bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Tau vaccines identifies diverse antibody binding profiles and efficacy, demonstrating that specific forms of Tau can be targeted by vaccines with subsequent functional impact.
Authors: Boyd Justin
Published: December 2022

Background

Immunotherapy has become a tractable path for Alzheimer’s disease therapies. One of the impediments of these therapies is their intrinsic limitation of targeting, particularly regarding Tau. It is unclear to what degree these therapies target the specific disease‐causing Tau form in each individual patient at the required time in disease progression. To address these challenges, Vaxxinity is developing a vaccine derived immunotherapy targeting Tau.

Method

Vaccines were designed by selecting various peptide sequences along the Tau protein, conjugating to Vaxxinity’s UBTh1 peptide and formulating with CpG and Adju‐Phos. Immunogenicity of vaccines were quantified in guinea pigs and mice by ELISA. Vaccine derived antibodies were characterized by Western Blot, dot blot, immunohistochemistry and Bio‐Layer Interfereometry. Vaccine efficacy was characterized by examining the effects of vaccine derived antibodies with in vitro assays (Tau aggregation and spreading) and quantifying Tau accumulation in the brains of vaccinated mice.

Result

Vaccines induced robust immunogenicity with high titers. Antibodies derived from vaccines exhibited diverse binding profiles, including the production of antibodies binding preferential Tau species and those appearing to bind total Tau. Efficacy was also observed within the in vitro assays, including reduction of Tau aggregation and spreading. Modest reduction of Tau accumulation was observed in mice, with more analysis pending.

Conclusion

Here we present early‐stage data illustrating that the Vaxxinity platform can target a range of Tau forms in a single vaccine. Animals vaccinated with a vaccine targeting Tau produce robust antibodies against a range of Tau forms (monomeric, oligomeric and fibrils), exhibiting high titers, selectivity, and avidity. Moreover, efficacy data from animal models support the potential for future efficacy in humans.
Predictors of Alzheimer’s disease risk in women with bilateral oophorectomy from the UK Biobank
Authors: Reuben Rebekah , McFall G. Peggy , Dixon Roger A. , Einstein Gillian
Published: December 2022

Background

Two‐thirds of individuals with Alzheimer’s disease (AD) are women and at age 45, the lifetime risk for AD is twice as high in women compared to men (Alzheimer’s Association, 2019). Early life events affecting 17β‐estradiol (E2) may be a mechanism behind this sex difference. Bilateral oophorectomy (BO) predicts cognitive decline, and neurodegeneration, and increased risk of AD in later life—adverse outcomes that are mitigated with E2 therapy (Gervais et al., 2020; Kantarci et al., 2018; Rocca et al., 2007; Zeydan et al., 2019). Our aim was to investigate compounding risk factors for AD in women with BO using UK Biobank data.

Method

We studied women aged 60 or older who had BO prior to age 49 with an AD diagnosis (n = 53) and without an AD diagnosis (n = 5418) from the UK Biobank (Sudlow et al. 2015). Data were analyzed using Firth’s bias‐reduced logistic regression in R 3.6.1 (R Core Team, 2019).

Result

Participants were on average 63.7 years old and 43.4 years old at BO. Women with BO who developed AD: (a) were significantly older, (b) had fewer years of education, (c) had an earlier age at BO, (d) less frequently used any form of hormone therapy (HT), and (e) were more frequently apolipoprotein E4 (APOE4) carriers. As age increased, AD risk increased by 25%; it deceased by 10% with greater years of education. Women with BO and an APOE4 allele were 5.2 times as likely to develop AD than those without an APOE4 allele. Finally, ever using any form of HT decreased AD risk by 54%.

Conclusion

This research fills a gap in understanding predictors of AD in a high‐risk group of women with early E2 loss. The heightened AD risk for women with BO and APOE4 is of note, as prior work suggests women with APOE4 may benefit less from HT (MacLusky, 2004). Further, the reduction in AD risk with any HT provides added support for HT in mitigating cognitive decline. Although details on HT formulation were unavailable, the specific use of E2‐based therapy may further decrease AD risk (Sherwin & Henry, 2008).
Validating a set of Verbal‐Paired‐Associates word‐pair lists for Repeat, Remote, Automated Testing
Authors: Kaula Alexander J , Taptiklis Nick , Cormack Francesca K
Published: December 2022

Background

Verbal‐Paired Associates (VPA) is a widely used memory task, typically administered by a trained rater, with lists of pairs of words learned over up to three attempts, followed by delayed recall. Automated scoring and administration could enable remote testing to monitor change over time but requires parallel forms of the test with equivalent psychometric properties. Here we describe the validation process and memorability characteristics of a group of 12 parallel forms of automated VPA.

Method

We generated 15 candidate VPA word‐pair lists based on prior modelling. Piloting and simulation‐based power calculations suggested a sample size of 375 would provide power of .8 to detect lists where the mean number of errors at the first attempt was more than one error different from the Grand Mean. We recruited 375 healthy participants aged 50‐90 years via the Prolific online platform. We used a mixed counterbalanced design with the aim of evaluating the memorability characteristics of the candidate set of word‐pair lists. Participants were tested twice on the VPA task using different word‐pair lists, separated by a distractor task. All testing was delivered via the NeuroVocalix platform on participants’ own devices at home and was administered and scored automatically using automatic speech recognition. Automated scoring results were reviewed by a human experimenter to ensure accuracy.

Result

Memory performance in individual word‐lists conformed broadly to our model‐based expectations, with significant correlations between predicted and observed performance (p < 0.05). We observed expected significant improvement in recall performance with repeated administration, showing learning of word pairs over the task. In this healthy sample there was only modest forgetting at delayed recall. Although performance was broadly equivalent across the different lists, the final selection of lists excluded three with the highest numeric difference in performance versus the overall grand mean, yielding 12 lists for repeated administration. Qualitative feedback showed good levels of acceptability and engagement with the task by participants.

Conclusion

We now have a set of 12 parallel‐form word‐pair lists for use with the automated NeuroVocalix system, with consistent performance characteristics enabling long‐term repeat testing remotely and at scale.
Temporal Association of Imaging Biomarkers of Cerebrovascular Disease and Alzheimer’s Disease
Authors: Cogswell Petrice M , Lundt Emily S. , Therneau Terry M. , Wiste Heather J. , Graff‐Radford Jonathan , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Vemuri Prashanthi , Petersen Ronald C. , Jack Clifford R.
Published: December 2022

Background

Alzheimer’s disease (AD) pathologic changes (e.g. amyloid and tau aggregation), and cerebrovascular disease often coexist, and it remains unclear whether these are mechanistically linked processes (Graff‐Radford, Brain 2019; Provenzano, JAMA Neurol 2013). Most studies evaluating these associations are cross‐sectional; however, establishing temporal relationships may provide additional insight into potential mechanistic associations. One method to assess the temporal evolution of a biomarker is the Accelerated Failure Time (AFT) model, which assumes a common pattern of progression for a given biomarker that is shifted earlier or later in time for each individual (Therneau, Neuroimage 2021). In this work we investigate the relationship of disease trajectories of cerebrovascular disease (via white matter hyperintensity, WMH, volume) and AD biomarkers (via amyloid and tau PET).

Methods

We included Mayo Clinic Study of Aging (MCSA) and Mayo Alzheimer’s Disease Research Center (ADRC) participants with amyloid PET, tau PET, and MRI, age > 50 years, and a clinical diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI) or Alzheimer’s disease dementia. The AFT model was fit with amyloid PET (PiB) global meta‐ROI SUVR, tau PET (flortaucipir) temporal meta‐ROI SUVR, and WMH volume as the tri‐variate endpoints, with APOE genotype, sex, education, total intracranial volume, and referral/population subject as covariates. A per subject/endpoint random effect represents individual adjustments for each biomarker to indicate if the subject's biomarker became abnormal earlier or later relative to their demographic peers, accounting for the covariates.

Results

The study included 1144 participants (Table 1). There was a strong correlation between earlier onset of amyloid and earlier onset of tau (r=0.64, CI=0.60‐0.67) (Figure 1, Table 2); early/late amyloid timing explained nearly half (0.642 = 41%) of the variation in tau onset. There were only weak associations between an individual’s WMH and amyloid PET onset adjustments (r=0.10, 1.0%) and WMH and tau PET onset adjustments (r=‐0.07, 0.5%).

Conclusion

This analysis supports a strong mechanistic relationship between amyloid and tau aggregation, as reported by others. However, our findings do not support a mechanistic association between WMH and amyloid or tau PET.
Clinical and genetic features of Lewy body pathology in autosomal dominant and sporadic Alzheimer disease
Authors: Vöglein Jonathan , Ryan Natalie S , Bateman Randall J. , Paumier Katrina L. , Cairns Nigel J , Franklin Erin E. , Perrin Richard J. , Xiong Chengjie , Jucker Mathias , Lashley Tammaryn , Arzberger Thomas , Herms Jochen , Dieterich Marianne , Höglinger Günter , Danek Adrian , Morris John C. , Fox Nick C , Levin Johannes
Published: December 2022

Background

Lewy body pathology (LBP) occurs in a substantial portion of individuals with autosomal dominant (ADAD) and sporadic Alzheimer disease (sAD) (Ringman, 2016; Cairns, 2015; Leverenz, 2007; Lippa, 1998). Whereas other non‐AD pathologies are frequent in sAD, LBP seems to be the most common co‐pathology in the relatively young ADAD population (Cairns, 2015). Knowledge of clinical and genetic characteristics of LBP in both ADAD and sAD is incomplete.

Method

Data from the National Alzheimer’s Coordinating Center, the Dominantly Inherited Alzheimer Network, the Queen Square Brain Bank at University College London and the Neurobiobank Munich were leveraged to compare individuals with ADAD and neuropathologically diagnosed sAD with and without LBP. Chi‐squared and Student’s t‐test were used for comparison of categorical and continuous variables respectively.

Result

The study included 139 ADAD and 4661 sAD autopsy cases. LBP occurred in 59% of ADAD and 38% of sAD cases. LBP was associated with a longer survival in both ADAD (10.1 vs. 8.6 years, p=0.024) and sAD (10.5 vs. 10.2 years, p=0.016). Memory disturbance occurred more frequently as the first clinical AD symptom in both AD variants when LBP was present (ADAD: 90 vs. 65%, p=0.005; sAD: 78 vs. 71%, p<0.001). In both ADAD and sAD, the presence of at least one APOE e4 allele was more common in individuals with LBP (ADAD: 40 vs. 21%, p=0.047; sAD: 57 vs. 46%, p<0.001). In ADAD, frequency of LBP did not differ between individuals with PSEN1 and APP mutations.

Conclusion

In this investigation of 139 ADAD and 4661 sAD autopsy cases, LBP occurred in about 60% with ADAD and 40% with sAD. In both ADAD and sAD, the presence of LBP was associated with longer survival, higher frequency of memory disturbance as the first AD symptom and positive APOE e4 status. Further study of these associations may increase our understanding of the role of LBP in AD.
Prognostic utility of baseline [18F]GTP1 tau PET signal for subsequent cognitive and functional decline in prodromal‐to‐mild Alzheimer's disease
Authors: Ruiz‐Uribe Nancy E , Manser Paul T , Bohorquez Sandra Sanabria , Baker Suzanne L. , Monteiro Cecilia , Teng Edmond
Published: December 2022

Background

Prior studies of tau PET tracers in participants with normal cognition and/or a broad range of Alzheimer’s disease (AD) severity suggest baseline tau PET signal is associated with subsequent rates of cognitive decline. However, the prognostic utility of tau PET imaging is less well‐established within more homogenous cohorts limited to specific AD stages and for cognitive versus functional decline. We addressed these questions by analyzing baseline [18F]GTP1 tau PET signal and longitudinal changes in cognitive and functional measures in the Phase 2 Tauriel study of semorinemab in prodromal‐to‐mild AD.

Methods

We analyzed data from a subset of Tauriel participants with prodromal AD (pAD; n=127) or mild AD (mAD; n=233) who underwent baseline [18F]GTP1 tau PET and longitudinal assessments with the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB), Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and/or Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL). As no treatment effects were observed with semorinemab in Tauriel, data were pooled across semorinemab and placebo arms. Associations between baseline [18F]GTP1 SUVRs and annualized longitudinal change on each measure were explored using Pearson correlations and multiple linear mixed effects regression models adjusting for relevant baseline covariates.

Results

Baseline cortical [18F]GTP1 SUVRs and longitudinal decline on clinical measures were significantly greater in mAD relative to pAD cohort. Prognostic associations with baseline cortical [18F]GTP1 were similar in pAD and mAD and more robust for predominantly cognitive measures (ADAS‐Cog13: pAD rs=0.37, mAD rs=0.35; RBANS Total Index: pAD rs=‐0.40, mAD rs=‐0.41) than measures incorporating functional status (CDR‐SB: pAD rs=0.27, mAD rs=0.29; ADCS‐ADL: pAD rs=‐0.12, mAD rs=‐0.26). Analogous results were seen using temporal or Braak stage regions of interest. [18F]GTP1 associations with cognitive decline generally remained significant after adjusting for baseline cognitive score, age, hippocampal volume, and education.

Conclusions

Higher baseline [18F]GTP1 tau PET signal was associated with faster subsequent clinical decline in both prodromal and mild AD. More robust associations were seen with cognitive relative to functional measures. These results bolster prior work that suggests a role for tau PET in patient selection/stratification in AD clinical trials.
Identification of ABCA7 SNP‐by‐CpG interactions associated with cognition in older African Americans
Authors: Chaar Dima Leila , Nguyen Kim , Wang Yi Zhe , Ratliff Scott , Mosley Thomas H , Kardia Sharon L R , Smith Jennifer A , Zhao Wei
Published: December 2022

Background

The ABCA7 gene confers the largest genetic risk for Alzheimer’s Disease (AD) in African Americans (AA) after APOE ε4. However, the relationship between ABCA7 and cognitive function has not been thoroughly examined in AA without dementia. We investigated the effect of genetic variants and epigenetic markers in ABCA7, as well as their interaction, on cognition in older AA without dementia.

Method

The sample included 629 cognitively normal AA from the Genetic Epidemiology Network of Arteriopathy (GENOA). Methylation at 72 CpG sites located within 5kb of ABCA7 were measured using the Illumina EPIC array. General cognitive function (cognition) was measured by taking the first principal component of five cognitive tests. The association between SNPs and cognition was assessed using linear mixed models controlling for age, sex, education, population structure and relatedness. The association between CpGs and cognition was assessed using the same model with further adjustment for white blood cell proportions, batch effects and smoking. We also evaluated SNP‐by‐CpG interactions.

Result

No SNPs were associated with cognition at p<0.05. A 1% change in methylation at three CpGs (cg22271697, cg11714200, cg12082025) was associated with a 0.02‐0.10 standard deviation (SD) increase in cognition (p<0.05; no associations significant at FDR q<0.1). Four SNP‐by‐CpG interactions were associated with cognition (FDR q<0.1). Contrast tests show that methylation is associated with cognition in some genotype groups (p<0.05): a 1% methylation increase at cg22271697 is associated with a 0.13 SD increase in cognition for those with the AA rs3764647 genotype, a 1% increase at cg06169110 is associated with a 0.35 SD decrease in cognition for those with the rs115550680 GG or AG genotype, and a 1% increase at cg00135882 is associated with a 1.19 SD decrease in cognition for those with a rs3764650 GG genotype.

Conclusion

While AD risk SNPs in ABCA7 are not associated with cognition in the full sample of older African Americans, some do interact with proximal methylation to influence cognition. This suggests that a complicated interplay between genetic and epigenetic factors in ABCA7 may influence cognition in cognitively normal AA. A similar mechanism may play a role in cognitive aging and decline.
An autopsy‐validated, easily deployable MRI predictor of Alzheimer’s disease tau pathology
Authors: Vogel Jacob W , Strandberg Olof , Gaiteri Chris , Cieslak Matthew , Covitz Sydney , Wolk David A. , Davatzikos Christos , Hansson Oskar , Satterthwaite Theodore
Published: December 2022

Background

Tau pathology is a hallmark of Alzheimer’s disease, but measuring this pathology in vivo with PET is expensive. MRI represents a low‐cost alternative for measuring in vivo disease progression, but is non‐specific. We present an MR‐based marker of tau‐specific pathology using machine learning (ML).

Method

1851 pairs of RO948 tau‐PET and T1‐weighted MRI scans were aggregated from 1262 BioFINDER II study participants. The Braak I‐IV ROI from Cho et al., 2016 was used to represent tau‐pathology. A tau‐positive threshold (SUVR=1.41) was defined using Gaussian mixture modeling, and Braak I‐IV SUVR was z‐scored using the mean and SD of the tau‐negative group. A grid search of 80 ML pipelines with 100 rounds of nested 5‐fold cross‐validation was performed while varying estimator, dimension reduction strategy, preregression of intracranial volume (ICV), and one vs multiple scans‐per‐subject. For all models, 294 features from Freesurfer were used. The best‐performing model was then applied to 1225 participants from the ROSMAP cohort, yielding MR‐predicted tau. A subset (n=159) of these participants had postmortem AT8‐immunostained tau pathology, Braak staging, TDP‐43 and lewy body pathology.

Result

The best pipeline involved random forest regression with FDR‐based feature selection (RMSE[95%CI]=3.67[3.6‐3.8]; R2[95%CI]=0.42[0.40‐0.45]; Figure1; Figure2A). (Lack of) ICV pre‐regression had the biggest positive impact across pipelines. This model significantly predicted zTau in both tau‐postive and tau‐negative individuals (Figure2B), and showed fair weighted precision (0.84) and recall (0.80) in tau‐positivity classification (Figure2C). Temporoparietal and medial temporal regions contributed most to predictions (Figure2D). When applied to ROSMAP, antemoretem MR‐predicted tau predicted postmortem tau pathology (p=0.001) and Braak stage (p=0.005; Figure3A) but not other pathologies (Figure3B), predicted clinical diagnosis and progression (Figure3C), and outperformed a common neurodegeneration marker (Figure3D‐F).

Conclusion

We create an easily deployable tau‐specific MRI biomarker, which was validated using postmortem tau pathology in a separate dataset. MR‐predicted tau provides a more specific non‐invasive biomarker for researchers without access to PET.
Examining cerebrovascular burden across the cognitive continuum in older adults with and without evidence of amyloidosis
Authors: Rivera‐Rivera Leonardo A , Cody Karly Alex , Betthauser Tobey J , Koscik Rebecca Langhough , Jonaitis Erin M. , Cadman Robert V. , Hermann Bruce P , Rowley Howard A. , Carlsson Cynthia M. , Chin Nathaniel A. , Eisenmenger Laura , Johnson Sterling C. , Johnson Kevin M
Published: December 2022

Background

This work characterized cerebrovascular health in human subjects spanning the cognitive spectrum with and without presence of Aβ using different neuroimaging techniques (Fig1).

Methods

Subjects (n=70) were clinically characterized into four groups: cognitively unimpaired (CU), CU‐Declining (at‐risk of progressing to clinical mild MCI based on traditional neuropsychological data), clinical MCI, and clinical dementia (Fig2). MRI: Vascular imaging: Whole‐brain 4D‐Flow data were acquired to characterize cerebrovascular health. pCASL with three post labeling delays was used to provide transit time corrected CBF maps. Structural imaging: T1‐weighted and T2‐FLAIR images were also collected for quantification of intracranial, hippocampal and white matter hyperintensity volumes. Hemodynamic measurements were extracted from intracranial arteries including the petrous ICAs, BA, MCAs, and veins SSS. Quantified flow parameters included: total cerebral blood flow, trans‐capillary pulse wave delay, and flow pulsatility index (PI). Trans‐capillary pulse wave delay was defined as the time shift between arterial and venous cardiac waveforms. PET: Aβ burden was assessed using 11C‐PiB PET imaging. Amyloid positivity (A‐, A+) was established as mean cortical PiB DVR >1.16. For A+ participants, amyloid time (i.e., estimated duration A+) was estimated using the sampled iterative local approximation algorithm. Differences were assessed using ANOVA followed by post‐hoc analysis (P<0.05 significance).

Results

Micro‐vascular tissue perfusion was statically higher in A+/CU when compared to other A+ groups in the GM, WM, and hippocampus (Fig3 and 4). Trans‐capillary pulse wave delay was statistically longer in A+/CU when compared to A+/CU‐Declining, A+/MCI, and A+/dementia (Fig5A). For A‐ groups trans‐capillary pulse wave delay was similar; yet, flow PI was statistically higher in A‐/CU‐Declining and A‐/MCI when compared to A‐/CU in the ICAs and MCAs (Fig5 C, D). Flow PI in A+/CU was higher than in A‐/CU.

Conclusions

Decreased micro‐vascular tissue perfusion and shorter trans‐capillary pulse wave delay in A+ subjects with cognitive alterations (e.g. CU‐Declining, MCI, Dementia) compared to A+/CU indicates decreased metabolism and increased small vessel stiffness may contribute to cognitive decline and/or are induced by amyloidosis. In contrast, for A‐ subjects significant differences in arterial flow pulsatility index between A‐/CU, CU‐Declining, and MCI suggests macro‐vascular arterial stiffness contributes to cognitive decline.
Genome‐wide association study of plasma apolipoprotein E levels and risk of dementia in older adults
Authors: Aslam Muhammad Muaaz , Fan Kang‐Hsien , Lawrence Elizabeth C , Bedison Margaret A , Snitz Beth E , DeKosky Steven T , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas
Published: December 2022

Background

The APOE 2/3/4 polymorphism is the greatest risk factor for Alzheimer’s disease (AD). This polymorphism is also associated with variation in plasma ApoE levels and explains about 20‐25% of its genetic variance; while APOE*4 lowers, APOE*2 increases ApoE levels. Lower plasma ApoE levels have also been reported to be a risk factor of future AD and all dementia, independent of the APOE 2/3/4 polymorphism (Ann Neurol 2015;77:301). To our knowledge, no genome‐wide association study (GWAS) has been reported on plasma ApoE levels. This study was aimed to identify novel genetic factors affecting plasma ApoE levels as well as to confirm if baseline plasma ApoE levels predict future AD dementia in an older and longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study.

Method

Baseline plasma ApoE levels were measured using an immunoturbidimetric assay in 3,031 older subjects (aged 72 to 96 years; 94.1% White). Genome‐wide genotype was performed on the available 2,737 DNA samples (96% White). Due to the small number in other ethnicities, we only included the 2,852 White subjects (2,412 cognitively normal, 440 with incident AD dementia) for plasma ApoE analysis. GWAS analysis on plasma ApoE levels was performed on 2,580 White subjects where both genotype and ApoE level data were available.

Result

As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (p for trend =1.7E‐10). There was no significant difference in plasma ApoE levels between cognitively normal and AD dementia subjects (p=0.55). GWAS analysis revealed the expected associations of APOE*2 (β= 1.12; p= 3.57E‐79) and APOE*4 (β= ‐0.35; p= 2.21E‐11) with plasma ApoE levels. In addition, we observed 5 novel genome‐wide significant associations on chromosomes 1 (β= 0.921; p= 5.36E‐10), 4 (β= 0.796; p= 4.31E‐08;), 7 (β= 0.722; p= 9.64E‐09), 11 (β= 0.268; p= 2.58E‐08), and 20 (β= 1.379; p=8.25E‐09).

Conclusion

We have identified multiple novel associations affecting plasma ApoE levels in addition to the established APOE association. However, we could not replicate the reported association of plasma ApoE levels with future AD, probably because of the older nature of our cohort.
Vessel distance mapping: a novel methodology for assessing vascular‐induced cognitive resilience
Authors: Garcia‐Garcia Berta , Mattern Hendrik , Vockert Niklas , Yakupov Renat , Schreiber Frank , Spallazzi Marco , Perosa Valentina , Speck Oliver , Duzel Emrah , Maass Anne , Schreiber Stefanie
Published: December 2022

Background

The association between cerebral blood supply and cognition has gained increasing interest, considering the remarkable anatomical variability of the circle of Willis. Thus, qualitative classifications of the arteries contributing to the hippocampal supply has been performed in previous studies to determine whether the additional presence of vessels might translate into cognitive differences and cerebral structural changes when coexisting with vascular pathology, to the extent of constituting a cognitive reserve. Nevertheless, the promising results in these regards are not without controversy. Hence, Vessel Distance Mapping (VDM) is here introduced, in order to ascertain the correlation of VDM‐metrics with each other and with cognitive status, as well as to elucidate which metrics have the greatest impact on cognition.

Method

A battery of cognitive tests was used (including ADAScog and MoCA) in 51 subjects (71 ± 8.5yrs) with (n=20) and without (n=31) cerebral small vessel disease. Their hippocampal‐related vessels were manually segmented by using high‐resolution 7T Time‐of‐Flight‐MRI. Vessel distance maps were generated by computing the distances of each voxel to its nearest vessel, obtaining 3 VDM‐metrics: global‐VDM (vessel density surrogate), VS‐VDM (vessel‐specific supply), and COMD (distance to the center of mass, reflecting vessel distribution). Hippocampal masks were used to assess the whole and subregional hippocampus. Regression models were applied for evaluating the interrelation among the metrics, and their association with cognition.

Result

High correlations were observed for intra‐metric comparisons, as well as when comparing whole hippocampal vs. sub‐hippocampal metrics. Greater values of VDM‐metrics reflecting higher distances among vessels were associated with poorer cognitive outcomes only in subjects affected by vascular pathology (global‐VDM R²=0.7248, p=0.0054; COMD R²=0.7248, p=0.0013). Metrics revealing vascular distribution (p=0,0053) and density (p=0,0169) were the most influential on cognition, and in this context those for the whole hippocampus predominated over the subregional ones.

Conclusion

A mixed contribution of vessel distribution and density is proposed to confer cognitive resilience, in a way consistent with anatomical fundamentals and with previous research findings. VDM provides a new, structure‐driven approach on which to raise new questions supported by the statistical robustness of a quantitative method with potential clinical implications.
Altered functional connectivity networks in logopenic progressive aphasia and posterior cortical atrophy
Authors: Singh Neha Atulkumar , Graff‐Radford Jonathan , Sintini Irene , Machulda Mary M. , Gunter Jeffrey L. , Lowe Val J. , Botha Hugo , Jones David T. , Jack Clifford R. , Josephs Keith A , Whitwell Jennifer L
Published: December 2022

Background

Resting state functional connectivity (rsfMRI) studies have shown functional network disruptions in logopenic progressive aphasia (LPA) (reduced connectivity within the left temporal language network) and posterior cortical atrophy (PCA) (reduced connectivity within ventral visual network). However, little is known about how these networks compare and how connectivity differs within and between networks in these atypical Alzheimer’s Disease (AD) phenotypes.

Method

Fifty‐nine amyloid‐positive PCA patients and eighty‐five amyloid‐positive LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent structural and resting state functional MRI. Spatially preprocessed data was analyzed using the CONN functional connectivity toolbox to explore the default mode network (DMN), salience, sensorimotor, left language, visual and memory networks, which were generated by averaging multiple regions‐of‐interest (ROI) within each network. The data was analyzed at both the voxel‐level and network‐level (ROI‐ROI).

Result

Voxel‐level differences in functional connectivity between PCA and LPA were observed in all networks (p<0.05; cluster size, FWE=0.05). PCA showed reduced connectivity in the occipital lobe in visual and memory networks, parietal lobe in language and DMN, and sensorimotor strip in sensorimotor network, particularly on the right, compared to LPA. Conversely, LPA showed reduced connectivity in the frontal cortex in salience, memory, visual and sensorimotor networks, inferior parietal lobe in visual network, and anterior temporal pole and sensorimotor cortex in the language network, compared to PCA. Between network differences (p<0.05; cluster size, FDR=0.05) were observed between groups, with PCA showing reduced connectivity between the visual and sensorimotor networks, while LPA showed reduced connectivity between the language and sensorimotor networks. The DMN was anti‐correlated to the language network in PCA, while it was positively correlated to the language network in LPA. In both phenotypes, the DMN was anticorrelated with the salience network. The visual network in PCA showed connections to all networks, while in LPA, it was only connected to the salience, language and DMN.

Conclusion

The atypical AD phenotypes were associated with multiple disruptions in connectivity, both within and between brain networks. Phenotype specific differences in connectivity patterns were noted in visual network for PCA and language network for LPA.
Tau pathology vulnerable neuronal subpopulation in Alzheimer’s disease
Authors: Kwon Taekyung , Lin Gen , Chancellor Sarah E. , Wachter Astrid , Abdourahman Aicha , Bennett Rachel E , Liao Fan , Pastika Timothy , Tamm Joseph A. , Venkat Nandini , Yanamandra Kiran , Grinberg Yelena , Kummer Markus P. , Das Sudeshna , Dellovade Tammy L. , Karran Eric H , Talanian Robert V. , Biber Knut , Ried Janina S , Serrano‐Pozo Alberto , Langlois Xavier , Hyman Bradley T.
Published: December 2022

Background

Tau pathology is known as a primary driver of neurodegeneration in Alzheimer’s disease (AD). Understanding its underlying molecular mechanism is critical in expanding our knowledge of AD pathogenesis and developing novel AD therapeutic strategies. However, interrogating tau induced neurotoxicity mechanisms has been difficult due to heterogeneous susceptibility of neurons to tau pathology. Here, we aim to identify the most vulnerable neuronal subpopulation to tau pathology in AD and reveal more clear molecular mechanisms of tau induced neuro‐toxicity/degeneration by analyzing gene expression changes in the vulnerable population.

Method

We performed single nuclei RNA sequencing and tau biochemistry from same tissue blocks of the same AD patients (5 brain regions of 32 AD donors with various Braak stages). About 1.5x106 neurons were enriched in total by NeuN antibody‐based flow cytometry sorting and these cells were clustered into 15 neuronal subpopulations based on their similarity in gene expression. We tested for association between relative neuronal population abundance and tau pathology readouts (phospho‐T231 ELISA, HT7‐HT7 SIMOA and HEK seeding). Based on the strength of correlation, we identified the neuronal subpopulation that reduces relative abundance in association with its tau pathology.

Result

We identified a tau vulnerable neuronal population that showed strong negative correlation between its relative abundance and tau pathology readouts in BA20 and BA46. The population was one of largest excitatory subpopulation distinguished by marker genes, CBLN2 and LINC00507. This outcome was supported by multiple published transcriptomics studies and histologically validated by multiplexed in situ hybridization and immunohistochemistry. Differential gene expression analysis of the vulnerable neuronal population identified a list of genes that potentially links tau pathology and neuronal death.

Conclusion

This study with large number of captured neurons for single cell transcriptomics and quantitative tau pathology readout for direct comparison to transcriptomics data enabled the discovery of a vulnerable neuronal subpopulation in more precise manner and revealed genes related to tau associated neurotoxicity more clearly. This result serves as a great starting point to further interrogate fundamental mechanisms of tau‐driven neurodegeneration in AD and accelerate therapeutic target and biomarker discovery.
Impaired retinal capillary function in patients with clinical Alzheimer’s disease
Authors: Jiang Hong , Simms Ava Gaye Yanique , Baumel Bernard , Rundek Tatjana , Wang Jianhua
Published: December 2022

Background

Extensive evidence indicates that vasculopathy, especially the level of microcirculation, contributes to neurodegeneration in AD. However, it is not easy to direct monitor cerebral microcirculation. The retinal microvasculature has been used as a surrogate to study cerebral vascular changes. Indeed, decreased retinal microvascular network densities were reported in patients with AD. The goal of this project is to determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) in patients with Alzheimer’s disease (AD).

Method

Twenty patients (age 60‐84, mean ± SD: 72.8 ± 7.7 yrs) with AD and 14 age‐matched cognitive normal controls (CN, age 62‐81, mean ± SD: 68.6 ± 6.7 yrs) were recruited. There were no differences in vascular risk factors including smoking, hypertension, hyperlipidemia, type 2 diabetes, and cardiovascular disease between groups (Chi‐square test, all P > 0.05). One eye of each subject in both groups was imaged. Retinal blood flow (RBF) was measured using a Retinal Function Imager and retinal capillary density (RCD, expressed as fractal dimension Dbox) was measured using optical coherence tomography angiography. RCF was defined as the ratio of RBF to RCD.

Result

RCF was 1.62 ± 0.56 nl/s/Dbox (mean ± SD) in the AD group, which was significant lower than that (2.56 ± 0.25 nl/s/Dbox, P = 0.0001) in the CN group. The change of RCF in the AD group represented 28% lower than the CN group. RCF was significantly related to RBF in the AD group (r = 0.98, P < 0.05) and the CN group (r = 0.65, P < 0.05).

Conclusion

Our study is the first to demonstrate the impaired retinal capillary function in patients with AD. The alteration of RCF was mainly due to decreased retinal blood flow, which the capillary network can transfer. The RCF may be developed as a biomarker to study cerebral microcirculation in patients with AD.
Altered PLD3 exonuclease activity impacts on lysosomal and mitochondrial homeostasis
Authors: Van Acker Zoë P. , Bretou Marine , Sannerud Ragna , Damme Markus , Annaert Wim
Published: December 2022

Background

Phospholipase D3 (PLD3) is a single‐pass type II membrane protein that is majorly localized to late endosomes/lysosomes (LE/Lys) where it functions as a 5'‐3' exonuclease that degrades ssDNA. Whereas PLD3 has been identified as risk factor for late‐onset Alzheimer’s disease (LOAD), knockout studies have resulted in conflicting data regarding its impact on the amyloid precursor protein metabolism. Moreover, the substrates for PLD3 in LE/Lys remain unexplored

Method

CRISPR/Cas9 gene editing was used to generate PLD3 knockout (KO) SH‐SY5Y cells that were subsequently stably rescued with wild‐type PLD3 and coding‐variants (M6R & V232M). All cell lines were evaluated for morphological and functional alterations of the LE/Lys compartment, including lipid profiling and analysis of the nucleotide content of LE/Lys magnetically isolated from the different cell lines. We optimized a PLD3 activity assay and analyzed the LE/Lys nucleotide content as a means to identify PLD3 substrates.

Result

We report that a PLD3 KO and LOAD‐associated risk variants lead to a significant lysosomal pathology, comprising an increase in the size of LE/Lys, more LAMP1 immunoreactivity, a reduced catabolic activity, an increased propensity for leakage and a marked increase in cholesterol content and in storage lipids. At the ultrastructural level, this is accompanied with the appearance of multilamellar bodies, sometimes including mitochondrial remnants. This is suggestive for a defective mitophagy, which we confirm on the light microscopy level using mKeima assays. Furthermore, we provide support for a role of PLD3 in the homeostatic degradation of mtDNA. We argue that when PLD3’s role is compromised, this leads to a build‐up of the lysosomal nucleotide content, impacting on the normal functioning of LE/Lys. We are currently analysing alterations in downstream cellular signaling pathways, including the TLR9 cascade.

Conclusion

Collectively, our findings subscribe a key role for PLD3 exonuclease activity in lysosomal homeostasis. Its dysfunction, as occurs in LOAD, leads to the co‐occurrence of lysosomal and mitochondrial defects.
The Image and Multimodal Classification for Alzheimer's Disease by Convolutional Neural Network and Combination with Long Short‐Term Memory using Tau‐PET images
Authors: PARK SANG WON , Yeo Na Young , Kim Jung‐Kyeom , Yum Sujin , Jang Jae‐Won
Published: December 2022

Background

We performed image and multimodal classification based on Convolutional Neural Network(CNN) and Combination with Long Short‐Term Memory(LSTM) using 2D and 3D Tau‐PET images for cognitively normal(CN), mild cognitive impairment(MCI), and Alzheimer's disease(AD) patients.

Method

Total of 276 subjects(CN=138, MCI=75, AD=63) were investigated in this study for CN‐MCI and CN‐AD classification. All subjects investigated in this study were diagnosed at baseline. Data were obtained from the Alzheimer's disease Neuroimaging Initiative(ADNI). The acquired images were converted voxel and pixel sizes to (1,1,1) and (1,1) by resizing for CNN‐LSTM using 2D axial images and CNN using 3D images. Axial images for 2D CNN‐LSTM deep learning were extracted from 3D images by selecting only axial value in array of 3D voxel. In the case of 2D images, 72 images per patient were used and sequentially arranged to perform deep learning analysis. The multi‐modal deep learning was applied to perform a fusion model using structured data such as clinical information (age, sex, education, MMSE, CDRSB) with images. The clinical information were divided into four groups (Table 1). The transfer learning was conducted for the CN‐MCI classification in 2D and 3D, respectively, using weights obtained from CN‐AD, respectively. All models were validated based on a five‐Stratified‐KFold.

Result

The average classification accuracies for CN‐AD using only images were 91.2 % and 84.6 % in 3D CNN and 2D CNN‐LSTM, respectively. Similarly, the average classification accuracies for CN‐MCI using only images were 82.6 % and 72.2 % in 3D CNN and 2D CNN‐LSTM, respectively. All modeling except 2D CNN‐LSTM for CN‐MCI classification exhibited a synergistic multi‐modal effect (Table 1).

Conclusion

Both the CN‐MCI and CN‐AD classification could be performed using tau‐PET images and clinical information. The results indicate that these methods may be applied to facilitate a clinical decision support system for diagnosing dementia.
A novel episodic memory test optimized for smart phone high‐frequency assessments
Authors: Anwyl‐Irvine Alexander L , Kaula Alexander J , Cashdollar Nathan , Taptiklis Nick , Cormack Francesca K
Published: December 2022

Background

Decline in episodic memory is a strong marker of neurodegenerative diseases, making it an important target for cognitive assessment. We present a new remote, repeatable, and brief assessment of episodic memory and visual short‐term memory (VSTM) for smart phone deployment. We evaluated this task for sensitivity to age and established cognitive measures of memory and attention.

Method

The task consists of a learning phase where participants see a sequence of items, then are asked to replicate the item order and location by dragging and dropping these items on‐screen. A recall phase follows a minimum 12‐hour delay, with replication of the earlier response. Each session takes less than 2 minutes. The first phase supplies metrics of spatial and order precision VSTM, with the second phase characterising long‐term episodic memory.

Experiment 1 (n=133) compares the task with CANTAB assessments of visuospatial memory. In Experiment 2 (n=80) the novel task was repeated twice daily for a week, alongside momentary mood ratings, and a more comprehensive battery of CANTAB tasks at baseline.

In Experiment 1, multiple regression and dominance analyses explore the independent and shared variance of measures in explaining age. In Experiment 2, clustering and multivariate autoregressive models outline differences in timeseries relationships between mood and memory, and age.

Result

Experiment 1 revealed that CANTAB measures and novel spatial and order metrics were correlated with age (r=.20 to r=.37, adjusted P= <.05). Multiple regression showed models with CANTAB Paired Associate Learning (PAL) score, and delayed novel spatial metrics were significantly predictive of age (t= ‐4.08, 3.17, p <.005). The dominance analysis revealed novel immediate precision overlapped with existing measures in predicting Age, while delayed precision had more unique variance (4.6% vs 0.62% unique sample variance explained in Age, accounting for PAL).

Experiment 2 characterised variance in individual learning curves over time and differing autoregressive processes associated with age and CANTAB measures.

Conclusion

We present a brief novel episodic memory task that can be deployed remotely, with delayed spatial precision significantly predictive of healthy Ageing. Additionally, we show this test’s suitability as a repeated assessment, compatible with high‐frequency study designs in older populations.
nSMase2 inhibition reduces tau propagation in Alzheimer’s Disease mouse models
Authors: Tallon Carolyn , Bell Benjamin J , Malvankar Medhinee , Thomas Ajit G , Yoo Seung Wan , Pal Arindom , Wu Ying , Coleman Kaleem , Joe Tawnjerae R , Sharma Anjali , Eren Erden , Zhu Xiaolei , Kannan Rangaramanujam M , Kapogiannis Dimitrios , Haughey Norman J , Rais Rana , Slusher Barbara S
Published: December 2022

Background

Alzheimer’s Disease (AD) is the most common form of dementia worldwide and is characterized by progressive neurodegeneration and cognitive decline, putatively driven by the accumulation Amyloid‐b and hyperphosphorylated Tau. Clinical trial successes focusing on reducing Amyloid‐b plaque levels in patient brains have been modest, spurring a renewed focus on tau. Tau spreads throughout the brain along anatomical pathways, correlating strongly with the disease progression severity. Recent evidence has highlighted extracellular vesicles (EVs) in enabling transcellular transmission of pathological tau in the brain in a ‘prion‐like’ manner and identified the inhibition of EV biogenesis via small‐molecule inhibitors of nSMase2 as a potential therapeutic avenue. However, presently available tool compounds are unsuitable for clinical development.

Method

To improve upon current inhibitors, we performed high‐throughput screening followed by extensive chemistry and identified two classes of compounds. The first, PDDC, has excellent potency, oral bioavailability, and brain penetration, as well as in vitro and in vivo EV inhibition. The second, DPTIP, has higher potency, but poor oral pharmacokinetics and modest brain penetration. To circumvent these limitations, we conjugated DPTIP to a brain‐targeting hydroxyl‐dendrimer delivery system (D‐DPTIP) and demonstrated CNS target engagement following oral dosing. We then chronically administered PDDC and D‐DPTIP to PS19 transgenic mice and WT mice seeded with an AAV‐hTau vector unilaterally stereotaxically injected into the CA1 hippocampal region. After chronic dosing, we quantified the levels of phosphorylated tau in the hippocampus in the PS19s and the contralateral dentate gyrus in the AAV‐hTau seeded model. We also characterized isolated neuronally‐derived plasma EVs from these mice.

Result

PS19 mice treated with PDDC had significantly reduced hippocampal tau and increased neuronal counts compared with vehicle. Additionally, PDDC treatment reduced the release of neuronally‐derived EVs into circulation with lower tau level trends. Similarly, seeded mice treated with either PDDC or D‐DPTIP had reduced tau staining intensity in the contralateral dentate gyrus. Importantly, neither compound induced significant toxicity in either model.

Conclusion

Observing significant reductions in tau burden in two separate AD models provides proof of concept for nSMase2 inhibition in slowing tau propagation, highlighting the promise of tested compounds as potential AD therapeutics.