bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphological alterations of the choroid plexus epithelium in Alzheimer’s disease
Authors: Van Cauwenberghe Caroline , Vandendriessche Charysse , Kremer Anneke , De Rycke Riet , Borghgraef Peter , Van Imschoot Griet , Van Wonterghem Elien , Lippens Saskia , Vandenbroucke Roosmarijn E
Published: December 2020

Background

The choroid plexus (CP), is a complex structure localized in the ventricles of the brain, which mainly consist of tightly connected choroid plexus epithelial (CPE) cells surrounding fenestrated capillaries. These CPE cells form the blood‐cerebrospinal fluid barrier and play a vital role in the maintenance of brain homeostasis. During Alzheimer’s disease (AD) several CPE related processes are severely affected (Brkic, 2015) and evidence indicates that CP‐derived extracellular vesicles play an important role in AD pathogenesis. In this study morphological alterations of the CPE cells were characterized in two distinct AD mice models (APP/PS1tg/wt and APPNLGF/NLGF). Additionally, we investigated the subcellular localization and performed quantification of multivesicular bodies (MVBs) and intraluminal vesicles (ILVs) using transmission electron microscopy (TEM) and 3D‐scanning electron microscopy (3D‐SEM).

Method

CP tissue was isolated from APPwt/wt, APP/PS1tg/wt, APPNLGF/NLGF mice at different timepoints (age 10w, 20w, 30w and 40w). Isolated CP was processed for TEM and 3D‐SEM imaging as previously described in (Balusu, 2016; Kremer, 2015). Visualization of the samples was performed using a TEM (JEOL) and FIB‐SEM (Zeiss) and manual segmentation of 3D‐SEM images was done using Microscopy Image Browser (Belevich, 2016).

Result

In both APP/PS1tg/wt and APPNLGF/NLGF mice morphological alterations of the CP are visible at the age of 20 weeks, the ultrastructure is damaged. The CPE cells lose their typical cuboidal shape, are more point‐shaped, the cytoplasm becomes more translucent, the nuclei are irregularly shaped and the mitochondria are more condensed. These changes become increasingly prominent as the mice age. In APPwt/wt mice, the same morphological alterations of the CP become visible at later age. Early during disease progression (10 w), we observed higher levels of ILVs in the CP of APP/PS1tg/wt compared to age‐matched APPwt/wt mice, while levels normalized at later stages. In APPNLGF/NLGF mice higher MVB and ILV levels are observed early during disease progression.

Conclusion

Ultrastructural changes of the CP epithelium are present in different AD mice models. Furthermore, we observed differences in levels of ILVs in the CP early during disease progression. Further research might give insights into the role of the CP and ILVs in AD pathogenesis.
Comparative diagnostic performance of plasma P‐tau217 and P‐tau181 in Alzheimer’s disease and frontotemporal lobar degeneration and correlations with [18F]Flortaucipir‐PET uptake
Authors: Thijssen Elisabeth H. , La Joie Renaud , Strom Amelia , Teunissen Charlotte E. , Dage Jeffrey L. , Rojas Julio C. , Rabinovici Gil D. , Boxer Adam L.
Published: December 2020

Background

Plasma P‐tau181 has previously been shown to be associated with tau pathology in Alzheimer’s disease (AD). P‐tau217 is a novel blood‐based biomarker. We assessed the diagnostic value of plasma P‐tau181 and P‐tau217 in the same cohort of patients across the AD and frontotemporal lobar degeneration (FTLD) spectrum.

Method

This retrospective study of 617 participants included 119 healthy controls, 74 cases in the clinical AD spectrum (57 amnestic, 15 lvPPA, 2 PCA; all biomarker‐confirmed) and 294 in the FTLD spectrum. The cohort included 15 AD and 67 FTLD autopsy‐confirmed cases and 66 Microtubule‐Associated Protein Tau (MAPT) mutation carriers. P‐tau concentrations were measured using custom electrochemiluminiscence‐based assays at Lilly. P‐tau217 was available in 513 cases, P‐tau181 in 614 cases, and both in 509. Amyloid‐PET was available in 352 cases and [18F]Flortaucipir (FTP)‐PET in 227 cases. The differentiating power of P‐tau181 and P‐tau217 was assessed across clinical and autopsy‐confirmed phenotypes, amyloid‐ and FTP‐PET status, and type of tau pathology in MAPT mutation carriers.

Result

Plasma P‐tau217 concentrations were increased 5.2‐fold in clinical AD (n=74) relative to controls (AUC=97%, p<0.001) and 3.8 fold relative to clinical FTLD (AUC=93%, p<0.001). P‐tau217 was increased 4.9 fold in autopsy‐confirmed AD compared to autopsy‐confirmed FTLD (AUC=92%, p<0.001). Plasma P‐tau181 was increased 2.6 fold in clinical AD compared to controls (AUC=93%, p<0.001) and 2.4 fold relative to clinical FTLD (AUC=89%, p<0.001). P‐tau181 was increased 2.5 fold in autopsy‐confirmed AD compared to autopsy‐confirmed FTLD (AUC=87%, p<0.001). There was no change in P‐tau217 concentrations in MAPT mutation carriers with mixed 3R/4R tau pathology compared to 4R tau pathology, whereas P‐tau181 was 1.4 fold increased (p<0.01). FTP‐PET SUVR was associated with P‐tau217 (ρ=0.78, p<0.001) and P‐tau181 (ρ=0.64, p<0.001). P‐tau217 could identify amyloid‐PET positive cases (n=317, AUC= 86%, p<0.001), and FTP‐PET positive cases (AUC= 96%, p<0.001, n=213) across diagnoses, with similar accuracy to P‐tau181 (amyloid‐PET AUC=81%, n=351, FTP‐PET AUC=90%, p<0.001, n=227).

Conclusion

Plasma P‐tau217 is comparable to P‐tau181 for differential diagnosis of AD and potentially superior for identifying FTP‐PET positivity. Additional investigations are necessary to explain potential differences in assay performance in MAPT mutation carriers that produce mixed 3R/4R tau, whose pathology is similar to AD.
Epitope prediction for oligomer‐selective antibodies in tau and Aβ
Authors: Plotkin Steven S. , Hsueh Shawn Ching‐Chung , Adekunle Aina , Peng Xubiao , Gibbs Ebrima , Roman Andrei , Zhao Beibei , Louadi Sarah , Kaplan Johanne , Cashman Neil R.
Published: December 2020

Background

Previous studies of Alzheimer’s disease (AD) pathology point to cytotoxic tau as a cause of neuronal cell death, which is induced or exacerbated by soluble misfolded Aβ oligomers. Soluble misfolded species of both tau and Aβ are both observed to propagate cell‐to‐cell. A method for identifying antibodies to tau and Aβ that are conformationally‐selective to propagative misfolded oligomeric forms, and which also have low affinity to isolated monomers or, particularly for Aβ, low affinity to fibrils, is thus a highly desired goal that holds significant promise for AD therapy.

Method

We have developed a novel computational platform to identify epitopes that may be selectively exposed on oligomers. Epitope prediction ideally uses an experimentally determined fibril structure as input, but the method alters this structure using molecular dynamics, to more accurately model the regions that may be exposed on soluble oligomers. Both primary sequence and structural conformation are taken into account: The epitope should be conformationally‐distinct from those conformations presented in the functional healthy protein. Epitope scaffolding is then employed to optimize the presentation of the epitope in animal immunizations, so that the resulting antibodies are predicted to be selective to misfolded oligomeric forms.

Result

Oligomer‐specific epitope predictions for tau and for Aβ have been used to raise preclinical antibodies that have selectivity for pathogenic tau and Aβ species. In vitro SPR measurements confirmed selective binding to synthetic oligomers and soluble pre‐formed fibrils (PFFs), vs. native healthy protein. As well, the antibodies showed little immunoreactivity toplaque or vascularAβ deposits via immunohistochemistry, while SEC fractionation of AD brain homogenate shows selective binding to toxic dimers, tetramers and dodecamers, in contrast to aducanumab and bapineuzumab. Tau antibodies recognized tau from AD brain extract, and inhibited seeding activity in a FRET assay. Aβ antibodies alleviated the cognitive deficits caused by oligomers in mouse NOR studies.

Conclusion

Lead antibodies to tau and Aβ developed using rationally designed conformational epitopes are likely to achieve greater therapeutic potency by selectively targeting soluble toxic oligomers, and reducing the risk of target distraction and ARIA.
Elucidating emerging therapeutics: P75 receptor modulation reverts tauopathy associated alterations in synapse‐relevant gene expression signatures
Authors: Latif‐Hernandez Amira , Losada Patricia Moran , Yang Tao , Tran Kevin C. , Liu Harry , Lehallier Benoit , Massa Stephen M. , Longo Frank M.
Published: December 2020

Background

In tauopathy mouse models, activity‐dependent synaptic plasticity, as measured by long‐term potentiation (LTP), is compromised. Treatment of tauopathy mice with LM11A‐31, a small molecule modulator of p75 neurotrophin receptor signaling, normalizes LTP. In the present study, we determined whether activity‐dependent gene expression profiles would be altered in stimulated hippocampus (HC) of tauopathy mice, and if prior in vivo treatment with LM11A‐31 would normalize elements of their transcriptional signature.

Method

6 month‐old wildtype and PS19 (P301S) mice were treated daily by oral gavage for 3 months with vehicle or LM11A‐31. Late‐LTP was used in acute HC slices to induce activity‐dependent changes at synapses. After completion of recordings, a RNA sequencing approach was followed to analyze activity‐dependent gene expression and generate transcriptomic profiles, using cutoffs of q<0.05 and fold change > 1.5.

Result

Analyses of the 36,175 expressed transcripts revealed that samples clustered based on the absence (‐) or presence (+) of LTP. Differential gene expression was found in WT/‐LTP vs WT/+LTP (550 upregulated, 176 downregulated genes); in Tau/‐LTP vs Tau/+LTP (1327 upregulated, 702 downregulated genes) and in Tau/+LM11A‐31/‐LTP vs Tau/+LM11A‐31/+LTP (338 upregulated, 143 downregulated genes). There was strong enrichment in pathways involving genes upregulated by LTP induction in all groups, including NF‐kappa B signaling. In contrast, cytokine activity was enriched within the transcripts that were upregulated with LTP in WT and Tau/+LM11A‐31 but not in the Tau group. Next, we analyzed LTP slices from all groups and found that altered gene expression between WT and Tau mice (996 upregulated and 320 downregulated genes) was changed in Tau/+LM11A‐31 (264 upregulated and 409 downregulated genes). GO, KEGG and Reactome enrichment analyses in WT/+LTP vs Tau/+LTP demonstrated that Tau mice show downregulated genes in neuronal system, calcium signaling, glutamatergic synapse and long‐term potentiation; and upregulated genes in aging, apoptosis and glial cell development pathways. Remarkably, the expression levels of genes from these pathways were largely reverted to WT pattern in Tau mice treated with LM11A‐31.

Conclusion

Modulating p75NTR might restore tauopathy‐related alterations in synapse‐relevant gene expression profiles. These findings point to candidate signaling modules for understanding synaptic impairment and therapeutic strategies.
Assessment of cortical vulnerability of the anterior cingulate cortex in the behavioral variant of Alzheimer’s disease
Authors: Berendrecht Evi , Gami‐Patel Priya , Blujdea Raluca E. , Singleton Ellen H. , Bouwman Femke , Pijnenburg Yolande A.L. , Scheltens Philip , van Swieten John C. , Papma Janne M. , Hoozemans Jeroen J.M. , Ossenkoppele Rik , Dijkstra Anke A.
Published: December 2020

Background

The anterior cingulate (ACC) and frontoinsular cortex (FI) are key regions implicated in behavior and social cognition. These regions harbor a novel cortical neuronal group, characterized by expression of the GABA subunit theta (GABRQ) and inclusion of Von Economo Neurons (VENs). This neuronal group is selectively vulnerable in the behavioral variant of frontotemporal dementia (bvFTD), but not in typical Alzheimer’s disease (typAD)(1). Currently, it is unknown whether this neuronal population is affected in the behavioral variant of AD (bvAD) compared to controls and typAD and whether there is a difference in local pathological burden and morphology between bvAD and typAD.

Method

Human post‐mortem tissue of the ACC was used to quantify the GABRQ‐neuronal population and burden and morphology of amyloid beta and tau pathology. We included 10 controls, 8 bvAD donors, and 10 typAD donors. One slide of 10 μm from each donor was used for quantification of Layer 5 GABRQ‐expressing VENs and pyramidal neurons. Layer 5 GABRQ‐negative neurons were counted using Stereoinvestigator software. Burden of pathology was assessed in sequential slides, where diffuse, coarse‐grained, and core amyloid‐beta plaques were quantified. Local tau pathology burden was assessed using ImageJ software. Tissue of the FI will be analyzed in a similar manner.

Result

The total number of GABRQ‐expressing neurons and VENs in the ACC of bvAD donors is similar compared to controls (p=0,22) and typAD (p=0,64)(Figure 1). Furthermore, no significant differences were observed in amyloid‐beta (p=0,38) and tau burden (p=0,09) or presence of different morphological amyloid‐beta plaques in the ACC. Results of FI analysis will be ready at AAIC 2020.

Conclusion

Our data suggest that the bvAD phenotype cannot be explained by ACC vulnerability to AD pathology. Future analysis of the selective vulnerability of the FI may elucidate whether GABRQ‐expressing neurons are disproportionally affected in bvAD.
Effect of decreased visual acuity on cortical thickness: A possible risk factor for neurodegeneration
Authors: Kim Ji Sun , Han Gyule , Park Yuhyun , Kang Sung Hoon , Kim Jaeho , Lee Jong Min , Seo Sang Won , Lim Dong Hui , Kim Hee Jin
Published: December 2020

Background

Cortical thickness is a biomarker for neurodegeneration. Ample evidence supports the idea that decreased sensory stimuli lead to degeneration of relevant central areas in the brain. We hypothesized that decreased visual stimuli might be associated with cortical atrophy in visual processing areas. Therefore, we investigated the association between visual acuity (VA) and cortical thickness in cognitive normal adults.

Method

We retrospectively analyzed the health screening data from the Health Promotion Center at the Samsung Medical Center from 2008 to 2014. In total, 2,810 cognitive normal subjects who checked corrected VA and Brain MRI were identified. The subjects were divided into 3 groups according to the VA of better eye: Group 1 (VA The higher VA value indicates better VA. Using multivariate regression analysis, cortical thickness of Group 1 and 2 were compared with Group 3. We also analyzed linear association between VA and cortical thickness. The analyses were performed after controlling for age, sex, hypertension, diabetes, hyperlipidemia, and intracranial volume.

Result

Compared to Group 3, Group 1 showed cortical thinning in the bilateral occipital, lateral temporal, and lateral parietal areas. Compared to Group 3, Group 2 also showed cortical thinning in the bilateral occipital, right lateral temporal, and bilateral lateral parietal areas. Linear association analysis showed that the lower VA was associated with cortical thinning in the bilateral occipital areas.

Conclusion

Our results showed that cognitive normal individuals with lower VA have cortical thinning in the posterior part of the brain which is responsible for visual processing. This suggest that good VA may have preventive effect for neurodegeneration.
Left frontal hub connectivity enhances task‐related brain network segregation and cognition in aging: Implications for reserve
Authors: Frontzkowski Lukas , Franzmeier Nicolai , Neitzel Julia , Luan Ying , Habeck Christian , Stern Yaakov , Ewers Michael
Published: December 2020

Background

Global connectivity of the left frontal cortex (LFC), a hub of the cognitive control network, is associated with higher fluid intelligence and relatively preserved cognition despite age‐ and Alzheimer’s disease (AD)‐related brain changes, rendering LFC‐connectivity a candidate substrate of reserve (Franzmeier et al. Brain 2018). Yet, the mechanisms by which LFC‐connectivity supports cognition at the functional network level remain unclear. Functional network‐segregation within the brain guards against diffuse network organization and is a fundamental brain property central to efficient cognitive processes. Given that the control network, and in particular the LFC, is thought to orchestrate activity of other functional networks (Cole, Nat Neurosci, 2013), we hypothesized that the association between LFC‐connectivity and higher cognitive abilities such as executive function is mediated via enhanced network‐segregation.

Methods

We applied 3 fMRI‐tasks per cognitive domain (i.e. fluid‐reasoning, memory, speed, vocabulary) in 255 non‐demented participants from the RANN study. We determined atlas‐based (Fig.1) whole‐brain functional connectivity during task‐fMRI using psycho‐physiological‐interaction analyses. Global LFC‐connectivity was assessed as mean task‐related LFC‐connectivity to the remaining ROIs. Network‐segregation was assessed as the difference of within‐network and between‐network connectivity normalized to within‐network connectivity (Chan et al., PNAS, 2014). For the three tasks per cognitive domain, we determined domain‐specific performance, LFC‐connectivity and network segregation scores via principal‐component analysis. Using linear regression and mediation analysis, we tested for each cognitive domain whether 1) higher LFC‐connectivity was associated with better cognition 2) and subsequently whether this association was mediated by network‐segregation.

Results

Higher task‐related LFC‐connectivity was associated with better performance in fluid‐reasoning (β=0.178, p=0.003,Fig.2A) but not in other cognitive domains (p>0.05). Higher LFC‐connectivity during fluid‐reasoning tasks was associated with network‐segregation (β=0.308, p<0.001, Fig.2B), which was associated with fluid‐reasoning performance (β=0.352, p<0.001, Fig.2C). In mediation analyses, we found that LFC‐connectivity effects on fluid‐reasoning performance were mediated by network‐segregation (bootstrapped mediation effect: β=0.0981,95%CI[0.0481;0.16], p<0.001).

Conclusions

LFC‐connectivity supports higher fluid reasoning performance in normal aging via enhanced brain network segregation, suggesting a potential mechanism by which LFC‐connectivity supports reserve in AD.
Language impairment in progressive supranuclear palsy and corticobasal syndrome: MLSE screening and its neural correlates
Authors: Peterson Katie A. , Jones P. Simon , Patel Nikil , Ingram Ruth , Patterson Karalyn , Rowe James B. , Garrard Peter
Published: December 2020

Background

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) change speech and language as well as motor function. Here, we used the new Mini Linguistic State Examination (MLSE), a brief, yet comprehensive language assessment tool, to investigate structural correlates of language impairment in PSP and CBS, alongside patients with the nonfluent variant of primary progressive aphasia (nfvPPA).

Method

Twenty‐eight patients (PSP N=8, CBS N=10 and nfvPPA N=10) and 24 aged‐matched controls completed the MLSE, the Addenbrooke’s Cognitive Examination III, and 3T PRISMA structural MRI. T1‐weighted images were processed using Freesurfer 6.0. The groups were compared using an ANCOVA of cortical thickness including age, gender and MLSE total score as covariates.

Result

PSP and CBS patients’ MLSE total scores were significantly (p<0.001) impaired compared to controls but better (p<0.05) than nfvPPA. For the MLSE subscores, compared to controls, PSP impaired motor speech (p=0.003), while CBS impaired phonology, semantics, and syntax (p<0.05). There was a positive correlation between cortical thickness with MLSE total score in the left inferior frontal gyrus pars triangularis, middle temporal gyrus, and supramarginal gyrus (p<0.001 unc).

Conclusion

The MLSE screening tool identifies speech and language deficits in PSP and CBS. Impairments were associated with atrophy in key regions of left hemisphere frontotemporal language networks. Future work will identify multisite scalability of the MLSE and its imaging correlates.
The association between polygenic hazard scores and clinical markers of Alzheimer’s disease following stratification for APOE genotype
Authors: De Marco Matteo , Manca Riccardo , Kirby Janine , Hautbergue Guillaume , Blackburn Daniel J , Wharton Stephen , Venneri Annalena ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Genome‐wide association studies have confirmed the APOE ε4 allele as the single‐nucleotide polymorphism (SNP) best associated with Alzheimer’s disease. These same studies, however, have found that a considerable number of other SNPs are associated with Alzheimer’s disease. The statistical association yielded by these other SNPs, however, is considerable weaker than that of the APOE ε4. It is unclear, therefore, whether these non‐APOE SNPs have similar effects in APOE ε4 carriers and non‐carriers. In this study, we investigated the association between a polygenic hazard score (PHS) for sporadic Alzheimer’s disease and clinical profiles of a large cohort non‐demented participants stratified by APOE ε4 status.

Method

A cohort of 776 participants was shortlisted from the entire ADNI database: 262 cognitively unimpaired participants (185 with a ε3ε3 genotype and 77 with a ε4ε3 genotype) and 514 participants with a diagnosis of MCI (241 with a ε3ε3 genotype, 212 with a ε4ε3 genotype and 61 with a ε4ε4 genotype). This same cohort was also split according to cerebrospinal amyloid (Aβ) positivity status, resulting into 275 Aβ‐ and 501 Aβ+ participants. Genome‐wide data, a structural brain MRI and cognitive profiles were available for each dataset. Genetic information was used for the calculation of a PHS, following the methodology by Desikan and colleagues [1]. Memory and executive composite scores were calculated for each dataset based on previously described procedures [2,3]. A voxel‐based morphometry was carried out to process T1‐weighted MRI images and obtain grey‐matter maps analysable at a group level. Linear models were devised in each sub‐cohort and for each APOE ε4 status to test the association between PHS and cognitive composites and between PHS and volumetric grey‐matter maps.

Result

PHS was a predictor of mediotemporal volume in MCI patients and a predictor of memory and executive functioning both in MCI and Aβ+ participants. Following APOE stratification, PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 MCI and ε3ε3 Aβ+ participants.

Conclusion

These results suggest that clinical phenotypes might be influenced by complex genetic interactions.
Identifying and predicting heterogeneity in cognitive decline among individuals with prodromal Alzheimer's disease using a latent class analysis
Authors: Jutten Roos J. , Sikkes Sietske A.M. , Papp Kathryn V. , Van Berckel Bart N.M. , Teunissen Charlotte E. , van Der Flier Wiesje , Scheltens Philip , Tijms Betty M.
Published: December 2020

Background

Individuals with prodromal Alzheimer’s disease (AD) show heterogeneity in their rates of cognitive decline, which is problematic for measuring (therapeutic) effects on cognition. We aimed to identify subgroups with homogeneous cognitive trajectories among individuals with prodromal AD in two large independent cohorts, and investigate which clinical and/or biological AD risk factors predict progression rate.

Method

Individuals with an abnormal amyloid marker (determined by either CSF Aβ‐42 levels or Florbetaben/Flutametamol/Florbetapir‐AV45 PET imaging) and mild cognitive impairment who had longitudinal cognitive data available were selected from the Amsterdam Dementia Cohort and ADNI (N=340, age =71.5±8.4, 43% female). We performed latent class mixed models (LCMM) to identify subgroups based on similarity of their trajectories on the Mini‐Mental State Examination (MMSE), and performed mixture modelling using individual MMSE slopes to validate those subgroups. We compared subgroups on baseline age, sex, years of education, ApoE‐e4 status, CSF tau and phosphorylated tau (p‐tau) and hippocampal volume using univariate logistic regression, and subsequently performed stepwise logistic regression with backward elimination to identify which baseline characteristics best predicted progression.

Result

Participants had 2.3±1.8 repeated assessments and a follow‐up of 2.3±1.6 [range=1‐8] years. LCMM identified three subgroups of MMSE progression, which were confirmed by mixture modelling: Group 1 (n=303, 88%) showing slowest progression (i.e. average 0.7 [range=0.4–1.9] points annual decline on MMSE); Group 2 (n=30, 10%) intermediate progression (average 2.6 [range=1.9–4.2] points annual decline on MMSE) and Group 3 (n=7, 2%) showing fastest progression (average 4.7 [range=3.3–6.2] points annual decline on MMSE) (Figure 1). No effects on progression were observed for age, sex, education and ApoE‐e4 (Table 1). Compared to individuals who slowly progressed, those with intermediate‐to‐fast progression had higher tau (OR=1.01, 95%CI=[1.01‐1.02], p<.001) and p‐tau (OR=1.03, 95%CI=[1.02‐1.05], p<.001) levels and lower hippocampal volume (OR=0.57, 95%CI=[.37‐.84], p=.006) at baseline. The model including both p‐tau (OR=1.03, 95%CI=[1.02‐1.05], p<.001) and hippocampal volume (OR=0.55, 95%CI=[.34‐.85], p=.01) best predicted fast progression.

Conclusion

Among individuals with prodromal AD, we identified three subgroups with different rates of decline on the MMSE, and demonstrated that baseline neurodegeneration markers were associated with faster decline. These findings have practical implications for clinical trial enrollment and predicting disease progression.
CSF biomarkers for frontotemporal dementia and its pathological subtypes
Authors: Campo Marta Del , Peeters Carel F.W. , Chen‐Plotkin Alice , van Der Flier Wiesje , Meeter Lieke H.H. , van Swieten John C. , Hu William T. , Irwin David J. , Pijnenburg Yolande A.L. , Teunissen Charlotte E.
Published: December 2020

Background

Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD) and is characterized mainly by the presence of aggregates of the proteins tau (FTLD‐Tau) or TDP43 (FTLD‐ TDP) in the brain, which likely require distinct pharmacological therapy. However, the clinical presentation of the pathological subtypes is heterogeneous and overlapping, making this diagnostic subtyping at present virtually impossible. Thus, there is a strong unmet need to identify body‐fluid biomarkers to discriminate FTD and its pathological subtypes. Most biomarker studies performed to date have analyzed pathologically heterogeneous populations. The few studies analyzing antemortem cerebrospinal fluid (CSF) with known underlying neuropathology have revealed several candidate biomarkers (e.g. p/tTau ratio). Despite these promising results, their specificity is still not optimal, most of the identified markers are awaiting further validation and their diagnostic accuracy remains to be evaluated.

Method

We have recently taken advantage of a novel high‐multiplex and sensitive antibody‐based proteomic technology to analyze >600 proteins in a large multicenter cohort providing CSF samples from controls (n=195) and FTD patients (n=199). For a subset of FTD cases, the underlying specific pathology was known (FTLD‐Tau=34: 18 autopsy‐confirmed and 27 MAPT mutation carriers; FTLD‐ FTLD‐TDP=54: 27 autopsy‐confirmed and 18 C9orf72 and 9 GRN mutation carriers). Differences in the protein expression profile were analyzed by GlobalTesting. Generalized linear modeling was used to identified classification protein signatures.

Result

We identified CSF protein biomarker signatures for specific diagnosis of FTD (8‐9 proteins, AUC>0.85). The proteins identified were related to mechanisms involved in immune system, extracellular remodeling and cell killing. There were no between‐group differences in the CSF protein profiles of the FTLD groups. However, differences in the absolute levels of some proteins were detected when autopsy‐confirmed cases and mutation carriers were analyzed separately.

Conclusion

The similarity of the CSF profiles between FTLD groups suggests shared pathological mechanisms. Alternatively, each subtype may be heterogeneous, which possibly results from analyzing together familial and autopsy‐confirmed cases. Taken together, the FTLD studies performed to date indicate a highly complex disorder challenging the development of efficient diagnostic and therapeutic markers.
Global shifts in DNA methylation and DNA hydroxymethylation across multiple brain regions in transgenic models of tau and amyloid pathology
Authors: Castanho Isabel , Murray Tracey K. , Harvey Joshua , Leung Szi Kay , Lunnon Katie , Ahmed Zeshan , Mill Jonathan
Published: December 2020

Background

There is increasing evidence to support a role for altered DNA modifications in Alzheimer’s disease (AD). Global changes in both DNA methylation (5mC) and DNA hydroxymethylation (5hmC) have been robustly reported in cancer, but not widely studied in AD. We quantified global levels of 5mC and 5hmC across multiple brain regions in two transgenic models of AD pathology, relating these to the progressive changes in tau and amyloid observed in the same samples.

Method

We investigated global DNA modification levels in brain tissue from rTg4510 and J20 mice using two independent approaches. We quantified hippocampal global DNA methylation in rTg4510 and J20 transgenic (TG) and wild‐type (WT) littermate control mice using an enzymatic‐based methylation assay combined with pyrosequencing. Using immunohistochemistry, we directly quantified levels of both 5‐methylcytosine (5mC) and 5‐hydroxymethylcytosine (5hmC) in multiple brain regions in rTg4510 and J20 mice.

Result

We identified both genotype‐associated and progressive temporal changes (interaction between genotype and age) in 5mC and 5hmC in rTg4510 TG and J20 TG mice compared to WT littermate controls in several brain regions. Levels of both 5mC and 5hmc were negatively correlated with levels of tau and amyloid pathology, reflecting some evidence from human AD brain.

Conclusion

We identified decreased levels of two DNA modifications (5mC and 5hmC) associated with accumulation of tau and amyloid pathology. Both genotype‐associated and progressive changes in 5mC and 5hmC measured by immunohistochemistry were observed, with these changes notably stronger in rTg4510 TG relatively to J20 TG mice, particularly in the hippocampus.
Plasma Aβ biomarker associated with cognitive decline in preclinical Alzheimer’s disease
Authors: Lim Yen Ying , Maruff Paul T. , Kaneko Naoki , Fowler Christopher J. , Villemagne Victor L.L. , Kato Takashi , Rowe Christopher C. , Arahata Yutaka , Iwamoto Shinichi , Ito Kengo , Tanaka Koichi , Yanagisawa Katsuhiko , Masters Colin L. , Nakamura Akinori
Published: December 2020

Background

Using immunoprecipitation‐mass spectrometry, we recently developed and validated a plasma composite biomarker for the assessment of Aβ levels. However, as yet, it’s utility to predict clinical and cognitive outcomes remains unclear. This study aimed to examine the relationship between this plasma Aβ composite biomarker and cognitive function in cognitively normal older adults in two independent cohorts.

Method

This is a longitudinal study conducted in two independent cohorts – the Australian imaging, Biomarkers and Lifestyle (AIBL) study and Japan’s National Centre for Geriatrics and Gerontology (NCGG) study. A series of linear mixed models were conducted to determine the relationships between plasma Aβ composite scores and cognitive decline. Cognitively normal (CN) older adults enrolled in the AIBL study (n=156) and the NCGG study (n=57) were included in this analysis. Participants had undergone Aβ neuroimaging using positron emission tomography (PET), cognitive assessments and provided blood samples. We derived a high‐performance plasma Aβ composite biomarker by immunoprecipitation with mass‐spectrometry. The main outcome measures were composites of episodic memory, executive function, language and attention.

Result

Both continuous and categorical measures of the plasma Aβ composite biomarker were significantly related to decline in episodic memory and executive function (Figure 1). The magnitude of effects of the plasma Aβ composite on episodic memory and executive function were comparable to that observed for the effects of PET Aβ levels on these same outcome measures.

Conclusion

Several plasma Aβ biomarkers have been developed, but none have yet been applied to investigate their relationship with cognitive outcomes. Our results have important implications for the use of this biomarker in the detection of at‐risk individuals.
Prevalence of memory impairment 2000‐2015 in Sao Paolo, Brazil
Authors: Ribeiro Fabiana , Duarte Yeda Aparecida de Oliveira , Santos Jair Lício Ferreira , Leist Anja
Published: December 2020

Background

Decreases in prevalence of memory impairment and dementia over the last two decades have been observed in different countries for cohorts entering older age. We sought to explore the changes in prevalence of cognitive impairment across four waves of the Health, Welfare and Aging survey (SABE) with data collected in Sao Paolo, Brazil, in 2000, 2006, 2010, and 2015.

Method

Mini Mental State Exam (MMSE) scores and covariate values were available for 5,191 respondents (62.4% female) aged 60 to 99 across four waves. Cognitive impairment was defined as having <=12 points on a 19‐point abbreviated version of the MMSE. Age group, educational attainment (no formal schooling, primary, secondary, post‐secondary), self‐reported heart disease, stroke, diabetes, hypertension, and BMI (<18.5, 18.5‐24.9, 25‐29.9, 30+) were adjusted for.

Result

In more recent waves, prevalence of cognitive impairment was higher for respondents aged 60‐64 years (9.0% in 2015 vs. 4.6% in 2000), 65‐69 years (9.7% in 2015 vs. 5.8% in 2006) and 70‐74 years (13.9% in 2015 vs. 5.8% in 2006). Between 2015 and 2000, respondents were increasingly more likely to report some formal education (90.8% vs. 75.3%), secondary (17.6% vs. 7.3%) or post‐secondary education (11.4% vs. 4.3%). Respondents were increasingly more likely to report hypertension (66.5% vs. 54.2%), diabetes (28.7% vs. 17.8%), and be overweight/obese (74.1% vs. 58.9%). In covariate‐adjusted logistic regressions, respondents in 2015 were more likely to show cognitive impairment compared to 2000 (OR 1.84, CI 1.20‐2.82). In age‐stratified analyses, younger respondents were more likely to show cognitive impairment over time (aged 60‐64 years: OR 3.52, CI 1.98‐6.26; aged 65‐69 years: OR 3.31, CI 1.50‐7.33; aged 70‐74 years: OR 3.11, CI 1.37‐7.09).

Conclusion

SABE respondents younger than 75 years showed higher prevalence of cognitive impairment in 2015 compared to respondents of the same age in earlier waves after adjusting for chronic disease burden and educational attainment. In contrast to decreases in prevalence of memory impairment in other countries and despite increases in educational attainment of SABE respondents, the findings suggest that the more recently born cohorts residing in Sao Paolo have entered older age in a cognitively less healthy status.
Deficits in learning are greater than memory dysfunction in preclinical Alzheimer’s disease
Authors: Lim Yen Ying , Baker Jenalle E. , Bruns Loren , Mills Andrea , Fowler Christopher J. , Fripp Jurgen , Rainey‐Smith Stephanie R. , Ames David , Masters Colin L. , Maruff Paul T.
Published: December 2020

Background

Reports from longer studies of preclinical Alzheimer’s disease (i.e., Aβ+ cognitively normal older adults) now show that performance on memory tests remains stable across re‐assessments, whereas in matched Aβ‐ controls, performance improves substantially (i.e. a practice effect). Such observations have led to proposals that the absence of expected practice effects may provide a superior cognitive marker of Aβ+ in older adults. However, an alternative explanation may be that disruption to MTL areas in preclinical AD manifest more strongly as deficits in learning than as a progressive decline in memory recall. Using a test designed specifically to measure learning over days, we aimed to determine the extent to which deficits in learning over 6 days are associated with Aβ+ and hippocampal volume in CN adults.

Method

Eighty CN older adults who had undergone positron emission tomography (PET) neuroimaging to determine Aβ status (n=42 Aβ‐ and 38 Aβ+), magnetic resonance imaging (MRI) to determine hippocampal and ventricular volume and repeated assessment of memory were recruited from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Participants completed the Online Repeatable Cognitive Assessment‐Language Learning Test (ORCA‐LLT), which required they learn associations between 50 Chinese characters and their English language equivalents over 6 days. ORCA‐LLT assessments were supervised on the first day, and were completed remotely online for all remaining days.

Result

Learning curves in the Aβ+ CNs were significantly worse than those in matched Aβ‐ CNs, with the magnitude of this difference very large (d=2.16, p<.001) (Figure 1), and greater than differences between these groups for memory decline since their enrolment in AIBL (d=0.52, p=.021), or memory impairment at their most recent visit. In Aβ+ CN adults, slower rates of learning were associated with smaller hippocampal, and larger ventricular volumes.

Conclusion

These results suggest that in CNs, Aβ+ is associated more strongly with a deficit in learning than any aspect of memory dysfunction. Slower rates of learning in Aβ+ CNs were associated with hippocampal volume loss. Considered together, these data suggest that the primary cognitive consequence of Aβ+ is a failure to benefit from experience when exposed to novel stimuli, even over very short periods.
Genetic risk, education and incidence of dementia
Authors: Ranson Janice M , Lourida Ilianna , Hannon Eilis , Littlejohns Thomas J , Ballard Clive , Langa Kenneth M , Hyppönen Elina , Kuzma Elzbieta , Llewellyn David J
Published: December 2020

Background

There is evidence that educational attainment increases cognitive reserve, and may prevent or delay the development of dementia. However, the extent to which education offsets or interacts with genetic risk is unknown. We therefore investigated the relationship between education and genetic risk for dementia.

Method

In this cohort study, we used data from UK Biobank including adults aged 60 years and older of European ancestry without cognitive impairment or dementia at baseline. Participants joined the study between 2006 and 2010 and were followed until 2016 or 2017. Genetic risk was estimated using a polygenic score for dementia incorporating 249,273 single‐nucleotide polymorphisms with low (lowest quintile), intermediate (quintiles 2 to 4), and high (highest quintile) categories. Education was categorized as low (no/other qualifications), intermediate (secondary/vocational qualifications), or high (college/university degree or other professional qualifications). The outcome was incident all‐cause dementia, ascertained through hospital inpatient and death records.

Result

196,383 individuals (mean [SD] age, 64.1 [2.9] years; 52.7% were women) were followed up for 1,545,433 person‐years (median [interquartile range] follow‐up, 8.0 [7.4‐8.6] years). Overall, 41.5% had low education, 31.0% had intermediate education and 27.5% had high levels of education. 20.0% had high polygenic risk scores, 60.0% had intermediate risk scores, and 20.0% had low risk scores. Of the participants with high genetic risk, 1.2% developed dementia compared with 0.6% of the participants with low genetic risk (adjusted hazard ratio, 1.92 [95% CI, 1.64‐2.24]). Of the participants with low education, 1.3% developed dementia compared with 0.7% of participants with high levels of education (adjusted hazard ratio, 1.51 [95% CI, 1.35‐1.70]). Of the participants with a high genetic risk and low education, 1.5% developed dementia compared with 0.4% of participants with low genetic risk and high education (adjusted hazard ratio, 2.79 [95% CI, 2.12‐3.68]). There was no significant interaction between genetic risk and education (p = 0.108).

Conclusion

Among older adults without cognitive impairment or dementia, high education was independently associated with lower dementia risk when accounting for genetic risk. Education may increase cognitive reserve even in those with a high genetic risk of dementia.
Preferential degeneration of the locus coeruleus in tauopathies relative to TDP‐43 proteinopathies
Authors: Ohm Daniel T. , Peterson Claire , Lobrovich Rebecca , Bahena Alejandra , Gibbons Garrett S. , Wolk David A. , Grossman Murray , Lee Eddie B. , Trojanowski John Q. , Irwin David J.
Published: December 2020

Background

The locus coeruleus (LC) is the brain’s primary source of norepinephrine and is vulnerable to neurodegeneration in Parkinson’s disease and tauopathies including Alzheimer’s disease (AD). However, detailed comparative studies of LC neurodegeneration between clinically similar tauopathies (FTLD‐tau) and TDP‐43 proteinopathies (FTLD‐TDP) are lacking. Using a large autopsy cohort, we tested the hypothesis that the LC has greater neuropathologic change in FTLD‐tau compared to FTLD‐TDP.

Method

The LC was examined in 333 patients representing autopsy‐confirmed FTLD‐tau (n=126), FTLD‐TDP (n=152), and two reference cohorts: clinical/pathological AD (n=36) and age‐matched healthy controls (HC, n=19). Pons tissue containing the LC was cut into 6µm‐thick sections and stained for hematoxylin and near‐adjacent sections immunostained for phosphorylated TDP‐43 (p409/410), hyperphosphorylated tau (PHF‐1), and AD‐neurofibrillary tau (GT‐38) to detect comorbid AD tau pathology in a FTLD‐tau subgroup (n=69). Blinded to diagnoses, an ordinal rating scale (0‐3) was used to semi‐quantitatively score tau inclusions, TDP‐43 inclusions, and neurodegeneration based on an averaged composite score of neuromelanin depigmentation and extracellular neuromelanin in hematoxylin sections.

Result

Tau burden in FTLD‐tau (median=2.5, IQR[2,3]) was greater than TDP‐43 burden in FTLD‐TDP (median=0.5, IQR[0,1]; p<0.0001). Similarly, neurodegeneration was greater in FTLD‐tau (median=1.5, IQR[1,2]) compared to FTLD‐TDP (median=1, IQR[1,1]; p<0.0001). Subanalyses of clinical subgroups with either dementia (n=117) or motor syndromes (n=124) found similar results: tau burden in FTLD‐tau was greater than TDP‐43 burden in FTLD‐TDP (dementia syndromes, p<0.0001; motor syndromes, p<0.0001); neurodegeneration was greater in FTLD‐tau compared to FTLD‐TDP (dementia syndromes, p=0.004; motor syndromes, p<0.0001). AD neurodegeneration (median=1.75, IQR[1,2]) was greater than neurodegeneration in FTLD‐tau (p=0.0004), FTLD‐TDP (p<0.0001), and HC (p<0.0001). HC neurodegeneration (median=1, IQR[0.5,1]) was significantly less than neurodegeneration in FTLD‐tau (p=0.002), but similar to the minimal neurodegeneration in FTLD‐TDP (p=0.38). Greater tau burden correlated with greater neurodegeneration (rho=0.35, p<0.0001). Only 39% of the FTLD‐tau subgroup had a mild burden of AD tau co‐pathology suggesting LC neurodegeneration was driven by FTLD‐tauopathies.

Conclusion

FTLD‐tau showed histological evidence of greater LC neurodegeneration compared to FTLD‐TDP, independent of clinical phenotypes or AD co‐pathology. These findings suggest FTLD‐tau‐mediated noradrenergic neurodegeneration may be a commonality of tauopathies that could help improve antemortem diagnoses and symptomatic treatments.
Development of a massively parallel reporter assay to identify functional regulatory variants in the PICALM Alzheimer disease associated locus
Authors: Nuytemans Karen , Van Booven Derek , Dykxhoorn Derek M. , Vance Jeffery M. , Pericak‐Vance Margaret A. , Griswold Anthony J.
Published: December 2020

Background

Most significant genome‐wide association markers for Alzheimer disease (AD) are in noncoding portions of the genome making assigning a corresponding gene involved in risk challenging. Coding variants identified in some these GWAS loci thus far do not explain the proportion of risk attributable to the associated markers, indicating a contribution of noncoding variants to AD. We set out to develop a high throughput method investigating the functional role of noncoding variants associated with AD using the PICALM locus on chromosome 14:85,600,000‐85,860,000, which has been associated with AD across multiple ancestries, as a proof of concept region.

Method

We used the gnomAD database of over 15,000 whole genomes to identify all variants located in the PICALM locus across a wide variety of ancestral populations (non‐Hispanic whites, Hispanics, African Americans, and Asians). We developed a pipeline for epigenomic annotation from available databases and the subsequent design of oligos carrying wild‐type and variant alleles for each variant. For unbiased analyses of functional potential to regulate enhancer activity of each of the alleles we established a large vector library for massively parallel reporter assays (MPRA) in AD relevant cell lines.

Result

We identified >23,000 variants for analysis in the 260 kb PICALM locus. More than 4,000 of those had prior evidence for location in transcription factor binding sites, putative promotors/enhancers and eQTLs. 180 bp oligos centered around the variant alleles were synthesized by TWIST Biosciences. 20 bp random barcodes were added to each of the oligos through PCR amplification with a barcoded primer library. Sequencing of the resulting vector library indicated highly efficient incorporation with 95% unique barcodes present in the library. Reporter gene GFP and a minimal promoter were subsequently cloned in between the oligo and the barcode to establish the final MPRA library for transformation in cell lines.

Conclusion

Here we established a computational framework for in‐silico epigenomic annotation and oligo design for subsequent high‐throughput analyses and developed an efficient protocol to create a final MPRA library with highly unique barcodes at fragment incorporation. Cell line transformations and transcriptome analyses of the PICALM library to identify regulatory variants are ongoing.