bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between amyloid‐β, plasma/brain GFAP, and neocortical tau: a Mendelian randomization study
Authors: Yang Hyun‐Sik , Kivisäkk Pia , Viera Andrea M. Román , Maa Courtney , Kirn Dylan , Bellier Jean‐Pierre , Liu Lei , Selkoe Dennis J. , Schneider Julie A. , Bennett David A. , Jager Philip L. De , Johnson Keith A , Sperling Reisa A , Arnold Steven E. , Chhatwal Jasmeer P.
Published: January 2025

Background

Plasma glial fibrillary acidic protein (GFAP) is associated with amyloid‐β (Aβ) and tau, but their causal relationships remain unclear. We used Mendelian randomization (MR; using genetic causal anchors to avoid reverse causation) to clarify the causal relationship between plasma/brain GFAP, Aβ, and tau.

Methods

Study participants are from two independent datasets: the Harvard Aging Brain Study (HABS) and the Religious Orders Study/the Rush Memory and Aging Project (ROSMAP) (Table 1). From HABS, we used baseline plasma GFAP (MSD platform) and Aβ (PiB PET cortical composite with partial volume correction [PVC]) and longitudinal inferior temporal (IT) tau (FTP PET SUVR with PVC) data. From ROSMAP, we used post‐mortem frontal cortex GFAP expression (RNA‐Seq) and midfrontal Aβ and tau burden (immunohistochemistry). We used linear regressions to assess the relationship between APOE ε4, GFAP, and Aβ. For MR, we performed instrumental variable (IV) analyses using APOE ε4 as the instrument. In HABS, we used linear mixed effect models to assess baseline GFAP ‐ longitudinal IT tau association. In ROSMAP, we assessed the cross‐sectional GFAP ‐ tau association (linear regression). All variables were standardized, and all models were adjusted for age and sex.

Result

In HABS, APOE ε4 carriers had higher baseline plasma GFAP (n=324, β=0.32, p=0.0025), but this association attenuated after adjusting for Aβ (p=0.42). MR suggested the causal effect of Aβ on plasma GFAP (2SLS β=0.40, p=0.0018). Baseline plasma GFAP predicted longitudinal increase in IT tau (n=187, β=0.051, p=1.9×10‐4); this association attenuated after adjusting baseline Aβ and its time‐interaction (p=0.16). We observed consistent results in ROSMAP: APOE ε4 carriers had higher frontal GFAP expression (n=609, β=0.26, p=0.0051), but this association attenuated after adjusting for Aβ (p=0.11). MR supported the causal effect of Aβ on brain GFAP (2SLS β=0.39, p=0.0085). The frontal GFAP– tau association (β=0.10, p=0.012) weakened after controlling for Aβ (p=0.50).

Conclusion

Our study leveraging APOE ε4 as a genetic causal anchor supports that Aβ is at the causal upstream of increased brain GFAP gene expression and elevated plasma GFAP (Figure 1A). By contrast, the neocortical tau – GFAP association is likely confounded by Aβ (Figure 1B‐C).
Cerebrovascular and Metabolic Alterations in a Mouse Model of Familial Alzheimer’s Disease Carrying the Notch3 C456R Mutation
Authors: Letica Leila , Choi Sang‐Ho , Dubberley Lauren R , Szczupak Diego , Park Jung Eun , Schaeffer David J , Silva Afonso C
Published: January 2025

Background

Vascular pathology associated with small vessel disease (SVD), such as microinfarcts and microbleeds, are common in elderly populations and significant contributors to cognitive impairment and dementia. Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), caused by mutations in the Notch3 gene, is the most prominent inheritable SVD, with a common etiology of subcortical strokes and dementia. This study aimed to investigate additive or synergistic effects of CADASIL‐related vascular alterations and familial Alzheimer’s disease (FAD)‐related amyloid pathology on cerebral metabolism of glucose and disease progression in a novel FAD‐CADASIL mouse model.

Methods

We bred 5xFAD mice to CADASIL mice carrying the Notch3 C456R mutation to create the novel FAD‐CADASIL mouse model. To investigate progressive alterations in cerebral glucose metabolism, 18F‐FDG was delivered to awake mice via a tail vein injection, with an average dose of 18.5 MBq. The mice were fasted for a minimum of 2 hours before 18F‐FDG administration. PET and CT acquisitions were completed after a 30‐minute 18F‐FDG circulation period using a Bruker Si78 instrument. Static datasets were analyzed for standard uptake values relative to the brainstem (SUVr) and corrected for glucose levels (SUVglc). Statistical tests included unpaired t‐tests and 1‐ & 2‐way ANOVA using GraphPad Prism 9.

Results

Whole brain SUVr values were decreased across age groups in 5xFAD, Notch3C456R, and 5xFAD/Notch3C456R mice compared to age‐matched WT controls. Blood glucose levels collected before ligand injection indicated an age‐dependent decrease in glucose levels across all genotypes. 5xFAD/Notch3C456R mice showed distinct reductions in whole brain SUVglc values compared to aged‐matched 5xFAD and Notch3C456R mice. ROI analysis of 3‐month‐old 5xFAD/Notch3C456R shows significantly decreased SUVglc levels in several cortical regions such as the striatum, cortex, hippocampus, hypothalamus, and thalamus when individually compared to WT, 5xFAD, and Notch3C456R mice (Figure 1).

Conclusion

We observed a significant synergistic effect of CADASIL on accelerating increased amyloid accumulation and reducing cerebral glucose metabolism in the novel FAD‐CADASIL mouse model. These results provide further key evidence of an association between cortical vascular pathology and Alzheimer’s Disease progression.

This research was funded by NIH/NINDS grant RF1NS117486.
White Matter Connectivity as an Early Biomarker of Alzheimer's Disease: A Structural MRI and Network‐Based Study in Mild Cognitive Impairment with Neuropsychiatric Features
Authors: Mohammad pajavand Amir , Grothe Michel J. , de Schotten Michel Thiebaut , Vergallo Andrea , Hampel Harald
Published: January 2025

Background

Neuropsychiatric symptoms (NPS), including depression and circadian rhythm disruptions, are early non‐cognitive markers along the Alzheimer’s Disease (AD) continuum. These pathological states are thought to resemble AD pathogenesis, both of which are characterized by a marked decline in adult hippocampal neurogenesis.

Method

96 elderly participants divided into three groups based on the global depression scale, neuropsychiatric inventory, clinical dementia rating, and mini‐mental status examination. Twelve MCI individuals with NPS (MCI+) and 49 without NPS (MCI‐) were classified, and 35 healthy individuals were matched for age and gender.

Voxel‐based morphometry and Tract‐Based Spatial Statistics were employed to conduct a comprehensive brain‐wide comparison between groups. We used a network‐based statistic method to probe deviations in brain structural WM connectivity.

Result

The Hippocampus, Amygdala, and sensory cortex (SSC) exhibited GM loss in MCI+ versus healthy individuals. Furthermore, structural WM connectivity reductions in the thalamus, pallidum, putamen, caudate, hippocampus, SSC, and frontal cortex suggest the involvement of the limbic system before overt volumetric GM loss in the same group analyses.

Conclusion

This study indicated structural WM connectivity loss within the Papez circuit before the GM integrity at the medial temporal lobe in individuals with MCI+ before their conversion to AD dementia. These findings shifted the focus to the Papez circuit during the prodromal phase of the disease, concurrent with pathological changes in the medial temporal lobe.
Plasma biomarkers combinations for prescreening rapid amyloid accumulation in cognitively unimpaired individuals at‐risk of Alzheimer’s disease
Authors: Contador José , Milà‐Alomà Marta , Escalante Armand González , Ashton Nicholas J. , Shekari Mahnaz , Ortiz‐Romero Paula , Karikari Thomas K , Vanmechelen Eugeen , Day Theresa A. , Dage Jeffrey L. , Zetterberg Henrik , Gispert Juan Domingo , Blennow Kaj , Suarez‐Calvet Marc
Published: January 2025

Background

Alzheimer’s disease (AD) blood biomarkers alone can detect amyloid‐β (Aβ) pathology in cognitively unimpaired (CU) individuals. We assessed whether combining different plasma biomarkers improves the detection of Aβ‐positivity and identifies rapid amyloid deposition in CU individuals.

Method

CU participants from the ALFA+ cohort were included. Among them, 361 had CSF Aβ42/40 and 328 amyloid PET‐scans [194 with two longitudinal scans; mean interval=3.35 (0.56) years]. Plasma Aβ42/40, p‐tau181, p‐tau231, GFAP, NfL (Simoa‐based) and p‐tau217 and t‐tau (MSD‐based) were measured at baseline (Table 1). We used simple and multiple logistic models to estimate Aβ‐positivity (defined as CSF Aβ42/40<0.071 or amyloid‐PET>12 Centiloids) or Aβ accumulation rate (“Fast accumulators” defined as >3 Centiloids/year). The model contained plasma biomarkers and demographics (age and sex) as covariates. We selected as "best model" (BM) that with lowest AIC. We defined parsimonious models as those with an AUC not significantly different (DeLong test) from BM or from each other yet outperforming single biomarkers and/or demographics models (FDR corrected). For the positive agreement closest to 90%, we calculated savings in lumbar punctures and amyloid PET‐scans.

Result

For CSF Aβ‐positive detection, BM included plasma Aβ42/40, p‐tau181, p‐tau217, p‐tau231, GFAP and t‐tau (AUC=0.84). All simpler biomarkers combinations included plasma Ab42/40 and p‐tau231 (Table 2A). For PET Ab‐positive detection, BM included plasma Aβ42/40, p‐tau181, p‐tau217, GFAP, NFL and age (AUC=0.88). All simpler biomarkers combinations included plasma Ab42/40 and p‐tau217 (Table 2B). Regarding fast accumulators’ detection, plasma p‐tau217 was the single biomarker with the highest performance (AUC=0.70). BM included plasma Aβ42/40, p‐tau217, p‐tau231 and GFAP (AUC= 0.76). BM and the plasma Aβ42/40, p‐tau217 and GFAP (AUC=0.75) combination were the only models that outperformed the age and sex combination and single biomarkers, except for plasma p‐tau217, Aβ42/40 (AUC=0.69) or GFAP (AUC=0.68) alone (Table 2C). The combination of biomarkers could save up to 11% of lumbar punctures or 44% of amyloid‐PET to detect Ab‐positive CU individuals and 16% amyloid‐PETs to detect fast Aβ‐accumulation compared to the best single plasma biomarker (Table 2).

Conclusion

In CU individuals, diverse combinations of plasma biomarkers detect Aβ‐positivity and future Aβ‐accumulation with high accuracy and can lead to substantial cost savings in AD detection.
Multilayer structural‐functional connectome changes are associated with amyloid‐β and tau pathologies in Alzheimer’s Disease
Authors: Yu Meichen , Sporns Olaf , Saykin Andrew J.
Published: January 2025

Background

Brain network studies in Alzheimer’s disease (AD) have primarily focused on structural and functional connectomes as separate entities. However, it remains unclear how brain structure interacts with brain function in AD.

Method

We included 75 cognitively unimpaired participants and 49 patients with AD. For each participant, we integrated a structural connectome (derived from DTI) and a functional connectome (derived from fMRI) into a multilayer structural‐functional connectome. We partitioned the DTI and fMRI maps into 68 Desikan‐Killiany ROIs. The links within the DTI and fMRI layers were formed by the structural and functional connectivity between the 68 ROIs, respectively. The interlayer links were defined by Pearson’s correlations between the connectivity vectors of ROIs from the two layers. We computed centrality values for each layer (i.e., nodal strength) and across layers (i.e., multiplex overlapping degree) and compared the centralities between patients and controls. We assessed spatial correlations between regional levels of amyloid‐β and tau pathologies and regional centrality values.

Result

In general, ROIs that showed higher centralities in both layers also showed higher multilayer centralities, while ROIs with both a low structural and functional connectivity were typically observed in the multilayer network. Multilayer centrality was lower in AD patients relative to controls at multiple brain areas, such as the entorhinal cortex, superior frontal, temporal, and parietal cortices. Both multilayer and single‐layer centralities showed stronger correlations with tau than with amyloid‐β loads. Of note, only the multilayer centralities were positively correlated (r = 0.23; p = .04) with the amyloid‐β levels, although DTI‐derived centralities showed a trend‐level correlation (r = 0.21; p = .086) with amyloid‐β deposit. In addition, all the three types of centralities showed significantly negative correlations with tau deposit levels. Of note, multilayer centralities showed a stronger correlation than single‐layer metrics, in the order of multilayer (r = ‐0.54; p < .0001) > fMRI (r = ‐0.47; p < .0001) > DTI (r = ‐0.38; p = .0017).

Conclusion

Our findings suggest that network centralities derived from a multilayer connectome might be more sensitive than those generated from each single layer in tracking and predicting amyloid‐β and tau spread.
Cerebrospinal fluid apoe glycosylation associates with biomarkers of Alzheimer’s Disease pathology
Authors: Nedelkov Dobrin , Tsokolas Zoe , Sible Isabel , Mack Wendy J , Han S Duke , Rodman John CS , Yassine Hussein N
Published: January 2025

Background

The apolipoprotein E (ApoE) Ɛ4 allele is associated with a significant risk for both late‐onset Alzheimer’s Disease (AD) development and cerebral amyloidosis, but the degree to which cerebrospinal fluid (CSF) apoE glycosylation affects disease progression is unclear. The objective of this study was to examine the relationship of CSF apoE glycosylation with t‐tau, p‐tau181, and Aβ1‐42 CSF levels, and to delineate the effect of the APOE4+ genotype (vs E4‐) on glycosylation.

Method

Total glycosylation and apoE isoform‐specific glycosylation were analyzed in baseline plasma and CSF samples from a longitudinal cohort of older individuals (n=188, ages 55 ‐ 89) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). ApoE glycosylation was assayed using Mass Spectrometric Immunoassay (MSIA) that simultaneously detects the apoE isoforms and their glycosylation percentage. We performed pairwise comparisons between each apoE isoform and utilized linear mixed‐effects modeling to analyze longitudinal associations of apoE glycosylation with AD biomarkers, adjusting for age, sex, race, education, and clinical status.

Result

We examined glycosylation as a function of individual apoE isoforms and found that both total and secondary CSF glycosylation had the same trend: the E4 isoform had an overall lower % glycosylation compared to E2 and E3 isoforms (p<0.0001). Similarly, the E3 isoform had lower total and secondary CSF % glycosylation compared to the E2 isoform (p<0.0001). We further assessed whether the % apoE glycosylation in the baseline samples were associated with CSF t‐tau, p‐tau181, and Aβ1‐42 CSF levels in the longitudinal samples. Total CSF and secondary CSF glycosylation demonstrated highly significant associations with decreased levels of t‐tau (p < 0.002; p < 0.02 respectively) and p‐Tau181 (p< 0.006; p<0.02 respectively) over a 10‐year period. Secondary CSF glycosylation was significantly positively correlated with increased CSF Aβ1‐42 levels over a 10‐year period (p < 0.04).

Conclusion

The degree of CSF ApoE glycosylation is strongly associated with concentrations of CSF t‐tau, p‐Tau181, and Aβ1‐42, and is predictive of biomarker changes over time. These novel discoveries underscore the importance of understanding the mechanisms involved in apoE glycosylation in the brain, which can lead to new targets and therapies for AD.
An X chromosome‐wide DNA methylation study of Alzheimer’s disease
Authors: Wang Lily , Zhang Wei , Gomez Lissette , Kunkle Brian W. , Lukacsovich David , Schmidt Michael A. , Varma Achintya , Griswold Anthony J. , Bush William S. , Martin Eden R.
Published: January 2025

Background

Sex is an important factor that contributes to both clinical and biological heterogeneity in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex differences in AD are still not well understood. DNA methylation (DNAm) is an epigenetic modification that regulates gene transcription and is known to be involved in AD. However, due to analytical and biological complexity, few previous DNAm studies analyzed the X chromosome, where many genes influencing cognitive abilities and immune functions are located.

Method

We performed a sex‐specific X chromosome‐wide analysis of the DNAm data generated by the longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. We used mixed effects logistic regression models with AD status as the outcome, adjusted for age, sex, batch, and immune cell‐type proportions, random subject effects, and corrected for inflation.

Result

Our analysis included 632 female DNAm samples (188 cases, 444 controls) and 652 male DNAm samples (239 cases, 413 controls), measured on blood samples of 179 and 219 independent subjects with ages older than 65 years. Given our modest sample size, we considered CpGs with suggestive significance at the prespecified significance threshold of P < 1×10‐5. In females, we identified 2 significant CpGs (cg04150893 and cg16580361), mapped to the intergenic region and gene body of the HMGN5 gene. No significant CpGs were identified in male samples. Interestingly, blood DNAm at cg16580361 is significantly associated with DNAm in the prefrontal cortex (Blood Brain DNA methylation Comparison Tool: r = 0.599, P = 1.74×10‐8). Consistent with our observed hypermethylation at cg16580361 in ADNI data (OR = 1.11, P = 6.14×10‐6), the HMGN5 gene is also significantly upregulated in the frontal cortex of female AD subjects (Agora database https://agora.adknowledgeportal.org: OR = 20.227 = 1.17, adjusted P = 5.7×10‐6). The HMGN5 gene is involved in the metabolism of the brain antioxidant glutathione. Decreased levels of glutathione have been implicated in both AD onset and progression.

Conclusion

Our analysis of the X chromosome in the ADNI study dataset nominated cg16580361 located on the HMGN5 as a plausible biomarker for AD. Future studies that validate our findings in larger and more diverse community‐based cohorts are needed.
A Brief Digital Neuropsychological Protocol – I: Using Artificial Intelligence Assisted Technology to Assess Process and Errors
Authors: Libon David J. , Swenson Rodney , Tobyne Sean , Price Catherine C. , Lamar Melissa , Cosentino Stephanie , Banks Russell , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro
Published: January 2025

Background

There is an urgent need for neuropsychological screening tests that are easily deployed and reliable. We have developed a digital neuropsychological screening protocol that is administered on a tablet, automatically scored using artificial intelligence, and requires approximately 10 minutes to administer. This tablet‐administered protocol assesses the requisite neurocognitive constructs associated with emergent neurodegenerative illness

Method

The digital protocol was administered to 77 ambulatory care/ memory clinic patients (Table 1). The protocol is comprised of a 6‐word version of the Philadelphia (repeatable) Verbal Learning Test [P(r)VLT], three trials of 5 digits backward (BDST), and the ‘animal’ fluency test. The protocol provides a panel of six traditional measures as would be obtained using paper/ pencil tests and manual scoring of (P[r]VLT free recall/ recognition hits, backward digit span, ‘animal’ fluency output); a variety of outcome measures quantifying errors and the process used to bring tests to fruition; and two separate, norm‐referenced summary scores measuring executive control and memory.

Result

Cluster analysis using the panel of 6 traditional measures classified participants into normal (nl= 23), amnestic MCI (aMCI= 17), dysexecutive MCI (dMCI= 23), and dementia (dementia= 23) groups. Subsequent analyses of error and process variables operationally defined key features associated with amnesia including rapid forgetting such as (P[r]VLT immediate free recall trial 2 vs. delay free recall (aMCI & dementia < dMCI & nl; p< 0.001), the production of extra‐list intrusion errors (dementia > nl; p< 0.002); profligate responding to recognition foils (aMCI & dementia > dMCI & nl; p< 0.001); key features underlying reduced executive measures (i.e., BDST perseveration/ related errors (dMCI & dementia > aMCI & nl, < 0.050); and the strength of semantic association from successive ‘animal’ fluency responses (nl & dMCI > dementia; p< 0.028). The novel executive and memory index scores dissociated all four groups from each other (p< 0.014).

Conclusion

This digitally administered and scored protocol yields patterns of impaired performance similar to paper/ pencil tests. The availability of both traditional and error/ process measures suggests that subtle, nuanced indications of early emergent illness may be identified in a fast, efficient, yet comprehensive way.
The ABCA1 agonist CS6253 shows favorable safety and pharmacokinetics in IND‐enabling toxicology and Phase 1 human studies aimed at the indication of Alzheimer’s disease
Authors: Johansson Jan O. , Winblad Bengt , Michaelson Daniel M , Zetterberg Henrik , Cummings Jeffrey L. , Yassine Hussein N
Published: January 2025

Background

ABCA1‐mediated cholesterol transport is a central feature in many lipid‐ dependent diseases including APOE4‐associated Alzheimer’s disease and atherosclerosis‐CVD. ABCA1 upregulation of RNA transcription by nuclear factors (LXR, RXR) have been associated with liver side‐effects because of the common promotor element for ABCA1 and Fatty Acid Synthase. The ABCA1 agonist CS6253, derived from the C‐terminal of apoE was designed to stabilize and enhance ABCA1 function, thereby providing a safe alternative to transcriptional upregulation. CS6253 has in various mice models shown favorable neuroprotective and vascular‐metabolic effects suggesting potential for APOE4 MCI/AD and mixed MCI/AD.

IND enabling studies in Wistar rats and Cynomolgus monkeys(cynos) were performed, and a Phase 1 SAD‐MAD study initiated, to explore the safety, PK and biomarker effects of CS6253.

Method

Conventional IND enabling toxicology studies, including 30‐day GLP studies in male and female rats and cynos were performed, in which CS6253 was injected as IV bolus injection every other day. Following clearing the IND a Phase 1 SAD‐MAD double‐blind, placebo‐controlled study was initiated, including elderly with and without APOE4 genotype, the SAD part ending in March 2024.

Result

Toxicology studies showed that cynos was the more sensitive species with the No Observable Adverse Effect Level (NOAEL) being 75 mg/kg. In plasma exposure/AUC in cynos was linear up to 25 mg/kg and showed already from 10 mg/kg transient increases in preb1‐HDL, small HDL and triglycerides which was associated with a significant increase in amyloidb42/40‐ratio.

Conclusion

Enhancing ABCA1 functions by CS6253 to form small HDL appears to be a promising approach with neuroprotective properties as indicated by pharmacology, IND‐enabling toxicology, and Phase 1 studies. The development of a safe and efficient ABCA1 agonist addresses several indications with unmet medical, notably for Alzheimer’s and brain vascular diseases.
ABCA7 high‐risk genotype predicts working memory decline among older cognitively healthy African Americans
Authors: Sheikh Mustafa , Piaszczynska Wiktoria , Arnasalam Alyssa , Oyono Arcande , Perez José Mojica , Budak Miray , Fausto Bernadette A. , Gluck Mark A.
Published: January 2025

Background

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline1. APOE‐ε4 has been identified as the most prevalent genetic risk factor for the early onset of AD, while ABCA7‐80 (rs115550680) has been shown to have a stronger effect size than the APOE‐ε4 allele and is associated with the development of late‐onset of AD among African Americans2,3. Although the efficiency of executive functions declines with age, some basic attentional functions and preserved knowledge may help mitigate the effects of aging on working memory4. Nevertheless, the impact of APOE ε4 and ABCA7‐80 genotypes on attention and executive function in preclinical AD remains unclear5. This study investigated the influence of APOE ε4 and ABCA7‐80 genotypes on working memory among cognitively unimpaired older African Americans.

Method

Participants were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. 838 participants (ages ≥ 60) completed saliva collection for genotyping and neuropsychological battery for cognitive assessment with a fraction repeating each assessment multiple times as part of returning visits. Simple linear mixed models were applied for longitudinal statistical analysis.

Result

ABCA7‐80 high‐risk genotype was found to be a risk factor for decreased cognitive performance, as assessed by Trail Making Test Part A (ß = 5.819, p = 0.030) and Part B (ß = 39.964, p < 0.001), Digit Span Total (ß = ‐2.092, p= 0.045), Controlled Oral Word Association (ß = ‐4.708, p = 0.019), as well as a significant association with increased depression.

Conclusion

The ABCA7‐80 high‐risk genotype may indicate early working memory declines in preclinical AD and may serve as a predictive biomarker among cognitively impaired older African Americans.
Comparing the diagnostic performance of plasma pTau181 and pTau217 for the identification of Alzheimer’s disease co‐pathology in Lewy Body Disease
Authors: Smith Alena , Plastini Melani J. , Ashton Nicholas J. , Montoliu‐Gaya Laia , Wilson Edward N. , Arslan Burak , Young Christina B. , Winer Joseph R. , Shahid Marian , Vossler Hillary , Kerchner Geoffrey A. , Cholerton Brenna , Andreasson Katrin I. , Yutsis Maya , Henderson Victor W. , Montine Thomas J. , Tian Lu , Mormino Elizabeth , Zetterberg Henrik , Poston Kathleen L. , Abdelnour Carla
Published: January 2025

Background

Lewy body disease (LBD) often co‐occurs with Alzheimer’s disease neuropathological change (ADNC), which can be detected using plasma pTau181 and pTau217. Few studies have investigated these biomarkers in LBD, nor have studies investigated plasma pTau217 in Parkinson’s disease (PD) cognitively normal patients (LBD‐CN), or in alpha‐synuclein positive (asyn‐positive) participants. Furthermore, uncertainties remain regarding LBD‐specific cut‐points for these biomarkers.

We aimed to determine whether there is a difference in the diagnostic performance of plasma pTau181 and pTau217 for detecting ADNC and amyloidosis in LBD. We also determine whether cut‐points for these biomarkers in LBD differ from those for AD. Finally, we conducted a sensitivity analysis in asyn‐positive participants.

Method

We included 230 Stanford research participants: 110 cognitively normal (CN), 43 LBD‐CN, 41 LBD with cognitive impairment (LBD‐CI), and 36 AD. Plasma pTau181 was measured with the Lumipulse G platform, and pTau217 with the ALZpath pTau217 assay. A‐syn positivity was assessed in CSF with SYNTap®. Diagnostic accuracy of pTau181 and pTau271 in distinguishing ADNC (determined by CSF pTau181/Aβ42) and amyloidosis (determined by CSF Aβ42/Aβ40 or amyloid‐β PET) were evaluated with receiver‐operating characteristic (ROC) analyses. The Youden index was used to determine optimal cut‐points in distinguishing ADNC and amyloidosis, and the DeLong test to compare model performance.

Result

In the LBD‐CI group, plasma pTau181 and pTau217 had similar diagnostic performance in distinguishing ADNC+ from ADNC‐ (Figure 1A). Similarly, in the LBD‐CN and LBD‐CI groups, both biomarkers had similar diagnostic performance in distinguishing Aβ+ from Aβ‐ participants (Figure 1B). However, in the sensitivity analysis, pTau217 outperformed pTau181 for detecting Aβ+ in asyn‐positive participants (AUC: 0.88, 95%‐CI: 0.77‐1 vs 0.77, 95%‐CI: 0.64‐0.90, p=0.045) (Figure 2B). Finally, plasma pTau181 and pTau217 cut‐points for detecting ADNC and amyloidosis in LBD differed from those for AD (Figures 1‐3).

Conclusion

We present, for the first time, the diagnostic accuracy of plasma pTau217 in LBD‐CN and asyn‐positive participants. Our results indicate that plasma pTau181 and pTau217 reliably detect concomitant ADNC and amyloidosis in LBD. Particularly, plasma pTau217 appears more sensitive for detecting amyloidosis in asyn‐positive participants. Additionally, our findings underscore the importance of establishing LBD‐specific cut‐points for AD biomarkers.
Measuring the Potential Risk of Re‐identification of Imaging Research Participants from Open‐Source Automated Face Recognition Software
Authors: Prakaashana Carl M. , Savvides Marios , Gunter Jeffrey L. , Senjem Matthew L. , Vemuri Prashanthi , Kantarci Kejal , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Schwarz Christopher G.
Published: January 2025

Background

Research subjects can potentially be re‐identified from de‐identified MRI, CT, and PET brain scans with up to 98% accuracy using Microsoft Azure’s cloud‐based commercial facial recognition software. This showed the need to “de‐face” publicly shared research brain scans. Subsequently, Microsoft has begun restricting its face recognition services, intending to prevent misuse. This study tests a variety of popular open‐source computer vision and facial recognition software packages to measure the re‐identification risk with only unrestricted free software.

Method

This study used brain MRI from Siemens 3T scanners and face photographs from 182 participants (ages 30‐90+) in the Mayo Clinic Study of Aging. Each participant had photos taken with an iPad, which were cropped loosely around the head and converted to black and white. A total of 81 renders (2D reconstruction images; Figure 1) were made from each 3D T2‐FLAIR MRI, simulating various camera and lighting positions. These face renders approximate black and white photos, allowing use with software packages developed for matching faces/features between photographs.

Open‐source Python packages (OpenCV, DeepFace, face_recognition, scikit‐learn) and their included pre‐trained models (designed for photographs) were used to match participant photographs to the labelled library of MRI‐based face renders. A correct match was recorded when the top‐scoring render or set of renders automatically chosen by the algorithm was from the MRI of the correct participant.

Result

Feature matching with ORB and SWIFT (both from OpenCV) produced no correct matches, despite a prior publication reporting moderate success. The best match rates (Figure 2) were 58‐59% accuracy using face_recognition or DeepFace packages with support vector machines (SVMs). Without SVMs, these packages performed modestly worse (51%‐55%).

Conclusion

While the highest match rates obtained by widely available open‐source packages (roughly 60%) are much lower than those of a limited‐access commercial product (Microsoft Azure, with 98%), they show that actors with only access to no‐cost readily available software could still re‐identify a research subject from a brain scan most of the time. This further highlights the need for image refacing software, such as mri_reface, to protect the privacy and identifies of research volunteers.
NODDI measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer’s disease pathology and cognitive outcomes
Authors: Parker Dana M , Adams Jenna N. , Kim Soyun , McMillan Liv , Yassa Michael A.
Published: January 2025

Background

Diffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer’s disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting‐edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD‐related changes in medial temporal lobe (MTL) WM than traditional tensor metrics.

Method

199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75; 60% female; cognitively unimpaired, n=121; cognitively impaired MCI/dementia, n=78) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate; Figure 1). A subset of participants received 18F‐florbetapir or 18F‐florbetaben to measure Aβ (n = 146; converted to Centiloids), 18F‐flortaucipir to measure tau (n=135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR‐SB) and memory composite score (ADNI‐MEM).

Result

NODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures (Figure 2). For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus (r=‐0.375; p<0.001) and the uncinate (r=‐0.373; p<0.001), and with ODI in the fornix ST (r =‐0.288; p=0.004). Both ODI and NDI across the majority of tracts were associated with CDR‐SB and ADNI‐MEM (see Figure 2). In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid‐beta, while MD in MTL tracts showed limited correlations with pathology or cognition.

Conclusion

NODDI metrics offer additional insights about MTL WM integrity in AD that were previously missed due to the limitations of DTI analyses. These results highlight the sensitivity of NODDI applied to multishell diffusion MRI acquisitions to further investigate how WM degeneration contributes to cognitive decline.
Assessment of the potential neuroprotective effect of PhKv toxin, isolated from Phoneutria nigriventer venom, in vesicular acetylcholine transporter‐deficient mice
Authors: Nogueira‐Souza Ana Caroline , Fonseca Cristina Guatimosim , Tenza‐Ferrer Hèlia , Borges Marcia Helena , de Marco Luiz Armando Cunha , Romano‐Silva Marco Aurélio , Gomez Marcus Vinícius
Published: January 2025

Background

Acetylcholine, a neurotransmitter critical for cognitive functions, including attention, memory, and sociability, is essential for maintaining synaptic integrity. Deficits in acetylcholine levels are linked to cognitive impairments. Heterozygous VAChT KD (VAChT KDHET) mice, characterized by reduced vesicular acetylcholine transporter protein production, exhibit cognitive impairments due to diminished acetylcholine release. This study explores the therapeutic potential of PhKv toxin, derived from the Brazilian wandering spider Phoneutria nigriventer, as an acetylcholinesterase inhibitor, aiming to prolong acetylcholine presence in the synaptic cleft of murine subjects.

Methods

Cognitive deficits in VAChT KDHET mice (n = 8) were assessed using the novel object recognition task. Thirty‐six VAChT KDHET mice were divided into three groups: PhKv (n = 12), galantamine (n = 12), and control/sham (n = 12). The PhKv group received subcutaneous vehicle (0.9% saline) and intracerebroventricular PhKv toxin (100 pmol/site). The galantamine group received subcutaneous galantamine (1 mg/kg) and intracerebroventricular vehicle (1x PBS). Controls received both vehicles. Preceding treatments, mice underwent habituation (HAB) and familiarization (FAM) in the novel object recognition test. Post‐FAM, mice received subcutaneous galantamine or vehicle, followed by intracerebroventricular PhKv or vehicle to minimize FAM‐related injection effects. After 24 hours, long‐term memory (LTM) was assessed.

Results

VAChT KDHET mice displayed impaired object recognition memory, with sex‐related short‐term memory differences. PhKv‐treated mice exhibited memory improvements comparable to galantamine‐ or vehicle‐treated mice, indicating potential memory enhancement. Further analysis revealed memory improvement in both vehicle‐treated and naive mutant mice.

Conclusion

PhKv shows promise in memory improvement, warranting in‐depth investigations into its mechanisms. Ongoing research explores the molecular aspects of PhKv’s action on acetylcholinesterase. Our study suggests PhKv’s therapeutic relevance in addressing cognitive deficits associated with acetylcholine dysregulation.
Cognitive impairment, brain connectivity, and long‐Covid: understanding the complex interplay
Authors: Hernández Micaela A , Travi Fermin , Kamienkowski Juan , Bianchi Bruno , Carello Agostina , Helou Belén , Crivelli Lucia , Slezak Diego Fernández , Sevlever Gustavo , Allegri Ricardo , Calandri Ismael Luis
Published: January 2025

Background

The persisting cognitive symptoms observed in individuals after a Covid‐19 infection (long‐Covid) remain an enigmatic aspect of the disease. Clinical descriptions in the literature are dissimilar, suggesting more than one clinical phenotype. Our study aims to explore cognitive performance and brain network of long‐Covid patients, to determine the neural correlates of cognitive impairment.

Method

Case‐Control study of individuals with cognitive complaints persisting at least 12 weeks after Covid‐19 infection, and age‐ and sex‐ matched healthy controls without history of covid‐19 infection. We performed a brain MRI with rs‐fMRI sequences and a neurocognitive test (NCT) based on the UDS‐3 protocol. We generated z‐scored neuropsychological data, normalized to the normal population, and averaged them to create 7 cognitive domains. We segmented rs‐fMRI data into seven distinct functional neural networks (Salience/Ventral Attention, Dorsal Attention, Default, Frontoparietal, Visual, Somatomotor, and Limbic) and measured network efficiency, largest connected component, average participation coefficient, and modularity. We applied a Wilcoxon test to assess the significance of differences in measurements over networks.

Result

Forty‐two subjects were recruited, 30 were female. Mean age 56 (±12). The control group consisted of 43 subjects, 25 were female. Mean age 59 (±9). The NCTs scores yielded statistical significant differences in long‐Covid subjects compared to controls, at memory (mean difference:‐1.12, IQR: ‐1.78; ‐0.32), attention (mean difference: ‐1.21, IQR: ‐1.80; ‐0.40), executive (mean difference: ‐0.82, IQR: ‐1.37; ‐0.12), and global composites (mean difference: ‐0.87, IQR: ‐1.36; ‐0.25). Regarding functional networks, we observed significant differences (p < 0.001) in the global and mean local efficiency of the Salience/Ventral Attention and Global networks, and to a lesser extent (p < 0.005 and p < 0.01) in the Default and Dorsal Attention networks (Figure 1).

Conclusion

Our study identified that long‐Covid subjects differ in their cognitive performance compared to controls with less effective and organized connection among Salience/Ventral Attention and Global networks.
Aβ42/40 and p‐tau 181 as disease biomarkers in Atypical Alzheimer’s disease
Authors: Singh Neha Atulkumar , Graff‐Radford Jonathan , Li Danni , Mielke Michelle M. , Machulda Mary M. , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Lowe Val J. , Josephs Keith A. , Whitwell Jennifer L.
Published: January 2025

Background

Blood plasma metrics provide excellent biomarkers of the presence of Alzheimer’s disease (AD) pathology in population cohorts. However, it is less clear whether plasma metrics correlate with PET measures of AD pathology in cohorts of patients with advanced AD disease, particularly in those with atypical clinical presentations of AD.

Method

Seventy‐seven patients (visual variant=43, language variant=32, motor variant=1 and dysexecutive variant=1) with PET biomarker‐confirmed atypical AD were recruited by the Neurodegenerative Research group at Mayo Clinic, Rochester, MN, underwent Aβ (Pittsburgh Compound‐B) and tau (18F‐flortaucipir) PET and provided a blood sample. Blood plasma analysis was performed to assess p‐tau 181 and Aβ42/40 ratio concentrations using the Quanterix Simoa platform. Multivariate linear regression models assessed the relationship between plasma concentrations and both global Aβ, atypical AD summary and regional tau PET measures. For each PET measure, two separate models were fit to assess the influence of each plasma biomarker separately, while the third model included all plasma measures to assess the combined influence of all biomarkers on PET uptake. To investigate differences in plasma concentrations between atypical AD phenotypes, we performed Mann‐Whitney’s test across the visual and language variants of AD.

Result

Plasma Aβ42/40 ratio showed positive associations with tau PET uptake, specifically within precuneus, parietal and temporal regions and was not associated with Aβ PET. There was no relationship between plasma p‐tau 181 and Aβ or tau PET uptake. However, the model that included both plasma biomarkers showed that with the addition of p‐tau 181, all significant associations between Aβ42/40 ratio and regional tau uptake were weakened to trends. The Aβ42/40 ratio continued to show no relationship with global Aβ‐PET uptake and plasma p‐tau 181 showed no relationship to PET measures (Figure 1). Lastly, no significant difference in plasma Aβ42/40 and p‐tau 181 levels was noted between the visual and language variants of AD (Figure 2).

Conclusion

The lack of associations between plasma concentrations and PET measures of Aβ and tau in this relatively advanced AD cohort may suggest that plasma concentrations have greater utility as diagnostic biomarkers of early AD as compared to advanced AD.
Utility of Plasma Biomarkers in Screening for Brain Amyloid in the 1Florida Alzheimer Disease Research Center (ADRC)
Authors: Barker Warren W , Velasquez Karen , Loewenstein David A. , Curiel Rosie E , Armstrong Melissa J , Rosselli Monica , Adjouadi Malek , Asken Breton M. , Vaillancourt David , DeSimone Jesse , Smith Glenn E. , Marsiske Michael , Fiala Jacob , Weber Darren M , Kim Jueun C , Herrera Mileidys , Velez‐Uribe Idaly , Duara Ranjan
Published: January 2025

Background

With the emergence of anti‐amyloid drugs, there is an increased need to determine the presence of brain amyloid in people using non‐invasive, cost‐effective biomarkers. The goal of this study was to determine the added and stand‐alone value of plasma biomarkers for predicting positive amyloid PET in a mixed sample of Hispanic and non‐Hispanic older adults.

Method

Participants (n=209) from the 1Florida ADRC at Mount Sinai Medical Center, Miami Beach had neurological and neuropsychological evaluations; MRI, rated positive (Hpc+) or negative (Hpc‐) for hippocampal atrophy on visual read; amyloid PET brain scans, rated amyloid positive (A+) or negative (A‐) on visual read; blood draws for APOE ε4 genotyping (e4+, e4‐); and plasma biomarkers including Abeta 42/40 ratio (Quest Diagnostics), p‐tau217 (ALZPath), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) (Quanterix). A base logistic regression model including age, sex, APOEε4 status, and hippocampal atrophy was a reference to assess the value of adding plasma markers in predicting A+/A‐. Areas under the receiver operating characteristic (ROC) were computed and DeLong’s approach was used to compare ROC curves. Youden’s index was used to identify optimal sensitivities/specificities to discriminate A+ from A‐ participants.

Result

Demographics and clinical data are shown in Table 1. In the base model, the AUC was 0.78 with both APOEe4 and hippocampal atrophy as significant independent predictors of A+ (Table 2). Prediction of A+ was improved by adding all plasma biomarkers (AUC=0.96; 93%/87% sensitivity/specificity), with APOEe4, Abeta42/40, and p‐tau217 as independent predictors. Adding either Abeta 42/40 (AUC=0.88) or p‐tau217 (AUC=0.94) alone to the base model also improved model prediction.

As stand‐alone predictors of A+, the optimal specific/sensitivity was 85%/89% for p‐tau217 and 77%/81% for Abeta42/40; p‐tau217 outperformed Abeta42/40 (AUC=0.92 versus 0.82) (Figure 1). There was a trend for the combination of both biomarkers to outperform p‐tau217 alone (AUC=0.94 versus 0.92).

Conclusion

Positive amyloid PET status can be predicted with high accuracy in an ethnically diverse population using combinations of biomarkers, APOE genotype, and a measure of hippocampal atrophy. As a stand‐alone biomarker, p‐tau217 performed better than other biomarkers in predicting amyloid status.
Multimodal Analysis of Behavior During Stroop Test for Characterization of Alzheimer's Disease Signs
Authors: Meyer Trevor , Favaro Anna , Oh Esther S , Irazoqui Pedro , Dehak Najim , Moro‐Velazquez Laureano
Published: January 2025

Background

Clinical rating scales and neuropsychological tests are commonly used for assessing sign and disease severity, yet lack detail in the early stages Alzheimer’s Disease (AD). Existing evaluation methods can be subjective, nonlinear, expensive, or reliant on anecdotal evidence making objective and consistent characterization and phenotyping of AD difficult. Multimodal analysis of patient behavior, rather than scoring of patient‐generated output which can be skewed by compensation strategies, presents a unique opportunity to objectively quantify AD related changes. Using the Stroop Test (ST), we present a multimodal analysis of eye movement and spoken responses during completion of ST tasks, with the goal to characterize patient behavior.

Method

17 individual AD subjects and 24 age‐matched cognitively normal controls (CTL) were recruited from the Johns Hopkins Memory and Alzheimer’s Treatment Center and the Movement Disorders Clinic at the Johns Hopkins University School of Medicine. Eight subjects returned for two or three follow up sessions at least 20 weeks apart, totaling 29 AD recording sessions. An Eyelink Portable Duo in head‐free‐to‐move mode was used to record eye movements and spoken responses. We analyzed subjects’ interaction with ST using several metrics relating to blinking, saccade, fixation, gaze, prosodic, accuracy, and timing characteristics. We summarize patient behavior abnormality by scaling behavioral metrics into positive z‐scores using CTL performance and summarize the overall abnormality as the average z‐score across 45 metrics.

Result

The average deviation across metrics correlates with MoCA scores (p<0.001). These metrics display significantly different distributions between the AD from CTL subjects (p<0.001). A visualization we’ve coined as a “sign profile” summarizes patient behavior abnormality during ST. In all subjects our abnormality measurement closely matches MoCA scores and clinician observations.

Conclusion

AD subjects execute the ST with eye movement and speech behaviors which significantly differ from CTL subjects, and subjects with longitudinal recordings show encouraging results for the use of this analysis in monitoring. By utilizing measures from more than one feature, we detect early clinical changes a single‐score test might miss. This analysis offers comprehensive patient profiling, providing an intuitive and quantitative understanding of patient signs enabling more accurate detection and management of disease.