bluuebunny/crossref_metadata_2025 huggingface dataset:
An automated pipeline for Centiloid quantification of amyloid‐β using multiple 11C‐PiB‐PET and 18F‐PET tracers
Authors: Gordon Elizabeth , Borrot Mathilde , Gueddou Ayoub , Jubault Thomas , Guizard Nicolas
Published: December 2023

Background

Quantitative measures of amyloid‐β (Aβ) pathology using positron emission tomography (PET) imaging are sensitive to identify pathological changes early in Alzheimer’s disease (AD). The Centiloid scale aims to standardize these in vivo amyloid quantifications to a 100‐point scale, where an average value of zero signifies high certainty of amyloid negativity and 100 identifies average typical AD Aβ‐pathology load (Klunk et al., 2015). The current study developed and validated a single and fully automated Centiloid quantification pipeline for multiple amyloid PET compounds.

Method

QyScore’s® fully automated pipeline was validated on 11C‐PiB‐PET and 18F‐PET images from the Centiloid project (https://www.gaain.org/centiloid‐project): 34 young controls [age = 31.5 ± 6.3 years] and 47 AD patients [age = 67.5 ± 10.5 years; CDR = 0.5–1]. 18F tracers included Florbetapir (FBP, N = 46), Forbetaben (FBB, N = 35), Flutemetamol (FTM, N = 74) and NAV4694 (NAV, N = 55). PET/MR image pairs were both co‐registered and normalized in the MNI template space. The fully automated segmentation from QyScore®, a CE‐marked and FDA‐cleared neuroimaging medical device, parcellated the masks of the grey matter tissue (target) and of the cerebellum (reference) region (Figure 1). The standardized uptake value ratio (SUVr) was computed as the ratio of the mean signal in both regions. Correlations of 11C‐PiB‐PET and 18F‐PET SUVr values with published SUVr data were computed. Further, correlations between 18F‐PET SUVr and paired 11C‐PiB‐PET SUVr were computed. Correlation coefficients (R2) > 0.7 were required to consider the Centiloid calibration valid.

Result

QyScore’s® fully automated quantitative pipeline produced SUVr values well within the bounds defined by the Centiloid method (SUVr_AD‐100 = 2.08 +/‐ 0.2; SUVr_YC‐0 = 1.01+/‐ 0.05; R2 = 0.99; slope = 1.00; intercept = ‐0.44). 11C‐PiB SUVr correlation coefficients with published values were above 0.99 (Figure 2). Correlation coefficients of 18F‐PET SUVr with 11C‐PiB‐PET SUVr were respectively 0.91, 0.95, 0.96, 0.99 (Figure 3).

Equations for converting to Centiloid were respectively

o Centiloid = 177.79 FBP_SUVr ‐ 183.56

o Centiloid = 153.08 FBB_SUVr – 152.93

o Centiloid = 122.39 FTM_SUVr – 120.97

o Centiloid = 90.20 NAV_SUVr – 91.61

Conclusion

We demonstrate the feasibility and reliability of a fully automated amyloid PET pipeline for multiple amyloid‐PET compounds (11C‐PiB and 18F) suitable for implementation in clinical trials.
Comparison of diffusion metrics in dementia
Authors: Beaumont Helen
Published: December 2023

Background

The recent FDA approval of a disease‐modifying drug for Alzheimer’s disease has stressed the need for a test which can be used at scale to detect neurodegeneration. MRI diffusion shows great promise (Douaud et al., 2013), and recently a multiplicity of analysis methods have been developed. We look at which diffusion analysis method might be most sensitive.

Method

We worked with data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Weber et al., 2021). Participants with Alzheimer’s disease (AD) and a group of age‐matched healthy controls (HC) were identified. T1 images were processed with FreeSurfer v7 (Fischl, 2012), providing tissue segmentations and cortical parcellations, as well as regional volumes. Diffusion images were preprocessed using the PreQual pipeline in native space (including FSL’s Topup and Eddy) (Cai et al, 2021), and analysed with Diffusion Tensor Imaging (DTI), Neurite Orientation Dispersion and Density Imaging (NODDI) (Zhang, Schneider, et al, 2012), Apparent Measures Using Reduced Acquisitions (AMURA) (Aja‐Fernández et al, 2022), Diffusion Orientation Complexity (DOC) (Haroon et al, 2009) and Probabilistic Index of Connectivity (PICo) (Parker et al, 2003). Regional values were extracted in FreeSurfer regions (grey and white matter).

Pairwise Mann‐Whitney U‐tests were carried out between AD and HC regional measures. Regions with the most statistically significant volume differences were selected; diffusion‐based metrics for these regions were calculated using weighted values and compared. The 10 metrics with the smallest p‐values were used to find the most significant regions, and these were compared with volumes.

Result

Participants: 100 AD (38 female, age 74.5±7.9 years) and 207 HC (132 female, age 72.0±7.4 years).

We selected the 25 most significant regions from the volumetric analyses. From these regions, the most effective diffusion metrics were DTI‐derived mean, axial and radial diffusivities, and 5 of the AMURA metrics.

Given the 10 most significant metrics, of the 15 most significant volumes, 8 were also in the top diffusion regions.

Conclusion

This study demonstrates that DTI metrics are most sensitive at differentiating HC from AD. If confirmed this has clinical significance, as these scans are widely available.
Associations between 5‐lipoxygenase activating protein (FLAP) genetic variation rs9551963 and Alzheimer’s disease phenotypes
Authors: Noor Shiropa , Mori‐Fegan Daniel K , Wong Yuen Yan , Wu Che‐Yuan , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

Background

Leukotrienes are inflammatory mediators, synthesized by 5‐lipoxygenase and its activating protein (FLAP), and their activity may play a role in Alzheimer’s disease (AD). In AD mouse models, inhibition of FLAP improved memory and reduced amyloid (Aβ) deposition. Single nucleotide polymorphisms (SNPs) of ALOX5AP, which encodes FLAP, have been implicated in ischemic stroke in humans. However, there is limited research on the relationship between ALOX5AP and AD. This longitudinal study investigated associations between the ALOX5AP SNP rs9551963 A/C and various AD phenotypes.

Method

Participants from the Alzheimer’s Disease Neuroimaging Initiative (phases GO, 2, and 3) diagnosed with AD, mild cognitive impairment (MCI), or clinically normal cognition (CN) were categorized as minor allele carriers (AC, CC) or non‐carriers (AA) of rs9551963. Mini Mental State Exam (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) % forgetting were selected to assess cognition. Cerebrospinal fluid biomarkers and MRI brain volumetric data were also considered. Interactions between rs9551963 genotype and time (baseline, month 24, and month 48) were measured in mixed models. All models controlled for age, sex, and APOE e4 status; education and baseline intracranial volume were additional controls in cognitive and volumetric analyses respectively.

Result

Minor allele carriers in the AD‐MCI Aβ‐positive group had worse decline on the MMSE (F1,297 = 5.33, p = 0.022, n = 521), and smaller volumes of whole brain (F1,146 = 7.13, p = 0.008, n = 408) and hippocampus (F1,132 = 6.38, p = 0.013, n = 377) over time that were not seen in other subgroups. In the AD subgroup, Aβ‐positive carriers had greater increases in RAVLT % forgetting scores (F1,135.5 = 6.19, p = 0.014, n = 158) and greater whole brain volume loss (F1,27.6 = 5.67, p = 0.024, n = 132), over time. These associations were not seen in Aβ‐negative participants.

Conclusion

Minor allele carriers of the ALOX5AP SNP rs9551963 who were Aβ‐positive showed greater loss of cognitive status and memory, and more hippocampal and whole brain atrophy, over time. These findings suggest a possible effect of leukotriene synthesis in the progression of AD.
Mechanisms of reduced Apolipoprotein E4 lipidation in iPSC‐derived astrocytes
Authors: Kerman Bilal Ersen , Makhlouf Maria E , Bantugan Mikaila Ann , Lee Joon , Meuret Cristiana Joy , Wang Shaowei , Cai Zhiheng , Tuck Tony , TCW Julia , Yassine Hussein N.
Published: December 2023

Background

Carrying the apolipoprotein E ε4 (APOE4) allele is the highest known genetic risk factor for late‐onset Alzheimer’s disease (LOAD). Although how APOE4 leads to LOAD is not known, dysregulated endo‐lysosomal trafficking and lipid metabolism are key defects associated with APOE4. Cholesterol accumulation in glia instigates intracellular trafficking defects, increases cellular stress, and disrupts secretion. Additionally, enlarged endosomes were observed in the frontal lobes of APOE4‐carrying individuals, decades before the appearance of Aβ fibrilization. Therefore, we asked if cholesterol and endo‐lysosomal trafficking dysregulation in APOE4 carriers were due to differential lipidation of APOE3 and APOE4.

Method

Localization of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in early, late, and recycling endosomal compartments were analyzed in human isogenic induced pluripotent stem cell (iPSC)‐derived neural cells and in cell lines treated with recombinant APOE in microscopic images. Membrane and cytoplasmic ABCA1 were compared using Western blots. Secreted high‐density lipoprotein (HDL) particles containing fluorescently tagged APOE3 or APOE4 were analyzed using ion‐mobility spectrometry. CS‐6253, an ABCA1 agonist peptide, was used to increase APOE lipidation.

Result

The protein levels of ABCA1, which mediates cholesterol and phospholipid efflux to the nascent apolipoprotein particles, were lower in APOE4/4 iPSC‐derived astrocytes compared to astrocytes derived from isogenic APOE3/3 iPSCs. Advanced image analysis revealed lower ABCA1 protein levels in Rab11+ recycling endosomes and less colocalization between ABCA1 and Rab7, a late endosome marker, in APOE4/4 astrocytes than APOE3/3 astrocytes. Consequently, less ABCA1 was detected at the cell membrane. Combined with previous data, these findings suggest APOE4 lipidation was reduced due to reduced ABCA1 activity. Additionally, BHK cells treated with recombinant APOE3 or APOE4 showed differences in ABCA1 localization that were altered by increasing APOE lipidation by activating ABCA1 via CS‐6253. Finally, fluorescently tagged APOE3 and APOE4 were incorporated in HDL particles and were secreted whose sizes were altered after CS‐6253 treatment, suggesting differences in lipidation levels.

Conclusion

We demonstrated that diminished APOE4 lipidation is, at least in part, due to dysregulation of endo‐lysosomal trafficking of ABCA1 and that increasing APOE4 lipidation could alleviate cellular defects.
Two‐year longitudinal outcomes of subjective cognitive decline in Hispanics compared to non‐Hispanic Whites
Authors: Boza Carolina , Zhang Yian , Shao Yongzhao , Masurkar Arjun V.
Published: December 2023

Background

Hispanics are at higher risk for Alzheimer disease (AD) than non‐Hispanic Whites (NHW), motivating further study of differences and risk factors at the preclinical level. Subjective cognitive decline (SCD) is considered a preclinical AD stage, but its features and outcomes in Hispanics are less studied. We investigated the differences in longitudinal change in SCD phenotype, cognition, and function among Hispanics compared to NHW.

Method

Longitudinal analyses were performed on consecutive participants with SCD who were evaluated at the NYU Alzheimer’s Disease Research Center. Inclusion criteria were self‐identification as Hispanic (n = 23) or NWH (n = 165) and a 2‐year follow‐up visit. Demographics, conversion rate to mild cognitive impairment (MCI), SCD characteristics, and psychometric performance were analyzed by t‐test, multiple linear regression models, or Cox models as appropriate. Models were adjusted for age, sex, education, depression, and baseline values.

Result

Hispanics were at higher risk for conversion to MCI (HR: 6.57, 95% CI 1.25‐34.47, p = 0.02596). Hispanic ethnicity was associated with increased SCD severity in time as measured via the total Brief Cognitive Rating Scale (BCRS) score (OR: 4.28, 95% CI 1.42‐12.83, p = 0.0094), and in specific BCRS domains: mood and behavior (OR: 0.18, 95% CI 0.03‐0.89, p = 0.0355) and calculation (OR: 29.68, 95% CI 4.02‐219.18, p = 0.0009). Global cognitive function by Mini‐Mental State Examination had a higher risk of declining in time in Hispanics (HR: 2.83, CI 1.09‐7.35, p = 0.0320). Likelihood of decline in domain‐specific tests associated with Hispanic ethnicity for Trails A (HR: 4.05, 95% CI 1.93‐8.47, p = 0.0002), Trails B (HR: 3.16, 95% CI 1.62‐6.14, p = 0.0007), and delayed paragraph recall (HR: 2.08, 95% CI 1.01‐4.24, p = 0.0444).

Conclusion

Hispanics present a higher risk of conversion from SCD to MCI than NHW. Apart from stage conversion, subjective and objective measure of cognition worsen more in Hispanics, but in a domain‐specific manner. These findings suggests that Hispanics not only decline at a faster rate, but that this decline is expressed with a different phenotype. This should be considered when studying this population in preclinical investigations.
Mitochondrial Genome‐Wide Association Study Investigating Indices of Mitochondrial Dysfunction in Mexican Americans Compared to non‐Hispanic Whites
Authors: Reid Danielle M , Rowe Megan , Housini Mohammad , Subasinghe Kumudu , Garlotte Isabelle , Barber Robert , Jones Harlan P , Thorpe Roland J. , Sun Jie , Zhou Zhengyang , Phillips Nicole
Published: December 2023

Background

Mexican Americans (MAs) endure racial/ethnic disparities in Alzheimer’s Disease (AD) risk, such as late‐stage diagnosis, earlier onset, and more severe forms of cognitive impairment (CI) compared to non‐Hispanic Whites (NHWs), despite low propensity for the genetic predisposition (e.g., APOE e4 has limited effect on MA AD risk). These complexities have challenged our understanding of AD etiology in this population. MAs are the fastest growing subpopulation within the Hispanic/Latinx population, and as they age, AD will disproportionately affect MAs. Common risk factors for developing CI in MAs include stroke, diabetes, obesity, and depression; however, the reason for the association remains unknown. Diabetes is three times more prevalent among MAs relative to NHWs, and mitochondrial dysfunction is implicated in both AD and diabetes. As a result, mtDNA can accumulate reactive oxygen species damage and elicit pro‐inflammatory processes upon release. Previously, we determined MAs exhibited elevated oxidative mtDNA damage and associated with AD, sex, tobacco abuse, and education compared to NHWs. Here, we hypothesize that mtSNPs will be associated with indices of mitochondrial dysfunction (e.g., mtDNA copy number [mtDNA CN] and 8oxoG variants) in MAs, particularly those with AD and/or diabetes, compared to NHWs.

Method

Whole mtDNA was amplified from extracted buffy coat PBMCs and plasma from 559 TARCC participants using REPLI‐g® Human Mitochondrial DNA Kit and sequenced via Illumina NextSeq. We performed a mitochondrial genome‐wide association study to identify variants associated with 8oxoG mutational load and altered mtDNA CN in MAs compared to NHWs. Analyses control for covariates like age, sex, education, diabetes, tobacco abuse, and depression.

Result

We will report haplogroup effects and determine if specific variants are associated with elevated oxidative burden and/or altered mtDNA CN to better understand population‐specific risks for mitochondrial dysfunction in connection to complex age‐related disease.

Conclusion

This study will establish if mtDNA‐based genetics is relevant to mitochondrial dysfunction (i.e., oxidative damage and/or altered mtDNA CN), which we have shown to be associated with cognitive decline. These results will be evaluated for population‐ and sex‐specific effects taking into consideration key comorbidities (e.g., diabetes). This data could help identify targets for precise approaches to help assess and reduce disease risk.
Characterization of an African ancestry‐specific protective allele of the APOE ε4 allele for Alzheimer’s disease risk
Authors: Wang Liyong , Vasquez Marina Lipkin , Nuytemans Karen , Rajabli Farid , Whitehead Patrice , Gearing Marla , Bennett David A. A , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Scott William K. , Schuck Theresa , Jin Fulai , Xu Wanying , Dykxhoorn Derek M. , Pericak‐Vance Margaret A. , Griswold Anthony J. , Young Juan I. , Vance Jeffery M.
Published: December 2023

Background

We recently identified a protective interaction between the APOE ε4 allele and an African ancestry‐specific allele (rs10423769_A) significantly reducing the odds ratio for Alzheimer’s disease by 75% in APOE ε4 homozygous carriers. rs10423769 is located approximately 2 mB upstream of APOE in a large area of segmental duplication, within a cluster of pregnancy specific beta‐1 glycoproteins (PSG) genes and a long noncoding RNA, lncRNA (ENSG00000282943). Hi‐C analysis in multiple brain cell types showed no direct chromatin interactions between APOE and the rs10423769 region. rs10423769 has been reported to be a splicing quantitative trait locus for the transmembrane protein 145 gene (TMEM145), which has the highest expression in cerebellum.

Methods

Since this interaction region is enriched for segmental duplications, long‐read whole genome sequencing was performed on 16 individuals (nine heterozygous and seven homozygous rs10423769_A carriers) using the Oxford Nanopore PromethION24 to more precisely map this variant. Expression of PSG genes (2, 4, 5 and 11), ENSG00000282943, and TMEM145 isoforms were analyzed by qPCR in cerebellum and frontal cortex of carriers and non‐carriers of rs10423769_A. Hi‐C analysis was conducted in these brain samples as well.

Results

Nanopore long‐read sequencing showed that rs10423769 is present as a single copy on chromosome 19. In the frontal cortex, preliminary Hi‐C results supported the presence of transcriptionally active chromatin over the PSG region in some individuals but not in others. Both PSG genes and the lncRNA had low expression in the frontal cortex and cerebellum. We observed higher TMEM145 expression in the cerebellum compared to frontal cortex and detected alternative splicing forms of TMEM145. There was a trend of increased expression of TMEM145 in rs10423769_A carriers, which was not statistically significant likely due to sample size.

Conclusion

We established that only one copy of rs10423769 exists in the modifying region, which will facilitate future haplotype analysis. The Hi‐C analysis suggested inter‐individual variations on chromatin structure over PSG genes in frontal cortex, although no expression of these genes was detected. Further analysis of regulatory activity of the region is ongoing. This modifier locus appears to represent a novel protective mechanism for APOE ε4.
Multi‐modal Neuroimaging Phenotyping of Mnemonic Anosognosia in the Aging Brain
Authors: Bueichekú Elisenda , Diez Ibai Palacio , Gagliardi Geoffroy Pierre , Kim Chan‐Mi , Mimmack Kayden J. , Sepulcre Jorge , Vannini Patrizia
Published: December 2023

Background

Mnemonic anosognosia (i.e., unawareness) is a behavioral condition characterized by a lack of self‐awareness of objective memory decline. In the context of Alzheimer’s Disease (AD), unawareness may be a sign of predementia stages. It contributes to disease severity, symptomatology worsening, and caregiver burden and is a good predictor of clinical progression. Here, we use in‐vivo multi‐modal neuroimaging to profile the brain phenotype of individuals presenting altered self‐awareness of memory during aging.

Methods

We used amyloid‐ and tau‐PET (N = 335) and resting‐state fMRI (N = 713) data of individuals from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies (Table1A). The neurocognitive profile of unawareness was characterized using between‐groups comparisons (omnibus and post‐hoc analyses) of the objective (LM delayed memory, and FCSRT free and cued scores) and subjective (MACQ) memory measurements of individuals classified as unaware of their memory impairment, compared to aware, subjective‐complainers and control individuals. To characterize the cortical burden of amyloid and tau and their modulatory effect on functional connectivity networks, we applied whole‐brain voxel‐wise GLM analyses, region‐of‐interest associations, and graph‐theory metrics (e.g., degree centrality).

Results

Unaware and aware individuals perform worse than the control group in objective memory tests, while unaware individuals differ from aware but not from controls in MACQ (Table1B). The unaware group presents elevated amyloid and tau burden in midline core regions of the default mode network (DMN) compared to aware, complainer or control individuals (p‐value<0.05) (Figure1AB). Tau spreading in controls showed significant connectivity toward DMN and lateral and medial occipito‐parietal regions (Figure1C). Unawareness is characterized by an altered network connectivity pattern modulated by tau accumulation in which hyperconnectivity is observed mainly in midline DMN and posterior occipito‐parietal regions (p‐value<0.05) (Figure2A). Degree centrality revealed the main connectivity hubs altered by tau deposits in unaware individuals (e.g., posterior regions) (Figure2B).

Conclusions

Mnemonic anosognosia is an early behavioral biomarker of AD pathology. Unawareness of memory decline leads to distinct brain phenotype, characterized by increased amyloid and tau burden, along with functional network connectivity disruptions, in several areas of the self‐referential brain network, including the posterior cerebral cortex of the human brain.
Plasma Alzheimer’s disease biomarkers and intraindividual cognitive variability measured by ecological momentary assessment in adults with type 1 diabetes
Authors: Fonseca Luciana Mascarenhas , Kivisäkk Pia , Hawks Zoë W , Jung Laneé , Bulger Jane , Grinspoon Elizabeth , Janess Kamille , Weinstock Ruth S , Chhatwal Jasmeer P. , Beeri Michal S , Cleveland Michael , Germine Laura Thi , Chaytor Naomi Sage
Published: December 2023

Background

Older adults with type 1 diabetes (T1D) have elevated risk of Alzheimer’s disease and related dementias (ADRD) compared to non‐diabetic controls. Because of oscillations in blood glucose, individuals with T1D are also prone to physiological and cognitive fluctuations. Intraindividual cognitive variability (IICV), or within‐person standard deviation across cognitive tests, has been proposed as an alternative marker of early dementia. The aim of this study was to characterize the relationships between ADRD plasma biomarkers and IICV in adults with T1D via ecological momentary assessment (EMA) of cognition during regular daily activities.

Method

Adults with T1D (age range 19‐84 yrs, mean = 48.9) who participated in the Glycemic Variability and Fluctuations in Cognitive Status in Adults with Type 1 Diabetes (GluCog) study and had available data on plasma β‐amyloid42/40, ptau181, NfL and GFAP levels measured using Quanterix assays were included in these analyses (N = 114). Cognition was assessed three times per day for 15 days. Within‐person measures of IICV were computed for each cognitive test after accounting for practice effects using multilevel modeling: Digit Symbol Matching reaction time (DSM‐RT; processing speed), Gradual Onset Continuous Performance Test d‐prime (GradCPT; cognitive control, attention), and Multiple Object Tracking accuracy (MOT; visual working memory). Multilinear regression models estimated associations between IICV and blood biomarkers, controlling for age, sex, education, person‐level mean cognition, and glucose variability (measured via continuous glucose monitoring).

Results

PTau181 and NfL were associated with IICV‐DSM‐RT (p<0.05). GFAP and β‐amyloid42/40 were not associated with any of the measures of cognitive variability investigated.

Conclusion

These findings suggest that pTau181 and NfL are associated with cognitive variability measured via EMA in an adult sample at risk for ADRD. This is the first study to (i) investigate the association between plasma biomarkers of dementia and IICV measured via EMA and (ii) report plasma biomarker results in individuals with T1D. The results encourage future studies investigating diabetes‐related factors that may contribute to increased dementia risk.
Reduction of neuropsychiatric symptoms and associated caregiver distress using a tetrahydrocannabinol and melatonin combination in dementia due to Alzheimer’s disease
Authors: Tangarife Maria Alejandra , Gutierrez Evelyn , Sanchez Laura Tatiana , Arbelaez María Juanita , Rodriguez‐Soacha Diego , Shahnawaz Saadia S , Ghazaryan Varduhi , Delgado‐Murillo Laura , Naranjo Maria Paula , Venegas Margarita , García David Silva , Pujals Karen Y , De Jesus William Julio , Grimaldi Claudia , Lanctôt Krista L. , Hong L Elliot , Mukunda Ram
Published: December 2023

Background

Neuropsychiatric symptoms (NPS) are features of Alzheimer’s Disease (AD) and a main cause of institutionalization. NPS in AD include agitation, depression, anxiety, elation, apathy, disinhibition, irritability, delusions, hallucinations and aberrant motor behavior. The onset of NPS worsens functional deficits by accelerating patients' cognitive decline and in 80% of cases increases caregiver burden and distress. NPS are difficult to treat and currently used medications have black‐box warnings, and weak evidence of efficacy in dementia patients. Here, we present preliminary data for improvement in NPI scores and NPI Caregiver Distress (NPI‐D) scores using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1).

Method

Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts‐2 and 3, one ml BID and TID were administered respectively with a minimum of 4‐days washout between Cohorts. For all three Cohorts the NPI / NPI‐D were administered at baseline and EOT of each Cohort. Daily, solicited and non‐solicited adverse events (AEs) were monitored along with vital signs. A Wilcoxon matched‐pairs signed‐rank test (R‐Studio, dplyr) was used to independently compare differences between mean NPI and NPI‐D scores at baseline and EOT.

Result

In Cohort‐1 mean NPI at baseline and EOT was 31.5 and 14.8 respectively (mean difference = ‐16.7, v = 55, p = 0.003). In Cohort‐2 mean NPI at baseline and EOT was 22.2 and 12.4 respectively (mean difference = ‐9.8, v = 48, p = 0.021). In Cohort‐3 mean NPI at baseline and EOT was 16 and 7.9 respectively (mean difference = ‐8.1, v = 35, p = 0.010). We report similar improvements in NPI‐D. (Cohort‐1: mean difference = ‐7, v = 15, p = 0.031; Cohort‐2: mean difference = ‐6.3, v = 43, p = 0.009; Cohort‐3: mean difference = ‐3.4, v = 30, p = 0.053). No changes in concomitant medication were observed. No serious AEs, no deaths, and no dropouts due to AEs were reported.

Conclusion

GC‐AD1 was safe and well tolerated and is potentially efficacious in reducing NPS and associated caregiver distress, clinically and statistically, in AD as measured by the NPI, warranting a larger placebo‐controlled study.
A radiomic features study in 18F‐FDG‐PET images to classify Alzheimer Disease patients using machine learning algorithms
Authors: Hernández Cruz Moisés Ebenezer , Avendaño Estrada Arturo , Rodríguez Miguel Ángel Ávila
Published: December 2023

Background

Radiomic features has demonstrate their utility to obtain important information in many diseases, specifically information about tissues or their metabolism that can be related to the diagnostic of a patient. In study of the Alzheimer Disease, there are some works in the use of radiomic features measured in Positron Emission Tomography (PET) images with [18F]fluorodeoxyglucose ([18F]FDG) to train machine learning algorithms and classify patients with and within the disease.

Method

A sample of 50 [18F]FDG‐PET studies of patients with neurological disease suspected was used. All PET images were normalized to a brain atlas space and then radiomic features were measured in all volumes of these atlas. Then the most important features correlated with the diagnosis of the Alzheimer Disease were found and used to train different machine learning algorithms and predict the diagnostic of patients. The shipping diagnosis was used as the target for training, and the same process using the classification of an Alzheimer Disease software tool called PMOD as the target was made.

Result

Some features that shows a correlation with the shipping diagnosis of patients and with the classification of the Alzheimer software tool PMOD were found. Most of them are features measured in parietal regions, and from a radiomic features family called Grey Level Co‐ocurrence Matrix. These features are related with tissue texture. Features with the most significant correlation with their shipping diagnosis and with PMOD classification were used to train machine learning algorithms and good results were obtained for both cases, with maximum accuracies of 0.91.

Conclusion

The correlation analysis helped to improve the training process, obtaining acceptable performance results in the classification of patients using their shipping diagnosis and PMOD classifications as the target. Some of these features shows a clear difference in their values between Alzheimer and control patients, perhaps a bigger sample of patients is needed to be sure of the relation between the feature and the disease. The results in this study suggest that it is possible to find radiomic features that can help us in understanding and diagnosing of Alzheimer Disease.
Leveraging doppler ultrasound imaging to measure pulse wave velocity changes in a mouse model of arterial stiffening to elucidate molecular pathways underlying cerebral damage
Authors: Baggeroer Caroline E , Pietri Peter A , Santisteban Monica M , Harrison Fiona E. , Jefferson Angela L.
Published: December 2023

Background

The highly vascularized brain is particularly vulnerable to changes in pulsatility of blood flow. With age, elastin in arteries breaks down and is replaced by collagen, making arteries less compliant and resulting in arterial stiffening. Stiffening alters pulsatility, which can be measured by pulse wave velocity (PWV), and damages small capillary beds and the neurovascular unit (NVU). The NVU is essential for proper delivery of oxygen and nutrients to the brain. Human studies have demonstrated associations between increased arterial stiffness and biomarkers of Alzheimer’s disease (AD) and neurodegeneration. We adapted a doppler ultrasound imaging method previously only used in rats to measure PWV in a mouse model of arterial stiffening to advance our understanding of the molecular underpinnings of AD and neurodegeneration.

Method

7‐month‐old, C57BL/6, male and female mice underwent a carotid calcification surgery, where the carotid artery was exposed to 0.3 mol/L CaCl2 (or saline as a control) for 20 minutes. PWV was measured using doppler ultrasound imaging before and after surgery. Two weeks post‐surgery, mice underwent behavioral testing, including locomotor activity, elevated zero maze, Barnes maze, and nest building. Collagen, calcium, and elastin levels in the carotid artery were determined 4 weeks post‐surgery by immunohistochemistry.

Result

Preliminary results demonstrate the carotid calcification surgery successfully increased PWV in mice three weeks post‐surgery. Surgery did not inhibit behavioral task performances two weeks post‐operative. Additional data collection is underway applying this method in two transgenic AD mouse models, APP/PSEN1 and P301S, which will include behavioral testing and histological assessment of NVU components, specifically endothelial cells (CD31/PECAM), pericytes (PDGRFb), and astrocytes (GFAP) in the hippocampus.

Conclusion

Elucidating a clear molecular link between increased arterial stiffness and cognition is essential to understanding how age‐related changes in systemic blood flow may influence AD pathology and neurodegeneration. Our preliminary results demonstrate that doppler ultrasound imaging, previously only used in rats, can be applied in mice as a reliable measurement of PWV. We will leverage this model to test the hypothesis that increased PWV is associated with worse spatial learning and memory, impaired functioning of the NVU, and increased AD pathology.
Salivary beta amyloid 1‐42 (Aβ42) for the diagnosis of Alzheimer’s disease: a systematic review and meta‐analysis
Authors: Phillips Geraint A , Butchart Joseph , Hope Suzy , Taylor Gordon , Strain William David
Published: December 2023

Background

Alzheimer’s disease (AD) neuropathology begins many years before dementia symptoms, however validated cerebrospinal fluid and neuroimaging biomarkers are not scalable to widespread use. Higher salivary beta amyloid 1‐42 (sAβ42) is associated with AD, but its clinical utility remains insufficiently evaluated. This systematic review and meta‐analysis quantifies and evaluates the diagnostic performance of sAβ42 in Alzheimer’s disease.

Method

Searches were performed in Ovid MEDLINE, Embase, CENTRAL, PubMed and Web of Science for studies published between January 1, 2000, and March 20, 2022, quantifying sAβ42 in adults with and without AD. All AD diagnoses and criteria were included. Studies without separate AD and control groups and quantitative sAβ42 measurements were excluded. Risk of bias and applicability were evaluated using the QUADAS‐2 tool. Diagnostic performance was assessed by a random‐effects meta‐analysis. Standardised mean differences in sAβ42 levels and 95% confidence intervals in AD and control groups are reported.

Result

Ten of 373 identified articles and 1 study from citation searching were included. Studies unable to quantify sAβ42 (3) and duplicating subject data (2) were removed, leaving 6 studies comprising 264 AD and 463 control subjects for meta‐analysis. Average sAβ42 differentiated AD from controls (pooled weighted SMD 1.83, 95% CI 0.54‐3.12, p = 0.006). However, high sAβ42 variability and substantial heterogeneity (I2 = 97%) limit the reliability of results. Mean sAβ42 levels were higher in AD versus MCI (p<0.0001) and MCI versus controls (p<0.001) but did not differentiate Parkinson’s disease from AD or controls. Age, AD severity and apolipoprotein E status did not reliably correlate with sAβ42 levels.

Conclusion

Alzheimer’s disease was associated with significantly higher sAβ42 concentrations compared with controls. However, the reliability and applicability of study results are significantly limited by widespread risk of bias and inherent low GRADE of evidence.
More research needed on Music programs in Nursing Homes and Senior Living Centers
Authors: Moses‐Eisenstein Michelle
Published: December 2023

Background

In the United States, most dementia care is provided in senior living centers/nursing homes. For various reasons, the response to residents’ behavioral problems is often medications which can have various side effects.

Method

We conducted a literature review in Google Scholar and Pubmed on music programs in nursing homes and senior living centers in order to explore the utility of non‐pharmacological programs.

Result

Several studies indicate that non‐pharmacological interventions such as music programs improve patient behaviors and can lead to a decrease in negative behaviors like agitation. One study found that individualized music programs are associated with reductions in behavioral and psychological symptoms of dementia and medication use. In another study of 4107 residents, Music and Memory program researchers found decreases in medication use and better behaviors. Music also improves memory in Alzheimer’s patients. Group music therapy can reduce depression among patients with dementia. A review of 25 Randomized Controlled Trials or Clinical Controlled Trials found most studies supported the argument that music programs improve mood, quality of life, and neuromotor performances. In particular, music can be customized to better suit the needs of the individual, as studies have shown the importance of selecting music connected to one’s social and national identity. Music programs in groups are also a great opportunity to facilitate social interaction.

Conclusion

The literature supports the need for the arts for seniors however there is a need for larger, more systematic data. Further, there appears to be a research gap on how the lack of funding and reimbursement for music in nursing homes impacts access. For example, do residents have the same access depending on their location (e.g. urban/rural), primary language(s), and/or number of Medicaid beds? Do artists have the training on how to respond if residents become agitated or confused? People with dementia and their caregivers could benefit greatly from more equity in arts access as well as training for artists who want to better support seniors.
Improving gene expression prediction models through the use of meta‐analysis summary statistics
Authors: Mews Makaela , Naj Adam C. , Below Jennifer E. , Bush William S.
Published: December 2023

Background

By focusing on a gene‐level rather than a single‐variant basis, transcriptome‐wide association studies (TWAS) assess the role of genetically regulated gene expression in disease risk and improve statistical power by reducing the multiple testing burden by over a 100‐fold. A key limitation of current TWAS approaches is the requirement for dense individual‐level datasets with both genotypes and gene expression measures to produce effective expression prediction models. We sought to improve the statistical power of AD TWAS by leveraging easily accessible summary statistics taken from large‐scale expression quantitative trait loci (eQTL) meta‐analyses.

Method

We used eQTLGen Whole Blood cis‐eQTL data (N = 31,684) as our source of meta‐analysis summary statistics. To perform gene‐based elastic‐net regressions using the summary statistics, we used the lassosum R package (Mak et al. 2017) with 1000 Genomes data as a genomic reference and GTEx v8 genotype, normalized Whole Blood gene expression and covariate data (N = 670) as a testing panel for model validation and dynamic selection of the optimal mixing/penalty parameters. The SNP‐weights generated by our models were subsequently applied to AD meta‐analysis summary statistics from Kunkle et al. 2019 (AD Cases = 21,982; Controls = 44,944) and Bellenguez et al. 2022 (AD/ ‘proxy’ AD Cases = 111,326; Controls = 677,663) via S‐PrediXcan to assess whether predicted gene expression is associated with AD risk.

Result

We found on average a 3.3% (SD: 0.05%) significant improvement in the predictive performance for 93.3% of genes models (N = 2,787) when using the same SNPs as the PredictDB model. Using models with the restricted SNP set, we identified four genome‐wide significant gene expression models (CTDNEP, p = 3.2e‐9; STK4, p = 1.6e‐13; RPS14, p = 8.8e‐38; POLR1H, p = 5.6e‐45) using Kunkle et al. 2019 summary statistics relative to only one using the PredictDB model (FBXO46, p = 6.6e‐15). When applying the Bellenguez et al. 2022 summary statistics, which contains a broader AD phenotype thru the inclusion of ‘proxy’ cases, we identified 12 genome‐wide significant gene expression models (Range: CHRNA2, p = 2.6e‐8; SLC24A4, p = 4.5e‐16) associated with AD.

Conclusion

Our findings show AD association studies based on TWAS approaches may be improved by meta‐analysis reference panels.
A CLU/APOJ GWAS AD risk variant suppresses the astrocytic response to plaques and reduces axonal and neuritic damage in 5xFAD mice
Authors: Milinkeviciute Giedre , Tran Katelynn , Da Cunha Celia , Mendoza‐Arvilla Adrian , Garcia‐Agudo Laura Fernandez , Neumann Jonathan , Walker Amber , Kawauchi Shimako , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N
Published: December 2023

Background

Genome‐Wide Association Studies (GWAS) implicate clusterin (CLU, also known as apolipoprotein J) as a risk factor for late‐onset Alzheimer’s disease (LOAD), with elevated expression of CLU being associated with increased risk of LOAD. The region surrounding the SNP risk allele rs2279590 is poorly conserved within the mouse genome. Consequently, to model the effect of the rs2279590 risk allele on development of AD‐related pathology in mice we developed mice with a partially humanized allele of Clu.

Method

CRISPR was used to substitute a 2kb region of human CLU (intron 7 to exon 9) containing the enhancer region and the rs2279590 SNP variant for the orthologous region of Clu within the C57BL/6J mouse genome. Clu‐rs2279590_h2kb mice were crossed with 5xFAD mice and aged to 4 and 12. Coronal brain sections were immunolabeled to visualize dense‐core plaques (ThioS), microglia (IBA1), astrocytes (S100β and GFAP), axonal (NfL) and neuritic (LAMP1) damage, confocal images of subiculum and cortical regions were taken and analyzed using Imaris software. In addition, brain Aβ and plasma NfL levels were quantified using meso scale discovery technology.

Result

5xFAD;Clu‐rs2279590_h2kb showed significantly reduced microglial density compared to 5xFAD mice in both brain areas at 4 months. By 12 months of age, microglial density was comparable between genotypes in cortex while in subiculum, elevated IBA1 cell density was observed in 5xFAD;Clu‐rs2279590_h2kb mice. Clu‐rs2279590_h2kb variant in 5xFAD background increased the density of S100β astrocytes in subiculum at 4 months and decreased the total S100β volume at 12 months. Reduced GFAP (reactive astrocytes) levels were found in cortex but not subiculum at 12 months. Despite comparable plaque load and insoluble Aβ42 levels, neuritic and axonal damage was decreased in the brain of 5xFAD;Clu‐rs2279590_h2kb compared to 5xFAD mice at 12 months. Plasma NfL was also significantly decreased.

Conclusion

Despite the minimal impact on Aβ plaque deposition, humanization of 2kb of Clu allele and introduction of rs2279590 risk SNP suppresses astrocytic response to plaques and is protective against axonal and neuritic damage which is mirrored by the reduced levels of plasma NfL.
Microglia from individuals with mild cognitive impairment (MCI) and AD show differences in transcriptional burst kinetics
Authors: Jin Bowen , Pericak‐Vance Margaret A. , Martin Eden R. , Farrer Lindsay A. , Haines Jonathan L. , Bush William S.
Published: December 2023

Background

Microglia are the innate immune cells in the central nervous system that responds to brain injury and pathogens. The loss of homeostatic microglia is associated with neurodegenerative diseases. Multiple studies of AD mouse models have identified AD‐associated microglia subtypes, e.g., disease associated microglia (DAM). However, studies of human microglia have not reported similar microglia subtypes. Therefore, how human microglia change in the presence of amyloid‐ protein deposition and phosphorylated Tau remains an open question.

Method

We have developed an approach that estimates transcriptional kinetics from scRNA‐seq data. This approach models how “bursty” and variable a gene expression is. We hypothesize that transcriptional bursts of key genes are different within AD cases compared to MCI individuals. We used the ROSMAP scRNAseq microglia dataset of 8 AD cases and 4 MCI cases and applied our approach to estimate the transcriptional kinetics for each subject. We then compared the difference in transcriptional kinetics of genes that are estimated both in AD and MCI.

Result

First, we found that 96% of microglia cells in AD and MCI shows a similar co‐occurrence pattern of expressed genes and, therefore, likely reflect the same cell type. Within the assumed homogeneous microglia cells, we identified two genes, C1QC and ACTB, showing significant differences in their transcriptional kinetics between AD and MCI cases. Both C1QC and ACTB show larger burst sizes in MCI than in AD cases (p‐value for C1QC:0.0038; p‐value for ACTB: 0.00918). Consequently, C1QC and ACTB show a higher expression level variability among microglia cells in MCI cases than AD.

Conclusion

Our result suggests C1QC and ACTB may be associated with AD risk via changes in variability of gene expression rather than total gene expression levels. The increased variability in transcription of C1QC and ACTB in MCI individuals relative to AD cases might indicate more mobile and active physiological states of microglia. These results may point to functional changes in these genes with AD progression and are prime targets for further experimental validation.
Multimodal and multiregional atlas of Alzheimer’s disease changes
Authors: Gabitto Mariano I , Travaglini Kyle J , Ariza Jeanelle , Close Jennie , Ding Yi , Long Brian , Rachleff Victoria M , Chakrabarty Rushil , Crane Paul K , Ferrer Rebecca , Gatto Nicole M , Goldy Jeff , Grabowski Thomas J , Guilford Nathan , Guzman Junitta , Hawrylycz Michael J , Hodge Rebecca D , Jayadev Suman , Kaplan Eitan S , Keene C Dirk , Larson Eric B , Latimer Caitlin S , Levi Boaz P , Mahoney Joseph T , Melief Erica J , Miller Jeremy A , Mukherjee Shubhabrata , Pham Thanh , Smith Kimberly , Torkelson Amy , Chakka Anish Bhaswanth , Lein Ed S
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common form of dementia. The progression of AD throughout the brain follows a stereotypical pattern that can be described by the quantification of histopathological changes in several brain regions. As part of The Seattle Alzheimer’s Disease Cell Atlas (SEA‐AD, https://sea-ad.org), we previously quantified pathological proteins in the middle temporal gyrus (MTG) and used them to describe disease progression, vulnerable cell types, and the MTG molecular changes related to disease

Method

In this work, we expanded our results and undertook a comparative approach. We measured a battery of neuropathological proteins (staining NeuN, AT8, IBA1, GFAP, 6e10, pTDP43, and a‐Syn immunoreactivity, and analyzing them with machine learning) in the middle temporal gyrus, the middle frontal gyrus, and medial entorhinal cortex in 84 donors. In addition, we undertook a multimodal single‐cell analysis of such regions, profiling cells using single‐cell RNA‐seq, ATAC‐seq, Multiome, and spatial transcriptomic.

Borrowing from our hierarchically resolved cell types in MTG, based on the BRAIN initiative cell type reference, we used machine learning algorithms to create multimodal cell type maps across regions. We used Bayesian statistics to identify differentially accessible regulatory elements, link them to the affected genes and the regulatory transcriptional machinery binding in such elements.

Result

We identified regional vulnerable neuronal populations and a core set of transcriptionally similar cell types susceptible to disease across the cortex. We created a cortex‐wide disease progression map combining neuropathological data from our three profiled regions with latent Bayesian statistical algorithms. In each area, we developed an AD pseudo‐progression timescale that describes the burden of disease in the area and, next, combined all areas to create a cortex‐wide holistic pseudo‐progression. We used the mapped cell types and our developed scale to synchronize changes occurring in each patient, describing abundances, gene expression, and chromatin accessibility modifications.

Conclusion

The progression scale developed in this study serves as a reference to align changes across brain regions and, in the future, to reconcile differences across cohorts.