associated with AD. We call these models the AD Biological Domains.

Method

The Common Alzheimer’s Disease Research Ontology (CADRO) was leveraged in association with literature mining to identify 19 parent endophenotypes that are largely sufficient to cover AD related pathology. These endophenotypes are instantiated as large sets of manually curated gene ontology (GO) terms and linked genes. This framework enables researchers to unambiguously move from an identified gene to a larger disease‐associated biological phenotype.

Result

We defined 19 biological domains in terms of constitutive sets of GO terms. A gene‐set enrichment analysis has confirmed that these 19 biological domains cover almost all AD‐enriched GO terms, barring those that fall outside the reach of the biological domains due to lack of specificity in biological implication. The size of the biological domains ranges from over a thousand GO terms for ‘Proteostasis’ and ‘Synapse’, and just over a dozen for the terms ‘APP Metabolism’ and ‘Tau homeostasis’. There is a low level of cross‐domain utilization of common GO terms, as the biological domains are effectively siloed in their definition, however, at the level of gene annotation we see high levels of promiscuity across domains, potentially providing a molecular trail to find interdependencies between domains. These biological domains are currently being used across several NIA‐funded consortia, including TREAT‐AD, AMP‐AD, MODEL‐AD, and have been adopted by partnered resources such as the AD‐Atlas and Agora. The full list of biological domains and associated GO terms and genes are openly accessible through the AD Knowledge Portal.

Conclusion

The biological domains are an open resource designed to provide a community driven definition of discrete areas of AD biology, allowing AD investigators to utilize a standard set of computationally accessible resources to define emerging transcriptomic and proteomic datasets in a unified manner, making cross study comparisons more informative.
Memory dysfunction in mild cognitive impairment (MCI) and early Alzheimer disease (AD) dementia is closely associated with synapse loss, and shows significant correlation with pathological tau in synapses and inflammatory glial cell responses in postmortem human brain
Authors: Taddei Raquel N , Perbet Romain , Wiedmer Anne E , Connors Theresa , Gaona Angelica , Melloni Alexandra N , Duff Karen E , Gomez‐Isla Teresa
Published: December 2023

Background

Synapse density loss is among the strongest histopathological correlates of dementia in AD. Prodromal stages of AD, comprising amnestic MCI and mild AD dementia, represent the most promising timepoints for interventions aimed at attaining efficacious neurobiological and clinical effects. Yet, the understanding of other contributing neuropathologic changes in these prodromal disease stages and their impact on early cognitive dysfunction remains limited.

Methods

We studied the visual cortex of 28 demented and non‐demented human brains who had died at Braak III‐IV stages of NFT pathology, and who showed a comparable β‐amyloid plaque burden and absence of NFT deposits in the studied brain region, and a group of age‐matched healthy controls. We used immunohistochemical analyses with artificial intelligence quantifications, expansion microscopy, synaptosome extractions, and Western blotting, to assess associations between antemortem MMSE scores and synapse densities, glial cell phenotypes, and pathological tau.

Results

We found a significant loss of presynapses (Synapsin 1+), excitatory postsynapses (PSD95+), and colocalized synapses (Synapsin1‐PSD95+) in the brains of demented compared to non‐demented and controls. Moreover, we observed an association between excitatory synapse loss and memory dysfunction (MMSE score) as well as rate of disease progression (MMSE loss/time). MMSE scores were further associated with increase in tau oligomers (TOC1+) and phospho‐tau (AT270+) in synaptosomes, but not with 4G8+ β‐amyloid burden. Additionally, disease severity and rate of progression were significantly correlated with inflammatory glial changes.

Conclusions

Our data suggest that excitatory synapse loss could serve as an early and robust neuropathologic correlate of disease severity and rate of progression from MCI stages of the disease, and be a closer and better determinant of cognitive decline than β‐amyloid and tau deposits. Moreover, early increases in soluble tau in synapses together with local inflammatory glial cell responses could drive development of incipient changes in memory function and serve as potential early biomarkers. Our results point to the importance of early detection and interventions aimed at synapse preservation from prodromal stages of AD, and suggest soluble tau and inflammatory glial cell changes as key targets in the early AD phases.
Assessment of brain oxygen extraction fraction between normal cognition and mild cognitive impairment in an elderly cohort using quantitative BOLD
Authors: Le Linh N. N. , Wheeler Gregory J. , Fletcher Evan , Blockley Nicholas P. , Fan Audrey
Published: December 2023

Background

This study is to quantify oxygen extraction fraction (OEF), an important physiological biomarker for brain hemodynamic impairment, in the elderly cohort using non‐invasive quantitative BOLD (qBOLD) modeling, which is an MRI method for assessment of hemodynamic and metabolic properties.

Methods

56 participants (75.4±7.0yo, 37F), including 46 cognitively normal (CN) individuals (75.2±7.3yo, 29F) and 10 mild‐cognitive‐impairment (MCI) patients (76.0±6.1yo, 7F), were recruited from UC Davis Alzheimer’s Disease Research Center cohort. MRI scans were acquired on a 3T scanner (Siemens Tim Trio) with a 32‐channel head coil, including an Asymmetric Spin Echo (ASE) scan (TR/TE, 2800/66ms; 2.3×2.3.x1.3mm3 resolution; FOV, 224mm; 13 values of the spin echo displacement time, from 0 to 52ms) and a T1‐weighted MPRAGE. T1‐weighted images were segmented into regions of interest (ROI), including gray matter (GM), white matter (WM), and cortical lobes (frontal, parietal, occipital, temporal) using FSL FAST. ASE signal curves were preprocessed and fit to two‐compartment qBOLD model with Variational Bayesian framework to estimate deoxygenated blood volume (DBV) and transverse relaxation rate (R2
’), which are used to quantify OEF with known physiological constants (Cherukara et al., NeuroImage 2019). Average OEF values were calculated and compared for each ROI between CN and MCI groups using pairwise t‐tests with Bonferroni correction. The correlation between OEF and age were assessed using a linear mixed effects model that accounted for subject clustering.

Results

Compared to CN, reduced DBV and increased OEF were observed throughout most of the brain on the group average level in MCI (Figure 1). In regional analysis, we observed a trend of increased OEF in MCI compared to CN in several ROIs, which was significant in the occipital lobe (p = 0.007) (Figure 2). In Figure 3, OEF was inversely correlated with age in the parietal lobe for CN (p = 0.026). In contrast, there was a positive trend of association between OEF and age for MCI across all regions.

Conclusion

This study showed that age has an association with brain oxygen extraction that are differently affected by normal aging and MCI. Higher brain OEF in MCI individuals may reflect changes in oxygen metabolism because of underlying pathology, including vascular injury and compensation for hypoperfusion.
Florbetapir PET Measurements of Amyloid Plaque Deposition are More Closely Correlated with Cross‐Sectional and Longitudinal Cognitive and Clinical Measurements Using a White Matter Reference Region of Interest
Authors: Bhargava Vedanshi , Wang Michele S , Chen Yinghua , Luo Ji , Weiner Michael S. W. , Landau Susan M. , Su Yi , Reiman Eric M. , Chen Kewei
Published: December 2023

Background

We previously reported stronger associations of FDG‐PET measured glucose hypometabolism with florbetapir PET measured Aβ deposition quantified using Standard Uptake Value Ratio (SUVR) with a cerebral white matter reference region (SUVRwm) compared to the commonly used SUVR with cerebellar reference region (SUVRcrblm) both cross‐sectionally and longitudinally (Wang et al., AAIC 2021). This study compared cross‐sectional and longitudinal associations of SUVRwm and SUVRcrblm with various cognitive/clinical measures

Method

Our study population consisted of 1133 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including 206 participants clinically diagnosed with AD dementia, 563 with Mild Cognitive Impairment (MCI), and 364 cognitively unimpaired individuals (CU). We computed partial correlation of SUVRwm or SUVRcrblm, covarying out baseline age and years of education, with Mini Mental State Exam (MMSE); Clinical Dementia Rating Scale Sum Boxes and Global (CDR‐SB and CDGlobal); Alzheimer’s Disease Assessment Scale (ADAS11, ADAS13); Auditory Verbal Learning Test – Short Term Memory, Long Term Memory, and Total (AVLT STM, AVLT LTM, and AVLT Total respectively). Steiger’s Z‐test was used to compare SUVRwm and SUVRcrblm correlation coefficient differences with each of these cognitive/clinical measures at uncorrected p = 0.05 significance. Analyses were carried out over all subjects and within each diagnostic group, first for baseline data and then longitudinally.

Result

Cross sectionally, correlations were significantly stronger with SUVRwm than with SUVRcrblm for all subjects in all cognitive/clinical measures (all p<1.314E‐04) with the strongest correlation of SUVRwmRef with MMSE (r = ‐0.4717 for SUVRwm and r = ‐0.3463 for SUVRcrblm; p = 1.93E‐13). The strongest correlation within AD subjects was found between SUVRwm and MMSE (r = ‐0.1432 for SUVRwm and r = 0.0459 for SUVRcrblm; p = 9.7063E‐04).

Longitudinally, stronger SUVRwm correlations than SUVRcrblm with each of these cognitive measures were also observed over all subjects (p<0.05), and significance with CDR‐SB and AVLT Total in AD; with MMSE, ADAS11, ADAS13, CDGlobal, CDR‐SB, AVLT Total in MCI; and with CDGlobal in CU.

Conclusion

The use of cerebral white matter reference region for florbetapir PET SUVR quantification demonstrated stronger associations between amyloid deposition and cognitive measures than cerebellar reference region.
Assessing the associations between plasma C reactive protein, Ab 42/40 ratio, global amyloid and entorhinal tau PET
Authors: Wheeler Koral V , Tennant Victoria R , Lee Noelle , Tubi Meral A , Matsiyevskiy Elizabeth , Terner Jamie , Hall Brandon J , Davison Marylan , Toga Arthur W. , O'Bryant Sid E. , Yaffe Kristine , Braskie Meredith N
Published: December 2023

Background

Lower plasma ratio of amyloid beta (Ab42/Ab40) has been associated with brain amyloid, however, the mechanistic link is unclear. Systemic inflammation may contribute to plasma Ab levels and promote or reduce the accumulation of Alzheimer’s disease (AD) neuropathology. C reactive protein (CRP) is an inflammatory marker implicated in amyloidosis. Using a cross sectional analysis, we evaluated the relationship between blood levels of CRP and Ab ratio, global amyloid positron emission tomography (PET), and tau PET in the entorhinal cortex where tau accumulates early. We hypothesized that Ab positivity would modify the relationship between CRP and AD pathology.

Method

In 969 cognitively normal participants (age: 50‐87, 781 Ab‐/188 Ab+) (Table 1) from the Health and Aging Brain Study‐ Health Disparities (HABS‐HD), we acquired 18F‐PI‐2620 tau‐PET, florbetaben amyloid PET scans, and plasma measures of Ab 42/40 and CRP. Subjects were categorized by Ab + or Ab ‐ by a global amyloid PET standardized uptake value ratio (SUVR) cutoff of 1.08. Within Ab groups, we performed multiple regressions to evaluate associations between 1) global amyloid and entorhinal tau‐PET SUVRs and 2) plasma markers of Ab ratio and CRP. We covaried for age, gender, education, APOE4, and scanner and used false discovery rate (FDR) for multiple comparison corrections.

Result

In Ab+ participants, higher amyloid (b = ‐0.31, p = 0.0005) and tau PET (b = ‐0.36, p = 0.004) were significantly associated with low Ab ratio, but not in Ab‐ for amyloid or tau, with significant interactions by Ab positivity for amyloid (b = ‐0.45, p = 2.65×10−6) and tau (b = ‐0.77, p = 0.0002) (Figure 1). In Ab+ participants, higher CRP was associated with higher Ab ratio (b = 0.21, p = 0.04) and a trend toward lower amyloid (b = ‐0.15, p = 0.084) and tau PET (b = ‐0.22, p = 0.084), but not in Ab‐ participants, with a significant interaction by Ab positivity for Ab ratio (b = 0.46, p = 0.011) (Figure 2) and amyloid (b = ‐0.11, p = 0.0006) and tau PET (b = ‐0.17, p = 0.016).

Conclusion

In cognitively intact Ab+ but not Ab‐ adults, higher plasma Ab ratio was associated with lower global amyloid and entorhinal tau PET. In Ab+ participants, higher CRP was associated with blood and brain amyloid and tau levels consistent with less AD pathology.
Peripheral insulin resistance and creatinine levels are associated with plasma phosphorylated tau
Authors: Yang Kao Lee , Ennis Gilda E. , Jonaitis Erin M. , Johnson Sterling C , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B
Published: December 2023

Background

Type 2 diabetes (T2D) and insulin resistance (IR) are associated with increased dementia risk, but their association with plasma AD biomarkers e.g., plasma phosphorylated tau (pTau) is unknown. Here, we tested the relationship between diabetes, IR, and pTau, as well as considering the influence of comorbid conditions (obesity and kidney disease) on plasma biomarker measurements.

Method

425 participants from the Wisconsin Registry for Alzheimer’s Prevention were included based on availability of plasma assays. Plasma pTau181 and pTau231 were measured using a single molecule array (Simoa) assay on Quanterix. Diabetes status at baseline visit was determined using fasting blood glucose and medication usage. IR was measured using the homeostatic model assessment of IR (HOMA2‐IR) and z‐scored. Obesity was indicated through body mass index (BMI) and kidney function was determined by blood creatinine levels. We used Welch’s t‐test to examine differences in pTau levels based on diabetes status. Pearson correlations tested the linear relationships between longitudinal pTau181 and pTau231 with baseline HOMA2‐IR, BMI, and creatinine. Two linear mixed effects models were fitted; one for each of the pTau markers. Each model included random intercepts and age‐related slopes with fixed effects of baseline z‐scored HOMA2‐IR, BMI, and creatinine. Results were considered significant at p<.05unadjusted.

Result

Sample characteristics are in the Table. Baseline HOMA2‐IR correlated with pTau181 (r = 0.066, p = 0.021), but not pTau 231. Baseline creatinine associated with both pTau181 and pTau231 (Figure 1). Creatinine was also longitudinally associated with pTau231 (β = 4.82, p = 0.004; Figure 2). When accounting for BMI and creatinine, HOMA2‐IR was no longer associated with longitudinal pTau181 or pTau231. Age was robustly associated with pTau181 (β = 0.04, p = 6.06×10−7) and pTau231 (β = 0.15, p = 5.21×10−7) change. Plasma pTau did not differ based on diabetes status.

Conclusion

IR associated with pTau181 but this relationship did not hold when adjusting for obesity and kidney function. Creatinine levels were associated with longitudinal changes in pTau231 levels. Age was strongly associated with pTau181 and pTau231 change, such that older age was associated with increasing pTau181 and pTau231 levels. Though this study was completed in a largely healthy cohort, the results suggest comorbid conditions are important considerations when utilizing plasma pTau biomarkers as primary outcomes.
A systematic review of drug interventions to enhance cognition in patients with primary central nervous system infections
Authors: Rizvi Syeda Taliya , Shah Jhankhana , Shaaya Sarah , Mollayeva Tatyana
Published: December 2023

Background

Although drug therapy is part of the clinical routine for individuals with central nervous system (CNS) infections, its efficacy with respect to cognitive impairments has not been systematically studied. We aimed to synthesize the evidence for optimal treatment decisions.

Method

We searched for experimental studies published in English prior to October 2021 in MEDLINE, Embase and Cochrane databases. We selected non‐randomized studies (NRS) and randomized control trials (RCT) of a drug efficacy versus placebo, another drug, or a combination of drugs. The certainty of the evidence was rated according to GRADE guidelines.

Result

We included eight RCTs and one NRS, involving a total of 805 patients (50.77% male patients; mean age 42.67±10.58; duration (in years) of primary CNS infections 4.69±3.16) with Lyme disease (LD), herpes simplex virus type 1 (HSV‐1), or Creutzfeldt–Jakob disease (CJD) studying the efficacy of antibiotics, antiviral, and non‐opioid analgesic drugs, respectively. The duration of the interventions varied, depending on the type of CNS infection and class of drug, with a range between four weeks in patients with LD treated with antibiotics and 18 weeks in patients with HSV‐1 treated with an antiviral drug. In patients with LD, antibiotics alone or in combination with other drugs enhanced certain cognitive domains relative to placebo. In patients with HSV‐1, the results were inconsistent. In patients with CJD, flupirtine maleate enhanced baseline cognitive scores. Of the available evidence, only one study had “low” risk of bias. An important limitation of the included studies was the lack of consistent reporting of adverse effects and safety parameters, which must be addressed in future work.

Conclusion

There is not enough existing evidence of sufficient quality to support the use of antimicrobials and non‐opioid analgesics in combatting cognitive deficits in patients with LD, HSV‐1, or CJD. Future clinical trials enrolling participants at earlier stages of primary CNS infections, at the time of greatest inflammation, and which address the elements of biases found in the existing clinical trials, are warranted.
Evaluation of HIVEP3 polymorphic variants and gene expression in Alzheimer’s disease
Authors: Dauar Marina Tedeschi , Picard Cynthia , Labonte Anne , Poirier Judes
Published: December 2023

Background

It has been increasingly recognized that neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease (AD). The HIVEP3 gene encodes a transcription factor that regulates inflammatory response, and variants in this gene have been associated with increased risk for Parkinson’s disease. HIVEP3 gene expression is transiently decreased following nerve damage, consistent with a role during neuronal remodeling . In the present work, we investigate genetic variants in the HIVEP3 gene as risk factors for AD, and study HIVEP3 gene expression in human cerebral cortex.

Method

We have used three different cohorts to assess the association of HIVEP3 polymorphisms with the risk of developing AD: the International Genomics of Alzheimer’s Project (IGAP), the Quebec Founder Population Cohort (QFP) and Kunkle et al. stage 1 GWAS dataset. In the QFP cohort, we measured HIVEP3 protein levels (using ELISA) and mRNA levels (using RT‐PCR) in the frontal cortex of autopsied‐confirmed AD and control subjects.

Result

We have found that the rs10493098 C variant is associated with increased risk of AD in IGAP 2009 (p = 0.018, OR = 1.04), QFP (p< 5 × 10−8, OR = 1.37) and Kunkle et al. 2019 stage 1 IGAP GWAS (p = 0.006). In the IGAP cohort, this variant is associated with increased risk of AD only in APOE4 negative participants (p = 0.0009). Cortical HIVEP3 protein levels are increased in subjects with AD compared to controls (p = 0.029) and in subjects with at least one copy of the rs10493098 C variant compared to non‐carriers (p = 0.03). There are no changes in mRNA levels as a function of disease status or presence of the rs10493098 C variant. There is no correlation between HIVEP3 protein or mRNA levels and senile plaques or neurofibrillary tangles densities.

Conclusion

We have identified a new genetic variant associated with increased risk for AD. The HIVEP3 rs10493098 C variant is associated with increased risk of AD, particularly in APOE4 negative participants. HIVEP3 proteins levels are increased in the frontal cortex of AD subjects compared to controls and in rs10493098 C carriers.
Charting the genetic architecture of Alzheimer’s disease across APOE*4 and sex
Authors: Belloy Michael E , García‐González Pablo , Castillo Atahualpa , Guen Yann Le , Kasireddy Nandita , Stewart Ilaria , Eger Sarah J , Young Christina B. , Mormino Elizabeth C. , Napolioni Valerio , He Zihuai , Altmann Andre , Greicius Michael D ,   Members of the GR@ACE/DEGESCO, GERAD, and EADB groups
Published: December 2023

Background

APOE*4 status and sex (and their interaction) are among the strongest risk factors for late‐onset Alzheimer’s disease (AD). We thus sought to perform large‐scale, stratified genome‐wide association study (GWAS) of AD to chart the role of common genetic variation in AD sexual dimorphism and heterogeneity of APOE*4‐related AD risk.

Method

The study overview and GWAS models are shown in Figure.1A. SNP‐array AD GWAS datasets primarily composing the ADGC, together with whole‐genome sequencing (WGS) from ADSP (NG00067.v7), provided case‐control diagnoses for phase‐1. The UK Biobank provided subjects with ICD codes and family history of AD status for phase‐2. Subjects were of European ancestry. Linear mixed model regressions were performed (LMM‐BOLT v.2.3.4) on AD outcome measures, adjusting for sex, APOE*4/APOE*2 dosage, genetic principal components, and array/batch/center. GWAS hits (P<5e‐*8) were evaluated for interactions effects (meta‐regression for phase1+2 meta‐analyses) and assessed in functional follow‐up analyses. The effect of stratification on genetic risk scores (GRS) predictive performance on AD risk was also evaluated.

Result

Stratified AD GWAS identified 28 loci/variants, including 5 known lead variants in known AD loci, 6 novel independent variants in known AD loci, and 17 novel loci (Figure.1B). 13 out of 17 novel loci showed varying degrees of functional support, with 4 also showing evidence for QTL colocalization (Figure.2). Many implicated genes showed prior support or effects relevant to AD: MARCHF10 was recently implicated as a risk gene for all‐cause dementia; EMP2 is a regulator of cell membrane composition, cell‐matrix adhesion, and blood vessel endothelial cell migration; SLIT2 binds APP, and EYA4 and TBC1D9 have respectively been implicated in brain tau deposition and MAPT haplotype‐stratified GWAS. Nonetheless, most novel hits were low/uncommon frequency variants and QTL colocalization evidence was limited. Further, there appeared to be no predictive benefit for stratified GRS analyses (Figure.3).

Conclusion

We identified novel loci/variants differentially associated with AD risk across APOE*4 and/or sex. Yet, we inferred relatively limited evidence for stratified effects (propensity for low frequency hits and no benefit for stratified GRS). Overall, our findings contribute to our understanding of the genetic etiology of AD, which in turn contributes to advance personalized genetic medicine.
Update from the ReDLat consortium
Authors: Ibanez Agustin ,   ReDLat
Published: December 2023

Background

The prevalence of dementia is notably high among Latinos, the largest and fastest‐growing minority community in the United States (US). Relatedly, brain health problems and dementia prevalence in Latin American countries (LACs) are overgrowing, along with the consequent clinical, social, and economic burden upon patients and their families. The Multi‐partner consortium to expand dementia research in Latin America (ReDLat) aims to identify AD and FTD’s genetic and socioeconomic/social determinants of health (SES/SDH) in LACs vs. the US.

Method

I will provide an update regarding recruitment, multimodal data harmonization, and clinical, genetic, cognitive, and multimodal neuroimaging.

Result

I will first present the sporadic and familial cases assessed, including patients with different genetic risk/mutations (PGN, TREM2, c9orf72, NAPT, TARDBP, PSN1/2, PRNP, ABCA7). I will present the first set of whole genome sequencing and the admixture analysis (57.8% Admixed American, 35.6% European, and 6.2% African). Then I will describe the progress regarding (1) contributions to AD and FTD, (2) SES/SDH impact on clinical‐cognitive‐neuroimaging signatures; (3) machine‐learning and computational approaches for brain‐phenotype characterization. Then the ReDLat expansion to (a) plasma biomarkers, (b) social epigenetics, and (c) natural speech analysis will be introduced. The renewal (2024) will expand ReDLat to include more familial presentations.

Conclusion

Focused on understanding non‐stereotypical, diverse, and underserved populations, we hope that ReDLat will promote the harmonization of global strategies to study, treat, and ultimately prevent dementia.
Amyloid/Tau/Neurodegeneration (ATN) image‐based biomarker trajectories of Alzheimer’s disease through 5‐year longitudinal follow‐up
Authors: Kim Han‐Kyeol , Cho Hanna , Lee Myung Jun , Lee Jae Hoon , Chun Joong‐Hyun , Ryu Young Hoon , Lyoo Chul Hyoung
Published: December 2023

Background

To investigate the progression of Alzheimer’s disease (AD) in image‐based Amyloid/Tau/Neurodegeneration (ATN) biomarkers through 5‐year longitudinal follow‐up.

Method

Among the participants who completed 18F‐florbetaben (FBB) for amyloid and 18F‐flortaucipir (FTP) for tau positron emission tomography (PET), and brain magnetic resonance (MR) imaging for neurodegeneration at a first visit, we enrolled the 145 participants who the studies at least twice [67 amyloid negative cognitive unimpaired (A‐CU), 10 amyloid positive cognitive unimpaired (A+CU), 68 amyloid positive cognitive impaired (A+CI)]. 70 participants completed the scans twice (25.2±3.1, months), and 75 participants completed the scans three times (57.9±7.4, months). We estimated the temporal trajectories of ATN biomarkers using a restricted cubic spline model and modified Euler method between baseline and annual change rates. The standardized uptake value ratio of FBB/FTP PET and hippocampal volume were used for representing each ATN biomarker, respectively.

Result

The FBB curve of the global cortex and AD‐specific regions reaches a plateau with a sigmoid appearance. FTP curves in the regions for Braak stages I‐II and III‐IV show similar sigmoid appearance while the global cortical and stage V‐VI tau curves show an exponential increase continuously. The hippocampal volume curve shows a linear decrease until the time point when the tau accumulation begins in the Braak stage I‐II, then decreases to a reversed sigmoid appearance.

Conclusion

Like the already known saturation of amyloid burden, it was also shown that the tau burden of the region for Braak stages I‐II and III‐IV saturated, but not in Braak stages V‐VI. Hippocampal atrophy seems to accelerate when tau begins to accumulate in early Braak stage regions. In future work, it is necessary to enroll patients at an advanced stage and collaborate with an international cohort.
Receptor specific mechanisms underlying psychedelic effects on affective behaviors
Authors: Jaques Yanabah , Ko MeeJung , Kaufer Daniela
Published: December 2023

Background

Alzheimer’s Disease (AD) patients experience affective symptoms. Conventional therapies to address affective symptoms have limited efficacy in AD, alternative options, like psychedelics, have received interest. Psychedelics work through serotonergic pathways ‐ a neuromodulatory system with dysfunction in AD ‐mechanisms underlying behavioral changes and potential efficacy of their use are unknown. Evaluation of mechanisms underlying behavioral effects is needed to determine their potential as interventions. Psychedelics act through serotonin receptors, not serotonin re‐uptake inhibition characteristic of typical antidepressants. We investigate psychedelics’ mechanism of action as a potential effector of hedonic tone to assess its potential use for affective symptoms in AD.

Method

WT mice were subject to one of three paradigms: (1) a 10‐day social defeat stress (SDS); (2) an injection of 2,5‐Dimethoxy‐4‐iodoamphetamine (DOI); or (3) SDS with DOI. SDS was used instead of an AD proteinopathy model to induce effects like anhedonia. Afterwards, mice underwent behavioral tests to evaluate compulsivity and affect. An additional group will receive DOI +serotonin receptor antagonists

Result

First, SDS increased time spent in closed arms of the elevated plus maze (EPM; p = 0.0068) indicating an increase in anxiety. It also increased nest shredding (NST; p = 0.206), indicating an increase in compulsivity.

Secondly, an injection of DOI decreased time spent in closed arms (p = 0.0151) indicating decrease in anxiety, and decreased nest shredding (p = 0.0325) indicating a decrease in compulsivity.

Lastly, we expect that DOI will decrease anxiety and compulsivity. We expect to find the inverse to be true in mice that receive DOI +antagonist.

Conclusion

We are showing that a traumatic stressor, like that a human might experience pre‐AD, induces potentially maladaptive affective behavioral changes. Here, we’ve demonstrated that psychedelics can act to recover affective dysfunction by activation of serotonin receptors. Because of degeneration of key serotonergic nuclei in AD, the use of serotonin reuptake inhibitors has limited efficacy for addressing symptoms like depression. Psychedelics may offer improved outcomes for AD patients in this regard due to its alternative mechanism of action. Further work to evaluate the efficacy of psychedelics in animal models more closely approximating AD‐type changes in serotonergic systems will help refine this understanding and guide potential clinical applications.
TREM2 protects against complement‐mediated synaptic loss via binding to C1q in neurodegeneration
Authors: Chen Xiao‐Fen
Published: December 2023

Background

The triggering receptor expressed on myeloid cells 2 (TREM2) is recognized as the strongest immune‐specific genetic risk factor for Alzheimer’s disease (AD), since its heterozygous R47H variant confers a 3‐4‐fold increased risk of AD. It has been widely acknowledged that TREM2 plays versatile roles in regulating microglial functions by interacting with a variety of ligands.

Method

We performed affinity‐purification coupled to mass spectrometry with the TREM2‐Fc fusion construct to identify new binding partners for TREM2. The binding of TREM2 to new partners was further confirmed by a solid‐phase binding assay, surface plasmon resonance assay, dot blot binding assay and proximity ligation assay. Next, the functional effects of TREM2 binding to new partners were determined both in vitro and in vivo. We further performed serial truncations to determine the amino acid sequence in TREM2 responsible for binding to new partners. Finally, the functional effects of TREM2 peptide binding to new partners were examined in both the physiological and pathological contexts.

Result

Here we show that C1q protein, the initiator of the classical complement pathway, is a binding partner for TREM2. TREM2 specifically attenuated the activation of classical complement cascade via high‐affinity binding to C1q in vitro. The formation of TREM2‐C1q complexes was also detected in human AD brain. Remarkably, the increased density of TREM2‐C1q complexes was associated with lower deposition of C3 but higher density of PSD95, pinpointing to a protective role of TREM2 against complement activity in AD brain. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement‐mediated microglial engulfment of synapses and accelerated synaptic loss with negligible effects on microglial density and tau pathology. We further identified a 41 amino acid sequence in TREM2 responsible for binding to C1q. In vivo administration of this short peptide reduced synapse removal by microglia and rescued synapse density in both the amyloidosis and tauopathy mouse models of AD.

Conclusion

Together, our results demonstrate a critical role for microglial TREM2 in restricting complement‐mediated synaptic elimination in neurodegeneration, providing new mechanistic insights into the protective roles of TREM2 against AD pathogenesis.
The association of English‐Spanish and Indigenous‐Spanish bilingualism with cognition among older adults in the Mexican Health and Aging Study (MHAS)
Authors: Renteria Miguel Arce , Petrosyan Sarah , Saenz Joseph , Arango Silvia Mejia , Aguila Emma , Barral Sandra , Tosto Giuseppe , Reyes‐Dumeyer Dolly , Samper‐Ternent Rafael , Obregon Alejandra Michaels , Wong Rebeca
Published: December 2023

Background

While several studies have reported a “bilingual advantage” in cognition among older adults, others have not. Most studies of bilingualism and cognitive aging are in urban settings among high income countries, limiting the generalizability among bilinguals residing in lower‐and middle‐income countries, such as Mexico. Additionally, the association of bilingualism and cognition among indigenous populations is unknown. In Mexico, there are almost 7 million speakers of indigenous languages, residing primarily in rural areas, and over 15 million people that report speaking English, predominantly in urban settings. To account for sociocultural factors confounding the type of bilingualism (i.e., English‐Spanish, Indigenous‐Spanish), we evaluated whether bilingualism was associated with better cognitive functioning among adults across urban and rural regions in Mexico.

Method

Analyses included participants from the Mexican Health and Aging Study (MHAS) aged 55 and older in urban (N = 1053, 12% Spanish‐English bilinguals) and rural (N = 814, 20% Spanish‐Indigenous bilinguals) areas. Participants reported speaking English and/or an indigenous language in addition to Spanish. Participants completed comprehensive cognitive testing assessing memory, language, executive function, and visuospatial domains. General linear models stratified by region evaluated bilingualism on cognitive domain performance covarying for sociodemographic factors.

Result

Sociodemographic characteristics differed by region and language group. English‐Spanish bilinguals in urban areas were younger, predominantly men, with higher education, less likely illiterate, and with greater U.S. migration history compared to monolinguals. In rural areas, Indigenous‐Spanish bilinguals were younger, with less education, higher prevalence of illiteracy, and less likely to have U.S. migration history compared to monolinguals. In urban settings, English‐Spanish bilingualism was not associated with performance on any cognitive domain (p>0.05). In rural settings, Indigenous‐Spanish bilingualism was associated with worse performance across all cognitive domains (p<0.01).

Conclusion

There was no evidence of a bilingual cognitive advantage among older adults residing in urban and rural regions in Mexico. While indigenous bilinguals demonstrated the lowest cognitive test performance, further work is required to understand the socioeconomic and environmental factors associated with bilingualism among indigenous populations in Mexico. Greater characterization of their bilingualism (i.e., age and context of acquisition, proficiency, frequency of use) across all languages can help elucidate the association between bilingualism and cognitive test performance.
Nuestro día (our day): The daily experiences of Latino ADRD family caregivers
Authors: Puga Frank , Wang Danny , Poe Abigail A. , Alvarez Loreli
Published: December 2023

Background

The prevalence of Alzheimer’s disease and related dementias (ADRDs) among the Latino population is 1.5 times higher than non‐Hispanic whites. Latinos develop ADRDs earlier and experience more severe symptoms than other ethnic and racial groups. Further, comorbidities, including diabetes, heart disease, and hypertension, have also been observed among Latino individuals living with ADRDs — introducing additional health issues, exacerbating ADRD‐related symptoms, and accelerating functional decline. Given these observed disparities, Latino ADRD family caregivers are uniquely susceptible to increased caregiving stress that can negatively impact their mental health over time. Previous studies have reported on stress and well‐being among Latino ADRD caregivers; however, relatively little is known about the day‐to‐day caregiving experiences and mental health of Latino caregivers. Thus, the purpose of this study was to examine daily contextual factors and variations in depression symptom experience among Latino ADRD family caregivers.

Methods

A national sample of Latino family caregivers (N = 71) completed daily diary surveys over 21 days (n = 2,481). Mixed‐level modes were used to examine relationships between daily caregiving stress, stress moderators, and depression‐related symptoms.

Results

Latino ADRD caregivers were more likely to report depression (OR = 1.14, 95% CI: 1.03‐1.25, p < 0.01) on a given day when behavioral symptoms of dementia were present and perceived as more bothersome than usual. A decrease in the daily odds of depression was observed on days when Latino ADRD caregivers reported receiving social support (OR = 0.69, 95% CI: 0.58‐0.82, p < 0.01), engaging in social activities with friends or other family members (OR = 0.38, 95% CI: 0.25‐0.58, p < 0.01), and engaging in self‐care activities (OR = 0.65, 95% CI: 0.46‐0.92, p < 0.05).

Conclusion

This study offers insight into the daily experiences and mental health of Latino ADRD family caregivers by identifying specific stressors and stress moderators associated with depressive symptoms experienced on a given day. The results of this study highlight modifiable factors for ecologically valid and culturally relevant interventions that mitigate the adverse effects of caregiving stress. Such interventions are critically needed as Latino caregivers are an underserved and underrepresented population in dementia care and aging research.
Glomerular filtration rate proteinuria and risk of dementia: a cohort study from the national health insurance database
Authors: Oh Mi‐Young , Kim Hyun Jung Kim , Lim Jae Sung , Ahn Hyeong Sik
Published: December 2023

Background

The previous studies had shown conflicting results about the association between kidney dysfunction and dementia. One of the causes may be the use of different indicators to define kidney dysfunction. Although estimated glomerular filtration rate (eGFR) and proteinuria reflect the kidney’s different aspects, few studies used both indicators to examine the association between kidney dysfunction and dementia. In addition, even in the same study, the correlation between kidney dysfunction and dementia was different depending on the indicator. We aimed to demonstrate the association between kidney dysfunction and dementia using renal indicators‐ eGFR and proteinuria independently or together.

Method

We used the National Health Insurance database covering the entire population in South Korea to identify and follow up with the population who checked up in the National Health Screening Program (NHSP) from January 2009 to December 2010. Dementia was defined as a newly diagnosed dementia among the population without a history of dementia before enrollment. We used Cox proportional hazard model to examine between eGFR or proteinuria and the risk of dementia.

Result

There were 283,747 incident dementia cases during 132,811,487 person‐years of follow‐up. The risk of dementia was progressively higher with lower eGFR; compared to eGFR≥100 mL/min, hazard ratio (HR) 1.09, confidence interval [CI], 1.07‐1.12 in eGFR 90‐100 mL/min, HR 1.08, 95% CI, 1.06‐1.10 in eGFR 60‐90 mL/min, HR 1.22, 95% CI, 1.19‐1.24, in eGFR 30‐60 mL/min, HR 1.99, 95% CI, 1.86‐2.12 in eGFR 15‐30 mL/min, and HR 3.05, 95% CI, 2.96‐3.14 in eGFR <15 mL/min or dialysis. The proteinuria was also correlated with dementia (HR 1.25, 95% CI, 1.23‐1.27) after adjusting eGFR. Proteinuria contributed to the stratification of the high‐risk patients for dementia in each eGFR stratum; HR 1.39[95% CI, 1.26‐1.53]in eGFR ≥100 mL/min, HR 1.28[95% CI, 1.21‐1.35]in eGFR 90‐100 mL/min, HR 1.23[95% CI, 1.20‐1.27] in eGFR 60‐90 mL/min, HR 1.24[95% CI, 1.20‐1.28] in eGFR 30‐60 mL/min, HR 1.06[95% CI, 0.89‐1.26] in eGFR 15‐30 mL/min, and HR 1.16[95% CI, 1.10‐1.22] in eGFR <15 mL/min or dialysis.

Conclusion

eGFR and proteinuria were associated with dementia independently. The use of both eGFR and proteinuria was useful for the stratification of dementia risk.
Direct Head Injection of Streptozotocin elicits Behavioral Deficiencies and Neurochemical Alterations Characteristic of Neurodegeneration in Lobster Cockroach; Nauphoeta cinerea (Blattodea: Blaberidae) Model
Authors: Famutimi Mayokun Ebunolu
Published: December 2023

Background

Neurodegeneration diseases are a group of diseases like Alzheimer’s disease that are characterized by poor cognitive abilities, neuromuscular deficiencies and locomotion difficulties. The goal of biomedical research is to seek to explore suitable experimental models to study such neurological disorders. Such suitable models must underscore the 3Rs of alternative research models ‐ replacement, reduction and refinement. The lobster cockroach (Nauphoeta cinerea) is one such model that is gaining global attention for their suitability to study human‐related diseases. Therefore, this study aims to model neuromuscular deficiencies and neurodegeneration associated with impaired glucose homeostasis in lobster cockroach (Nauphoeta cinerea).

Method

Acute neurotoxicity was achieved by injecting 74 and 740 nm streptozotocin (STZ) injection per cockroach head and the cockroaches were monitored for 7 days. Thereafter, their survival rate, mortality and behavioral profiles for neuromuscular function including the total time immobile, total distance traveled, time spent in periphery and average speed were assessed on the seventh day, after which the cockroaches were assayed for biomarkers of neurodegeneration and oxidative stress.

Result

The results showed that the survival rate, average speed and total distance traveled were reduced significantly, while STZ increased the mortality, time spent in periphery and total time immobile. Furthermore, STZ induced an increase in acetylcholinesterase activity, lipid peroxidation and total reactive oxygen species. In addition, the results also suggest an impairment in glucose‐trehalose conversation mechanism.

Conclusion

These results are obvious indications of behavioral impairments and metabolic disruptions which affect neuromuscular function and are indices of neurodegeneration. This therefore, suggests that direct injection of STZ to cockroach head is a useful, effective and reproducible model in evaluating neuromuscular deficiencies and neurodegeneration associated with brain glucose metabolic dysregulation.
Incidence and symptomatology of ARIA
Authors: Filippi Massimo
Published: December 2023

Background

To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti–β‐amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.

Method

A literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence‐Based Medicine.

Result

Twenty‐two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid‐attenuated inversion recovery and T2‐weighted sequences were termed ARIA‐E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA‐H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA‐E incidence was further associated with treatment dose, affecting the 55%of ApoE ε4 carriers in the high‐dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3%of ARIA‐E cases at higher treatment doses across RCTs, whereas ARIA‐H cases were generally asymptomatic. Most ARIA‐E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA‐E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6%across RCTs.

Conclusion

Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid‐modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real‐world clinical settings.
Different correlates of memory decline in Alzheimer’s diseases and Frontotemporal dementia: evidence from a novel digital biomarker
Authors: Parra‐Rodriguez Mario A , Fernandez Gerardo
Published: December 2023

Background

Oculomotor behaviours (i.e., eye tracking ‐ ET) linked to cognitive performance can differentiate between the trajectories of neurodegeneration that lead to the Alzheimer’s disease Syndrome (ADS) or Fronto‐temporal Dementia (FTD). We recently reported that a novel digital biomarker that combines ET and Short‐Term Memory Binding (STMB) accurately predicted among MCI patients who would develop ADS or non‐AD dementias (Parra et al., 2022). A sub‐group of the latter group developed FTD. We investigated the correlates of these different neurodegenerative pathways.

Methods

The study involved 32 MCI patients of whom 24 developed ADS and 8 FTD in a three‐year longitudinal study. We also recruited 42 controls (HC). Saccade Amplitude and Fixation Duration were measured at baseline while participants performed the STMB Task. This task assesses the ability to detect changes between two consecutive arrays of bicoloured objects. Changes affect either colours (control condition) or colour combinations (binding condition).

Results

Saccade Amplitudes and Fixation Durations were affected in both MCI‐ADS and MCI‐FTD patients. However, patterns of impairment significantly differed between these risk conditions. Mean Saccade Amplitude followed the pattern MCI‐FTD > MCI‐ADS > HC (p <0.0001) with such responses being significantly more pronounced during retrieval than encoding, particularly in the MCI‐FTD group. Mean Fixation Duration followed the pattern HC > MCI‐FTD > MCI‐AD (p <0.0001) which was similar across memory processes.

Conclusion

While memory deficits in MCI‐AD appear to be driven by encoding impairments, as suggested by both ET metrics, deficits in MCI‐FTD appear to be largely accounted for by impairments in retrieval. The fact that such a distinct pattern was more pronounced for Saccade Amplitudes points toward an early involvement of the frontal lobes. Identifying different correlates of memory impairment in MCI patients at risk of these common neurodegenerative diseases would be challenging for pure cognitive assessments. This highlights the role that the novel digital biomarker can play in refining theories of memory decline and in phenotyping dementia risk profiles.

Parra, M. A., Juan Granada, J., & Fernández, G. (2022). Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. https://doi.org/10.1002/dad2.12386. eCollection 2022.