bluuebunny/crossref_metadata_2025 huggingface dataset:
Men show increased brain aging with respect to women among Cognitively Normal Individuals
Authors: Casanova Ramon , Lu Lingyi , Hsu Fang‐Chi , Anderson Andrea , Barnard Ryan , Justice Jamie , Bateman James R. , Lockhart Samuel N. , Walker Keenan A. , Hughes Tim M. , Kritchevsky Stephen B , Espeland Mark A. , Craft Suzanne
Published: December 2023

Background

There is an increasing interest in using machine learning and artificial intelligence to estimate chronological age using neuroimaging data. The gap between chronological age and estimated brain age (brain age gap, BAG) is used as a measure of accelerated/resilient brain aging. Previously, BAG has been associated with cognitive status. However, whether the BAG varies across sex and cognitive status have been less explored. The present study examines these associations and validates a voxel‐based machine learning approach based on the elastic net regression (ENR) for BAG calculation.

Method

Using data from the Atherosclerosis Risk in Communities Study (ARIC) study, the Wake Forest School of Medicine Alzheimer’s Disease Research Center (WFSM‐ADRC) clinical cohort and Alzheimer’s Disease Neuroimaging Initiative (ADNI), we examined associations of BAG across cognitive status and sex. We used structural MRI scans from 1853 ARIC participants (ages 67‐90, 60% females), 508 from the WFSM‐ADRC (55‐95 yo., 66% females) and 584 ADNI cognitively normal (CN) participants (55‐90 yo., 57% females). All images were aligned into a common template and the derived gray matter (GM) probability maps from ADNI MRIs were used as input to train the machine learning algorithm. Once the model was fitted the ARIC and WFSM‐ADRC GM probability maps were provided as input to the algorithm to estimate the BAG values. Finally, an age bias correction was applied. Linear regression methods were used to investigate differences between groups. Age, race, education, sex, and cognitive status were included in the model.

Result

We found in both ARIC and WFSM‐ADRC participants that differences in BAG values between CN‐MCI and MCI‐Dementia participants were highly significant. In addition, when we examined differences in BAG values across sex per cognitive status, we found again in both cohorts that differences were only significant for CN individuals. See Table 1 for details.

Conclusion

Our analyses show that our approach to estimate chronological age using high‐dimensional ENR, produces BAG values which are strongly associated with cognitive status. The increased severity of cognitive impairment is related to accelerated brain aging. Differences in BAG between men and women were significant for CN individuals only.
Cell‐Based Genetic Subtypes Predict Neuroimaging Biomarkers and Clinical Conversion to Alzheimer’s Disease
Authors: Sahelijo Nathan , Rajagopalan Priya , Priyadarshi Dhawal , Goldstein Daniel , Nho Kwangsik , Shen Li , Huang Heng , Davatzikos Christos , Saykin Andrew J. , Thompson Paul M , Jun Gyungah R
Published: December 2023

Background

The complex etiology and slow progression of AD have complicated efforts to establish robust patient subtypes resulting in high attrition rates among late‐stage clinical trials. We developed a novel procedure to stratify at risk individuals to develop AD using network‐based polygenic risk scores from brain cell‐type specific transcriptome signatures.

Method

We previously computed cell‐based polygenic risk scores (cbPRSs) in the Alzheimer’s Disease Neuroimaging Initiative (Sahelijo et al. 2022). Recently, we computed cbPRSs in 8,481 Framingham Heart Study (FHS) participants using the same genetic markers used in ADNI. We defined low‐ and high‐risk genetic subtypes using the first and the fourth quartiles of the cbPRS distributions, respectively. We conducted association tests with domain specific cognitive tests and neuroimaging biomarkers using subtype risk status as a binary outcome in cognitively normal (CN), mild cognitive impairment (MCI), AD, and all subjects from ADNI. We compared conversion rates from CN and MCI to AD between subtypes using a Cox proportional hazard regression in ADNI and FHS. Using brain‐wide gray matter volume maps with voxel‐based morphometry we compared brain atrophy patterns between subtypes in ADNI corrected for multiple comparisons using Standard FDR at q = 0.05.

Result

Genetic subtypes for astrocytes (Ast‐M2) and oligodendrocytes (Oli‐M45) showed significant association with memory and executive function impairment, decreased hippocampal volume, increased amyloid deposition, and decreased glucose metabolism using all subjects from ADNI (P<1.39E‐3). These associations for memory impairment, global amyloid deposition, and decreased glucose metabolism remained significant only in MCI subjects (best P<7.23E‐09). Conversion rates for Ast‐M2 and Oli‐M45 genetic subtypes were significantly different in both ADNI (P<8.67E‐5) and FHS (P<3.90E‐9). These differential conversion rates for Ast‐M2 and Oli‐M45 in FHS were not fully explained by presence of APOE ɛ4 allele (P<0.05 in ɛ4 non‐carriers). Voxel‐wise whole brain analysis identified significant atrophy in bilateral hippocampi, entorhinal cortex, and amygdala for Ast‐M2 (P = 0.0007) and Oli‐M45 (P = 0.001).

Conclusion

We demonstrate that polygenic risk scores informed by cell type specific brain transcriptomic networks can stratify at risk subjects with AD related changes in imaging biomarkers and higher chance of progression to AD. These findings provide insight into early detection of cell‐type specific at‐risk individuals for AD.
T1w/T2w MRI ratio brain signature across degenerative syndromes and their cognitive impairment continuum and mixed presentations
Authors: Potvin Olivier , Duchesne Simon , Dieumegarde Louis
Published: December 2023

Background

We aimed to investigate the ratio’s signature in diverse clinically‐defined neurodegenerative syndromes and their cognitive impairment continuum. Our hypothesis was that higher cognitive impairment would be associated with lower cortical T1w/T2w ratio in all clinical subtypes.

Method

We used standardized MRI data obtained from participants in the COMPASS‐ND study of the Canadian Consortium on Neurodegeneration in Aging. T1w images were resampled down to T2w resolution; after co‐registration, intensities were standardized between 1‐100 and the ratio computed. Brain segmentation was then performed using FreeSurfer 6.0 on T1w images with the Desikan‐Killiany‐Tourville and default subcortical atlases. Participants included 109 cognitively intact elderly (CIE), 131 subjective cognitive decline (SCD), 252 mild cognitive impairment (MCI), 113 vascular‐MCI (V‐MCI), 55 mixed vascular‐Alzheimer’s dementia (V‐AD), 76 Alzheimer’s disease (AD), 21 Lewy‐body dementia (LBD), 33 fronto‐temporal‐dementia (FTD), 77 Parkinson’s disease (PD), 35 PD‐MCI and nine PD with dementia (PDD). Since the between‐vendor distributions differed (Fig1), Z scores were computed separately for each scanner vendor (GE, Philips, or Siemens) with CIE as a reference group. ANCOVA with age as covariate and FDR correction were conducted between each group and CIE.

Result

No significant effect of age was observed. Compared to CIE, significantly higher T1w/T2w ratios were observed in SCD for most of the brain (57/86 regions), in MCI for six frontal areas only, while decline was observed in AD throughout the brain (Fig1). V‐MCI showed lower ratios in subcortical areas only while V‐AD had pronounced lower ratios in subcortical areas as well as in 11 cortical areas. PD had marked lower ratios throughout the brain with the exception of an intact corpus callosum (Fig2). Contrariwise, FTD only displayed a lower ratio in the corpus callosum whereas PD‐MCI and LBD did not show any significant difference with CIE.

Conclusion

We observed clear distinct patterns of T1w/T2w ratios for SCD, MCI, AD and PD groups. Since this ratio does not seem specific to a neural biological substrate, the meaning of these differences remains to be determined. Nevertheless, these results suggest that simple MRI measures such as the T1w/T2w ratio can highlight underlying mechanisms in various neurodegenerative processes.
The potential utility of genetic susceptibility to life course modifiable factors for dementia prevention
Authors: Jung Sang‐Hyuk , Lee Dong‐Gi , Shen Li , Kim Dokyoon
Published: December 2023

Background

Potentially modifiable risk factors for dementia prevention, intervention, and care based on efforts to curb the increasing prevalence of dementia have been presented by the dementia committees. These risk factors for developing dementia need to be managed throughout the life cycle. However, the criteria for prioritizing risk management in subtype dementias caused by various factors are still uncertain in clinical practice. In this study, using a polygenic risk score (PRS) approach, we investigated the association of genetic susceptibility to life‐course modifiable factors in each subtype of dementia, including all‐cause dementia, and evaluated the utility of using it for predicting dementia.

Method

We utilized 5,974 all‐cause dementia cases and propensity‐matched healthy control data from UK Biobank. We generated APOE isoforms and Alzheimer’s disease (AD)‐PRS (excluding APOE regions) derived from the IGAP 2019 genome‐wide association study (GWAS) using genotyped data. Then, we performed a regression analysis to confirm the associations between AD‐PRS, APOE status, and each type of dementia. In addition, to investigate the genetic susceptibility of life‐course modifiable factors, we generated PRSs related to 18 life‐course factors for dementia prevention using independent GWAS summary statistics. Then, using each life‐course factor PRS, multivariate regression analysis was conducted to evaluate whether PRS is associated with each type of dementia independent of age, sex, genetic principal components, APOE status, and AD‐PRS.

Result

The APOE status and AD‐PRS showed significant associations with all‐cause dementia as well as AD dementia (ADD), vascular dementia (VD), and frontotemporal dementia (FTD) (Figure 1). In the multivariate regression analysis, hypertension, and body mass index PRSs showed significant associations with ADD and VD. In addition, vascular risk factors such as type 2 diabetes, high‐density lipoprotein, and systolic blood pressure PRSs showed significant associations with VD. In particular, in FTD, unlike other subtype dementias, only depression genetic susceptibility and relationship were found.

Conclusion

We observed that genetically predicted life‐course modifiable factors were associated with risks of several types of dementia independently of the well‐known non‐modifiable risk factors (APOE status and AD‐PRS). Our findings suggest the potential utility of prioritizing candidate modifiable factors that should be primarily managed for dementia prevention in personalized medicine.
Partial inhibition of complex I improves bioenergetics via improved glucose uptake/utilization and mitochondrial function in a cellular model of Alzheimer’s disease
Authors: Nguyen Thi Kim Oanh , Trushin Sergey , Trushina Eugenia
Published: December 2023

Background

Alzheimer Disease (AD) currently has no effective treatments. A consistent failure of recent clinical trials focused on Aβ or pTau necessitates the identification of novel therapeutic targets and strategies. Since abnormal brain energy homeostasis and mitochondria dysfunction underlie early stages of AD, the development of treatments to restore these defects could be beneficial. We synthesized small molecules that selectively and mildly inhibit mitochondrial complex I (MCI) which restored synaptic and cognitive function in APP/PS1 and 3xTgAD mice. One of the most important mechanisms improved by the treatment included restoration of glucose uptake/utilization that resulted in augmented cellular energetics in mouse brains. However, mechanistic relationship between MCI inhibition, glucose uptake/utilization and mitochondrial function remains to be determined.

Method

Neuroblastoma SH‐SY5Y cells that express mutant human APP protein (APPswe) and WT cells were treated with MCI inhibitors in a time‐ and dose‐dependent manner. Flow cytometry was used to measure the translocation of glucose transporters to the cell surface. Changes in protein expression in response to treatment were assessed using Western blot analysis. Changes in mitochondrial morphology were monitored using electron microscopy. Cellular energetics was assessed using a Seahorse Extracellular Flux Analyzer. The non‐radioactive Glucose Uptake‐Glo™ assay was utilized for measuring glucose uptake in cells.

Results

Treatment of with SH‐SY5Y‐APPswe cells with MCI inhibitors within an hour increased surface translocation of GLUTs enhancing glucose uptake and utilization. The effect persisted for 48 hrs. The mechanism of enhanced glucose uptake was associated with AMPK‐dependent activation of NRF2 pathway but not AKT. Furthermore, the improvement in the bioenergetic parameters including Spare Respiratory Capacity, an indicator of the mitochondrial ability to produce energy under stress conditions, and ATP levels were found 24 hrs after the compound treatment. Treatment activated mitochondrial morphofunctional pathway (e.g., fission, fusion, biogenesis and turnover) consistent with the improved cellular bioenergetics. Similar mechanisms were confirmed in the brain tissue of 3xTgAD mice treated with one of the compounds.

Conclusions

Partial MCI inhibition activates multiple mechanisms essential for improved energy homeostasis and mitochondrial function. These mechanisms could be consistently induced by our compounds in vivo and in human brain cells support translational potential of this therapeutic strategy.
Dysregulation of memory‐induced protein synthesis in tauopathies
Authors: Evans Harrison Tudor , Kalava Srinidhi V , Yu Astra , Adler Drew , Alapin Jessica , Oliveira Mauricio M , Klann Eric
Published: December 2023

Background

Protein synthesis is a vital biological process, important for many neuronal and cognitive processes such as synaptic plasticity and the formation, updating, and extinction of long‐term memories. Recent studies have identified dysregulated translation as a molecular hallmark of many neurodegenerative diseases, including tauopathies such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and corticobasal degeneration (CBD) (Evans et al., EMBO J, 2019; Evans et al., Acta Neuropathoc Comms, 2021; Elder et al., Commun Biol. 2021). This dysregulation of protein synthesis is thought to be driven in part by pathogenic alterations to tau, a neuronally enriched microtubule binding protein.

Method

Here, we have utilized a series of de novo proteomic analyses, including in vivo non‐canonical amino acid (NCAA) tagging, surface sensing of translation‐based ribosome speed of elongation (SunRiSE), and polysome profiling, to explore both in vitro and in vivo how mutant human tau alters translation in a variety of tauopathies models, including the PS19 mouse strain, human neurons from a FTD patient‐derived inducible pluripotent stem cells (iPSCs) line, as well as in transfected HEK293 cells.

Result

Using these techniques, we have found that both P301S and V337M mutant human tau can severely impair protein synthesis, even when protein degradation is inhibited. Our data also suggests that the dysregulated translation is caused, at least in part, by impaired elongation, with SunRiSE assays showing that P301S and V337M mutant human tau both slow elongation rates. We also have demonstrated that FTD‐mutant tau impairs protein synthesis in CA1 hippocampal neurons in PS19 mice and are determining whether learning‐induced increases in hippocampal protein synthesis following contextual fear conditioning are impaired in these mice.

Conclusion

Together, our results demonstrate that FTD‐mutant tau can severely impact several important components of the cellular translational machinery. Furthermore, our results also contribute to the growing evidence that impairments in protein synthesis are a feature of neurodegenerative diseases. This work was supported by the Alzheimer’s Association (H.T.E), Leon Levy foundation (H.T.E.), the Rainwater foundation (H.T.E.) and NIH grant NS121786 (E.K.).
Partial inhibition of complex I restores mitochondrial morphology and mitochondria‐ER communication in hippocampus of APP/PS1 mice
Authors: Panes‐Fernandez Jessica , Nguyen Thi Kim Oanh , Gao Huanyao , Christensen Trace , Stojakovic Andrea , Trushin Sergey , Salisbury Jeffrey L , Fuentealba Jorge , Trushina Eugenia
Published: December 2023

Background

Alzheimer’s Disease (AD) has no cure. We showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induced adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD.

Methods

Analysis of mitochondrial morphology and mitochondria‐endoplasmic reticulum (ER) contacts (MERCS) was done in the hippocampal CA1 tissue from APP/PS1 mice treated with CP2 and compared to APP/PS1 and non‐transgenic mice treated with vehicle using serial block‐face scanning electron microscopy (SBFSEM) and three‐dimensional (3D) EM reconstructions combined with western blot analysis and next generation RNA sequencing.

Results

We demonstrate that CP2 treatment restores mitochondrial morphology and mitochondria‐ ER communication, reducing ER stress in the APP/PS1 mouse brain. Using 3D EM reconstructions, we found that mitochondria in AD dendrites existed primarily as mitochondria‐on‐a‐string (MOAS), a morphological phenotype that is difficult to detect using conventional 2D EM or fluorescence spectroscopy. Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple MERCS known to contribute to abnormal lipid and calcium homeostasis, and ER stress in AD. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis.

Conclusions

These data provide novel information on the role MOAS play in AD. Our data demonstrate that in response to energetic stress, mitochondria in dendrites acquire MOAS phenotype with increased interaction with the ER, which may synergistically contribute to the AD development. Since CP2 treatment alleviated the ER stress and improved mitochondrial dynamics and function, these data further support the development of partial MCI inhibitors as disease modifying strategy for AD.
Synaptic density is correlated with Aβ plaques and neurofibrillary tau tangles across the clinical and biologic Alzheimer’s disease continuum
Authors: DiFilippo Alexandra H , McLachlan Max , McVea Andrew K , Bettcher Brecca , Jonaitis Erin M. , Ennis Gilda E. , Pasquesi Mary‐Elizabeth , Davenport Nancy J , Thor Yer , Grover Ethan , Hudson Sarah , Barnhart Todd E , Engle Jonathan W , Betthauser Tobey J , Johnson Sterling C , Bendlin Barbara B , Christian Bradley T.
Published: December 2023

Background

The extent to which amyloid‐β burden and neurofibrillary tau tangle burden are associated with synaptic degeneration in vivo is not well known. PET imaging was used to examine the cross‐sectional relationship between neurofibrillary tau tangle burden and amyloid‐β plaque burden with synaptic density among individuals who spanned the clinical and biologic Alzheimer’s disease continuum.

Method

Participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study. N = 64 participants were included in the analysis based on completed cognitive testing, structural MR and PET imaging using [11C]PiB DVR for amyloid burden, [18F]MK‐6240 SUVR for regional neurofibrillary tau burden, and [11C]UCB‐J DVR for regional synaptic density burden analysis. Amyloid burden was indexed as a global [11C]PiB DVR representing the mean of brain regions that typically accumulate amyloid. UCB‐J DVR and MK‐6240 SUVR regions of interest were selected based on the histopathological staging of tau pathology in Alzheimer’s disease with a focus on regions of tau pathology described by earlier and later Braak stages. The first composite region of interest (ROI1) comprised the hippocampus and entorhinal cortex, and the second (ROI2) comprised the amygdala, fusiform, lingual gyrus, and the inferior temporal gyrus. Linear correlations (Pearson’s r) tested the relationship between UCB‐J DVR and PiB DVR, as well as UCB‐J DVR and MK‐6240 SUVR.

Result

Global [11C]PiB DVR showed a moderate negative relationship with UCB‐J DVR in ROI1 (r = ‐0.42, p = 0.0006) and a weak relationship with UCB‐J DVR in ROI2 (r = ‐0.33, p = 009). [18F]MK‐6240 SUVR and UCB‐J DVR were negatively correlated in ROI1 (r = ‐0.44, p = 0.0003) and in ROI2 (r = ‐0.42, p = 0.005).

Conclusion

Both amyloid burden and tau pathology were associated with lower synaptic density. Tau and synaptic density appeared to show moderate correlations among brain regions involved in both earlier and more advanced tau pathology, whereas amyloid burden appeared to be more strongly related to synaptic density in brain regions where more advanced disease is typically observed.
Pathogenesis of ARIA
Authors: Carare Roxana O. O
Published: December 2023

Background

AD is characterised pathologically by the deposition of amyloid‐beta peptides in the extracellular spaces of the brain as plaques and cerebral amyloid angiopathy (CAA). Observations on human post‐mortem brains and experimental studies in mice demonstrate that amyloid‐beta is deposited in the basement membranes of capillaries and basement membranes of arterial smooth muscle cells, within the Intramural Periarterial Drainage (IPAD) pathways.

Method

Pathological studies performed on human post‐mortem brains from the first ELAN trial demonstrated that after active immunization against amyloid‐beta, despite the disappearance of plaques, CAA worsened and both Abeta 40 as well as Abeta42 were present in the vascular wall. This suggests that Abeta42 solubilised from plaques has become entrapped in the IPAD pathways.

Result

Experimental immunization in rodents against a cerebral protein demonstrate that within 24h, immune complexes are formed in the basement membranes of capillaries, impairing IPAD. By 7 days after immunization, inflammatory cuffs of perivascular cells are present, but, in a normal adult mouse, IPAD is restored.

Conclusion

This suggests that clearance of fluid and solutes can be restored even in the context of immune cell recruitment if the vascular wall is healthy.
Network‐based Genetic Subtyping for Target Prioritization and Drug Repositioning: The Artificial Intelligence for Alzheimer’s Disease (AI4AD) Consortium
Authors: Jun Gyungah R
Published: December 2023

Background

Alzheimer disease (AD) is a progressive neurodegenerative disease with complicated underlying disease mechanisms. The clinical and neuropathological heterogeneity of AD may be explained by specific disease mechanisms at a brain cell‐level. We postulate that the path to effective treatment of AD depends on identifying distinctive subtypes linking to specific disease mechanisms at brain cellular level.

Method

We developed a novel precision medicine framework using polygenic risk scores defined by co‐regulated cellular networks to stratify individuals into low and high‐risk groups (genetic subtypes) for brain cell‐type specific networks. We prioritized genes from the cell‐based networks using a graph‐based ranking (PageRank) algorithm. We investigated molecular signatures of the prioritized genes for the subtypes using autopsied brains from the Framingham Heart Study (FHS). We validated the signatures using isogenic APOE lines of human pluripotent stem cell (hiPSC)‐derived astrocytes. Existing drugs targeting for the genetic subtypes were identified using drug perturbation database and clustering algorithms using compound structures from the PubChem database

Result

We identified six preserved and AD associated co‐expressed gene networks for astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells. The top‐ranked astrocyte network was enriched with Parkinson’s disease, Alzheimer’s disease, mineral absorption, and ribosome pathways. The most important gene in the astrocyte network was the APOE gene, which its expression was increased in AD compared in control brains with elevated complement C4A level. We confirmed elevated expression of both APOE and C4A levels in APOE4 compared in APOE3 hiPSC‐derived astrocytes. We identified three drugs targeting the astrocyte subtype, all of them previously modulated expression of the prioritized genes in the drug perturbation database. Clustering algorithm identified multiple compounds targeting the prioritized genes in the astrocyte network with at least 80% similarity in structure.

Conclusion

The newly established framework provided the potential implication in genetic subtype driven drug repositioning in AD. In future, we will develop novel graph neural network approaches to identify comprehensive genetic subtypes and drugs targeting the subtypes in collaboration with internal and external members from the AI4AD consortium.
A review of recommended outcomes and measurement tools within Core Outcome Sets (COS) developed for dementia
Authors: Tran Hanh Dao
Published: December 2023

Background

A core outcome set (COS) is a minimum set of health outcomes to be measured for a given condition. COS can be developed for specific populations, interventions, or settings, so several COS may exist for a condition e.g., dementia. Comparison of the outcomes and measurement tools informs which outcomes should be considered by stakeholders when assessing quality of care.

Method

COS developed for people living with any type of dementia were identified through the COMET database1 and handsearching references of eligible papers. Data was extracted on COS scope (population, intervention), stakeholders, development methods, and the outcomes and tools recommended within each COS. Recommended outcomes were classified against COMET’s taxonomy2 and tools were grouped by outcome across COS.

Result

Ten papers outlining 14 COS were identified (Table 1). Nine included people living with dementia, carers or care organisations in the consensus process. Eleven specified use for a disease stage or intervention. Eleven COS were for research use, one for routine care, and two for both settings. 87 outcomes covering a range of domains were recommended (Table 2). Function/Activities of Daily Living, Cognition, Patient behaviour/ neuropsychiatric symptoms, QoL, and Family Carer QoL were all recommended by at least four COS. Eight COS included recommendations of how to measure the outcomes, but tools differed across the COS.

Conclusion

Multiple COS for dementia have been identified. Most of these have been developed for research, specific interventions, or stages of dementia. Although the majority involved people with dementia or their carers, further quality assessment is needed. Evaluation of recommended outcomes and quality of COS development is required where multiple COS exist, or COS scope does not directly match the proposed area of application. This information can be used by stakeholders from the intended setting to select or ratify the most pertinent outcomes instead of creating additional COS.

1
https://www.comet‐initiative.org/

2Dodd S et al. A taxonomy has been developed for outcomes in medical research to help improve knowledge discovery. J Clin Epidemiol. 2018;96:84‐92.
Cerebral Blood Flow and Arterial Transit Time Variations in Elders with Long COVID
Authors: Patel Milan , Cohen Alexander D , Pommy Jessica , Umfleet Laura Glass , Franczak Malgorzata , Swanson Sara J , Obarski Shawn , Agarwal Mohit , Wang Yang
Published: December 2023

Background

Many COVID‐19 patients experience persistant neurological symptoms that often extend beyond the period of acute infection, referred to as “Long COVID”, where most patients reported brain fog and cognitive dysfunction. While elderly individuals are more vulnerable to possible enduring cognitive impairments after acute COVID‐19 requiring hospitalization, there is increasing concern that older patients with Long COVID will be at high risk for developing Alzheimer’s disease (AD) and dementia. Although there is emerging recognition of Long COVID, its underlying neuropathology remains unknown. This study aimed to investigate neurovascular function using advanced MRI perfusion in elder patients with Long COVID.

Method

Well‐matched elderly Long COVID patients (n = 14, mean age = 60.1±4.3 years, 12F, 2M) and control subjects (n = 25, mean age = 60.4±7.2 years, 19F, 6M) underwent neurocognitive testing as well as neuroimaging. Patients were seen 711.57 ± 165.02 days after the initial mild non‐hospitalized COVID‐19 infection. Clinical cognitive complaints of Long COVID patients included memory changes (n = 12, 85.7%), attention (n = 12, 85.7%), speech/writing (n = 9, 64.3%), and multitasking (n = 9, 64.3%). Brain perfusion was evaluated using an advanced 3D pseudo‐continuous arterial spin labeling (pCASL) sequence with Hadamard encoded multiple post‐labeling delays (PLDs), enabling estimation of Cerebral Blood Flow (CBF) and Arterial Transit Time (ATT) ATT and ATT corrected CBF.

Result

Conventional MRI scans (T1, T2, and FlAIR) appear normal in all subjects. Voxelwise comparisons between Long‐COVID and control subjects showed a significant global decrease in the ATT (p < 0.05, cluster corrected at α < 0.05), along default mode and other key networks, where there is a trend of decreased CBF (p<0.05, uncorrected) specifically in the frontal lobe in those with Long COVID.

Conclusion

These preliminary results in an aging group indicate that neurocognitive effects of Long COVID could be attributed to neurovascular dysfunction, even in those cases with initial non‐hospitalized mild COVID‐19 of more than 500 days. The novel finding of diffusely decreased ATT could be something attributable to the unique neurovascular mechanism of Long COVID. Future longitudinal research following the progression of those elderly Long COVID patients with known abnormal neurovascular function to fully evaluate their risk for developing AD and dementia.
Mechanistic modeling of tau biomarkers for amyloid load. A Quantitative Systems Pharmacology study of amyloid‐tau interaction.
Authors: Geerts Hugo , Bergeler Silke , Walker Mike , Van der Graaf Piet
Published: December 2023

Background

Recent clinical trials with amyloid antibodies have suggested a beneficial effect on cognitive scales after clearing most of the amyloid load. Interestingly, substantial reduction in plasma or CSF tau biomarkers were documented providing interesting insights into the amyloid‐tau interactions in the human AD patient.

Method

We developed a Quantitative Systems Pharmacology (QSP) platform for late MCI‐prodromal AD subjects that combined an earlier published Physiology‐Based Pharmacokinetic (PBPK)‐ QSP model of amyloid aggregation with a novel QSP model describing the impact of amyloid monomers on glutamatergic and nicotinic neurotransmission and neuronal firing, the neuronal activity‐dependent tau release, subsequent tau uptake in the afferent neuron and dynamics of tau biomarkers in CSF and plasma.

Result

The combined model quantitatively reproduced (1) the cortical hyperactivity and higher tau biomarker levels associated with increasing amyloid deposition in observational studies, (2) the differential decrease in CSF and plasma tau biomarkers in clinical trials with various amyloid antibodies. Dynamics of monomeric brain Ab40 and Ab42 and their effect on neuronal firing, rather than reduction in SUVR can better explain the clinically observed changes in CSF or plasma tau between aducanumab, lecanemab, donanemab and gantenerumab. The range of commonly used comedications and common dopaminergic and serotonergic genotype variants affecting neuronal activity can partially explain the variability of tau biomarkers response as downstream effects of amyloid removal.

Conclusion

This study suggests a direct link between amyloid dynamics and plasma / CSF tau levels through modulation of neuronal activity. The calibrated QSP model sets the stage for modeling long‐term effects of amyloid therapy on tau pathology progression and identification of optimal trial design for combination therapies.
Preparation of Novel Donepezil Long‐Acting Injectable, IVL3003, and its Pharmacokinetic Study via Subcutaneous Injection in Dogs and Monkeys
Authors: Lee Mase , Lee Sangno
Published: December 2023

Background

Donepezil is a selective oral acetylcholinesterase inhibitor to treat Alzheimer’s disease (AD). Most patients with AD need help with taking oral donepezil for forgetfulness etc. Therefore, long acting injectables (LAIs) can improve patient’s compliance and quality of life. Because of narrow therapeutic window of donepezil, precisely size controlled microsphere technology is needed for drug release control. We have developed IVL3003 as a novel sustained release monodisperse subcutaneous (SC) LAI of donepezil for one month using IVL‐DrugFluidics® technology. The purpose of this study is to evaluate the physicochemical characteristics of IVL3003 and investigate the inter‐species pharmacokinetic profile differences in beagle and monkey models.

Method

Various one month formulations of donepezil microspheres were prepared by IVL‐DrugFluidics®. Characterization of IVL3003 was performed by scanning electron microscopy (SEM), and the size distribution was measured by laser particle size analyzer (PSA). The amount of donepezil and encapsulation efficiency (EE, %) was determined by HPLC. Size distributions were expressed as span value and CV(%). Non‐clinical models were used to optimize formulations and to evaluate their pharmacokinetic properties. IVL3003 was administered to male beagle dogs (n = 3/group, 11 months old, body weight 9∼11 kg) and male cynomolgus monkeys (n = 3/group, 30∼50 months old, body weight 2.6∼3.3 kg). Plasma concentrations were monitored for one month.

Results

The SEM images of the microspheres appeared spherical and smooth. Donepezil was well encapsulated and homogeneously. The EE(%) of microspheres was 97.5% and the residual solvent was 232.2 ppm. The span value was 0.25 and CV(%) was 10.01%. The plasma concentrations of donepezil were maintained for 28 days without any initial burst and had small individual variation. There was no big difference between species in plasma concentration and showed a similar PK profile in both.

Conclusions

As we postulated, narrow distribution of the particles was led to improvement of controlled‐release characteristics. These results proved the excellence of IVL‐DrugFluidics® as an ideal microsphere fabrication method in manufacturing uniform and monodispersed microspheres. Long‐acting injectable, IVL3003 is expected to increase the compliance and the safety in the treatment of Alzheimer’s patients. We have filed Ph I for IVL3003 recently as the 1st donepezil containing LAI.
Identification of leukocyte surface biomarkers associated with late‐onset Alzheimer’s disease
Authors: Li Yihan , Huang Xin , Fowler Christopher J , Trounson Brett , Pertile Kelly , Wang Haihua , Wiley James S , Masters Colin L , Gu Ben J
Published: December 2023

Background

Altered innate immunity has been long associated with late‐onset Alzheimer’s disease (AD) and its associated blood‐based biomarkers are important for AD diagnosis and prognosis.

Method

We collected 38 participants from the AIBL study, including 22 cognitive normal (CN) individuals with negative amyloid burden (Centiloid [CL] < 15), 5 CN individuals with positive amyloid burden (CL > 15), and 11 mild cognitive impairment (MCI) and AD cases. A total of 17 leukocyte surface antigens were examined by flow cytometry immunophenotyping and compared between healthy controls (CN Ab ‐ve), pre‐clinical patients (CN Ab +ve), and clinical cases (MCI & AD), including CD36, MerTK, Clec7a, RAGE, Tyro3, CR1 (CD35), CX3CR1, CCR2, Axl, LILRB2, LILRB3, LILRB4, PILRA, and P2×7.

Result

We identified leukocyte surface markers differentially expressed between HC, pre‐clinical patients, and clinical cases. Mean fluorescence intensities of CD85d and CD85k were significantly reduced in pre‐clinical patients and cases compared with HC, implicating CD85d and CD85k downregulation in AD pathogenesis. Significant upregulation of RAGE, Tyro3, CCR2, CD85a, and PILRA was also noted in cases compared with HC. Leukocyte surface expressions of RAGE, CCR2, PILRA, and CD85k were significantly associated with the Preclinical Alzheimer’s Cognitive Composite (PACC), which is one of the most accurate estimates of cognition in AD diagnosis.

Conclusion

Our preliminary investigations into these leukocyte markers demonstrated their dysregulations in pre‐clinical stage of AD, implicating early deficits in innate immunity, as supported by genomic studies of AD. This project will continue collecting more AIBL participants up to 200 to evaluate leukocyte surface markers more comprehensively, which would benefit AD screening and diagnosis.
Exploring older people’s attitudes and preferences around the use of their routinely collected healthcare data in brain health research
Authors: Prieto Cristian Andres Gonzalez , Yates Susan , Rodriguez Claudia Rivera , Wilson Daniel , Dobbie Gillian , Cullum Sarah J
Published: December 2023

Background

Over 50% of dementia in NZ may be due to high prevalence of risk factors such as hypertension, diabetes and cardiovascular disease. If so, a better understanding of the relationships may present ways to mitigate the risk of dementia. Community‐based epidemiological studies would provide definitive evidence but are resource‐intensive so we need to explore alternative sources of data such as routinely collected health information.

The overarching aim of our research is to use a machine learning model to identify population groups at high risk of cognitive decline and/or dementia. But first we need to gauge the appetite of service users to have their personal data used in this way. This study aimed to explore the attitudes and preferences of people aged 55+ living in Counties Manukau regarding the use of their de‐identified health data and understanding their concerns and degree of comfort in different scenarios.

Method

An anonymous online survey was conducted with people aged 55+ from NZ European, Māori, Pacific, Chinese and Indian communities currently engaged with older adult health services in Counties Manukau District in 2022. We offered service users the opportunity to complete the survey by telephone if preferred, and the opportunity to be interviewed in languages other than English to ensure adequate representation of the local population.

Result

Over 85% of the participants were aware of how their health information was used for service development and assessing population trends, and about 80% were comfortable or very comfortable with data being used in this way, assuming data were stored securely and confidentiality was assured. Participants generally felt that patients’ permission was required if data were being analysed by people other than health professionals or being used by commercial companies, and that there should be transparency about these uses. There were some specific cultural concerns about patients’ data being used after their death.

Conclusion

This study supports the idea that the local population are generally supportive of researchers using their de‐identified routinely collected data for research purposes that will benefit the population from which the data were taken, but specific cultural concerns need to be addressed.
Clinical Study of PET‐validated EEG‐machine learning algorithm predicting brain amyloid pathology in pre‐dementia Alzheimer’s disease
Authors: Kim Nam Heon , Park Ukeob , Wang Min Jeong , Lee Chunghwee , Jeong Jee Hyang , Park Kee Hyung , Hong Yun Jeong , Shim Yong Soo , Kim SangYun , Choi Seong Hye , Yang Dong Won , Kang Seung Wan
Published: December 2023

Background

Currently positron emission tomography (PET) is used as the initial or sole biomarker of β‐amyloid (Aβ) brain pathology, which may inhibit Alzheimer’s disease (AD) drug development and clinical use due to cost, access, and tolerability. Machine learning (ML)‐based EEG biomarkers may address these challenges. Previous studies have confirmed their ability to accurately discriminate between normal, mild cognitive impairment (MCI) and Alzheimer’s dementia. However, few quantitative EEG (QEEG) biomarkers have been validated with Aβ PET. We developed a QEEG‐ML algorithm to predict brain Aβ pathology among subjective cognitive decline (SCD) and MCI patients, and validated it using Aβ PET.

Method

EEG (19‐channel, eye‐closed, resting‐state) and Aβ PET data were collected from 160 human subjects with MCI (77 Aβ+, 83 Aβ‐). We excluded 45 data (23 Aβ+, 22 Aβ‐) for test verification. QEEG absolute power, relative power, power ratio, and connectivity between channels (iCoherence) comprised the input features, from which the most relevant predictive features were identified using four methods (Random Forest Importance (GBM, XGB), ElasticNet, Whitney‐Mann). We then trained six ML algorithms (SVM, Logistic, KNN, Naive Bayes, Random Forest(GBM/XGB)) using each relevant feature set, yielding 24 models (4 sets * 6 algorithms). The 45 test data sets were input into each model to compare their performance. Then, 111 MCI data (56 Aβ+, 55 Aβ‐) and 165 SCD data (31 Aβ+, 134 Aβ‐) were classified by the model for 3rd validation.

Result

In test validation, the best‐performing model showed 77.8% accuracy, 81.8% sensitivity, 73.9% specificity in discriminating Aβ+ from Aβ‐. In 3rd data validation, the best‐performing model showed 72.1% accuracy, 71.4% sensitivity, 72.7% specificity in MCI. In SCD, it showed, 69.1% accuracy, 64.5% sensitivity, 70.2% specificity.

Conclusion

These findings suggest that our novel ML‐based QEEG biomarker can accurately predict the presence of brain Aβ plaque. Additional benefits of such a biomarker include reduced expense, wide availability, and high‐throughput screening and response monitoring. Future studies will assess utility as primary AD screens, adjunctive use with PET, and as a support in clinical rationales for Aβ PET and treatment choice in AD.
Investigation of tau post‐translational modification based on T217 and T231 in human plasma as new biomarkers
Authors: Yoon Hyosang , Kwon SunSang , Jeong Seongeun , Kim Han‐Kyeol , Cho Hanna , Lee Soo Hyun
Published: December 2023

Background

Post‐translational modification (PTM) of human tau protein is of high importance as an indicator for predicting the progress of Alzheimer’s disease (AD). Particularly, phosphorylation and O‐glycosylation on tau have been observed at relatively high levels in Alzheimer’s disease (AD) patients and healthy controls, respectively [1]. Recently, a study reported that an increase in the level of phosphorylation at T217 and T231 was observed in the initial stages of the preclinical Alzheimer’s continuum [2]. Reference: [1] C. Alquezar et al. Frontiers in Neurology, 11 (2021) 595532. [2] Marc Suárez‐Calvet et al. EMBO Molecular Medicine, 12 (2020) e12921.

Method

To investigate the PTM of tau protein in human blood plasma, an electrochemical sensor with 1 µm gap between working and counter electrodes was performed and obtained Taumeter indicating the ratio of phosphorylation and O‐glycosylation on the surface of tau protein, where antibodies for phosphorylated T217 and T231 were used [3]. To explore the clinical association, standardized uptake value ratio (SUVR) of amyloid‐positron emission tomography (PET), mini‐mental state examination (MMSE), and clinical dementia rating scale sum of boxes (CDR‐SB) were also investigated and compared to Taumeters. Reference: [3] Yoon et al. Alzheimer’s & Dementia, 18 (2022) e061465.

Result

A total of 43 participants (normal control (NC, n = 15), mild cognitive impairment (MCI, n = 14), and AD (n = 14) were investigated. Taumeters for T217 (p = 0.00423, AUC = 0.82667) and T231 (p = 0.00034, AUC = 0.86222) were obtained and analyzed through one‐way analysis of variance (ANOVA) between NC and AD groups (Figure 2). In regression analysis, Taumeter for T217 (r = 0.23824, p = 0.12394) was more correlated with amyloid‐PET SUVR than Taumeter for T231 (r = 0.28072, p = 0.06824) (Figures 3a‐b). Taumeter for T217 (r = ‐0.51246, p = 0.00044) was also more correlated with MMSE score than Taumeter for T231 (r = ‐0.07186, p = 0.64701) (Figures 3c‐d). Taumeter for T217 (r = 0.57937, p<0.0001) was more correlated with the CDR‐SB score than Taumeter for T231 (r = 0.16254, p = 0.29768) (Figures 3e‐f).

Conclusion

In this study, we investigated the correlation between Taumeters for T217 and T231, amyloid‐PET SUVR, MMSE score, and CDR‐SB score. As a result, Taumeter for T217 indicates more strong correlation with analytical results of amyloid‐PET SUVR, MMSE score, and CDR‐SB score than Taumter for T231.
Association between Auditory Impairment and the Onset of Alzheimer’s Disease: The LIFE Study
Authors: Fukuda Haruhisa , Fujii Takayuki , Maeda Megumi , Murata Fumiko , Ono Rei
Published: December 2023

Background

The prevalence of Alzheimer’s Disease (AD) has seen an upward trend due to the demographic shift towards an aging population in Japan. The possible association between auditory impairment and the onset of AD has been previously proposed, however, it remains a subject of ongoing discussion. This study aimed to investigate this association using data from 13 municipalities in Japan.

Method

From the LIFE Study, 13 municipalities that possessed both long‐term care certification questionnaire and medical claims data were identified as eligible for inclusion. The study population consisted of individuals who had newly applied for long‐term care certification between April 2013 and October 2021. The study population consisted of individuals who displayed no cognitive impairment at the time of application and had not been diagnosed with dementia within the preceding six months, inclusive of the month of application. The month succeeding the application was established as the index month, and the interval from this month to the onset of AD (ICD‐10 codes F00 or G30) was assessed. The Cox proportional hazards model was utilized to examine the risk of AD onset in relation to auditory status as reported on the long‐term care certification questionnaire.

Result

The study cohort consisted of 33,067 participants, with a mean follow‐up duration of 21.0 months. At the index month, 60.2% of the patients were female, and the mean age was 79.5 years. In the course of the follow‐up period, 1,827 (5.53%) individuals developed AD. Auditory impairment was not found to be correlated with the incidence of AD. The hazard ratio (HR) for the development of AD in relation to auditory impairment was 1.31 (95% Confidence Interval: 0.65 ‐ 2.64).

Conclusion

The examination of the long‐term care certification questionnaire data did not reveal any correlation between auditory function and the onset of AD. The limitations of this study include the inability to determine the use of hearing aids or the timing of onset of auditory impairment. Further investigations are necessary to clarify the relationship between auditory function and dementia.