bluuebunny/crossref_metadata_2025 huggingface dataset:
Post‐covid cognitive performance in subjects at risk of developing dementia in Uruguay
Authors: Mariani Francesca , Damian Andres , Bocos Laura , Cortabarría Lucia , Leites Alice , Santero Sofia , Contreras Valeria , Ferrando Rodolfo , García‐Fontes Margarita , Reyes Laura , Arredondo Florencia , Abin‐Carriquiry Juan Andrés , Menendez Mercedes , Amestoy Alejandra , Torheim Maren , Superchi Roberto , Suarez Ramon , Preciozzi Fabian , Fernandez Lucia , Uriarte Laura , Dansilio Leandro , Dansilio Sergio , Charamelo Ana , Allegri Ricardo Francisco , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sevlever Gustavo , Sosa Ana Luisa , Calandri Ismael Luis , Crivelli Lucía , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Velilla Lina M , Yassuda Monica Sanches
Published: December 2023

Background

the study of the medium and long‐term consequences of coronavirus infection (SARS‐CoV‐2) is of great relevance from the clinical and public health perspective. Recent evidence has shown that patients may present cognitive complaints after overcoming the acute stage of infection, particularly memory disturbances. Although significant progress has been made in the knowledge of this sequel, the studies are generally limited by small sample sizes, cognitive screening techniques with ceiling effects, and samples with healthy subjects without comorbidities, among others. The objective of this study is to compare the cognitive performance of subjects at risk of developing dementia with and without a history of SARS‐CoV‐2 in Uruguay.

Method

participants from the LatAm FINGERS Uruguay Project were included. Performance in the different cognitive tests (symbol‐digit, trail making A, trail making B, free and cued selective remingind test) included in the project protocol was compared between the participants with and without a history of covid infection.

Results

27 subjects with a history of covid infection prior to baseline cognitive assessment and 62 subjects without a history of covid infection were analyzed. None of the participants had serious complications or requiring hospitalization due to SARS‐CoV‐2 infection. The performance of both groups in attentional, executive and memory tests was compared. There were no significant differences between groups.

Conclusions

the impact of covid on cognition is still a controversial topic. In our sample of subjects at risk of dementia, there was no evidence of impaired cognitive performance due to SARS‐CoV‐2 infection. More studies in underrepresented populations with larger samples are needed to address this issue.
The impact of sex on the progression of AD atrophy‐based subtypes
Authors: Inguanzo Anna , Poulakis Konstantinos , Oltra Javier , Ferreira Daniel , Mohanty Rosaleena , Westman Eric
Published: December 2023

Background

Recently, longitudinal subtypes in AD have been identified based on their different brain atrophy trajectories (Poulakis et al. 2022 Nat Commun), which follow either mediotemporal or cortical pathways. The mediotemporal pathway, which is the most prevalent, includes three longitudinal subtypes: the limbic predominant plus (LPA+), the limbic predominant (LPA), and the minimal atrophy (MA) subtypes. While the LPA+ is characterised by the fastest rate of atrophy starting in the entorhinal cortex and later spreading to the temporal lobe and the rest of the cortex, the LPA is restrained to atrophy in temporal regions. The MA subtype, on the other side, is characterised by minimal atrophy in mediotemporal areas. Although the discovery of brain atrophy trajectories in AD represents a significant contribution towards precision medicine, the impact of sex – a major risk factor for AD – on these trajectories has yet to be explored.

Method

We used longitudinal magnetic resonance imaging data as well as clinical data (up to 5 timepoints) from 3 international AD cohorts (ADNI, J‐ADNI and AIBL). AD individuals had previously been identified, as one of the following longitudinal subtypes: LPA+ (N = 23, 61% females), LPA (N = 93, 48% females), and MA subtype (N = 189, 48% females). We applied linear mixed effect models (LMMs) on 34 cortical and 7 subcortical regions to assess differences in sex within each AD longitudinal subtype. Results were adjusted for ageing effects, cohort, disease duration and intracranial volume.

Result

LPA+ females showed greater atrophy over time compared to LPA+ males in frontal regions as well as in the lingual and the parahippocampal gyri. LPA females tended to show greater atrophy in the medial orbitofrontal cortex compared to LPA males. Finally, within the MA subtype, females showed greater atrophy than males in the hippocampus over time.

Conclusion

This study demonstrates that sex‐specific regional vulnerabilities are crucial to consider in the study of AD heterogeneity, particularly within the mediotemporal pathway. Our results reveal that females exhibit distinct atrophy patterns over time compared to males in different AD subtypes, emphasizing the importance of investigating sex‐related differences to develop more targeted and effective interventions for AD.
Enhanced memory for negative words is associated with amnestic mild cognitive impairment and in vivo cerebral amyloid‐β burden independently of depression
Authors: Mah Linda , Verhoeff Nicolaas Paul L.G. , Butters Meryl A. , Fischer Corinne E. , Flint Alastair , Graff‐Guerrero Ariel , Herrmann Nathan , Lanctôt Krista L. , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. ,   PACt‐MD Study Group
Published: December 2023

Background

Emotion dysregulation was studied as a potential risk marker for Alzheimer’s disease (AD) by assessing emotional memory in high AD‐risk groups characterized by the presence of mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) and by evaluating the relationship between emotional memory and in vivo cerebral amyloid‐β deposition.

Method

435 participants enrolled in the PACt‐MD clinical trial of cognitive remediation plus transcranial direct current stimulation were evaluated at baseline. The sample included 127 older adults with amnestic mild cognitive impairment (aMCI), 51 non‐amnestic MCI (naMCI), 60 rMDD without MCI, 81 rMDD+aMCI, 42 rMDD+naMCI, and 74 cognitively unimpaired older adults (CU). Diagnoses were established during a consensus conference based on psychiatric, medical, and neuropsychological assessment. Emotional memory was assessed by evaluating immediate and short‐term delayed recall of 15 personality adjectives (5 each of positive, negative and neutral words) from the Emotional Verbal Learning Test (Mah et al., 2017, American Journal of Geriatric Psychiatry, 25:1160). A subset (N = 167) completed a Positron Emission Tomography (PET) scan with carbon‐11 Pittsburgh Compound B ([11C] PIB). Valence and diagnostic group effects on recall were assessed using mixed ANOVA. Regression modelling assessed the association between emotional memory bias and amyloid‐β burden.

Result

Relative to CU, both aMCI and rMDD+aMCI groups showed enhanced memory for negative words at immediate recall, which persisted after short delay in the aMCI group only (F(1, 339) = 2.66, p = .048; Figure 1). Enhanced memory for negative words at short delay was predictive of in vivo cerebral amyloid‐β deposition (standardized beta = .117, t = 1.84, p = .067), over and above the contributions of age, sex, Apolipoprotein E genotype, depression diagnosis and symptoms, and long delayed verbal recall (F(4,154) = 25.8, p<.001, R2 = .41; Figure 2).

Conclusion

The association between enhanced memory for negative personality adjectives and aMCI replicates earlier work in single‐domain aMCI (Mah et al., 2017) and suggests that aMCI is characterized by a negativity bias in memory. These findings, taken together with the relationship between a negativity bias in memory and amyloid‐β burden, suggest that emotion dysregulation, in the form of enhanced memory for negative information, is a potential marker of AD risk.
Sex differences in plasma biomarkers for identifying Aβ pathology in CN and MCI individuals: Implications for Clinical Trials
Authors: Milà‐Alomà Marta , Aloma Zachary Hausle Mila , Zobel‐Thropp Pamela , Tosun Duygu
Published: December 2023

Background

Our objective was to investigate whether sex influences plasma biomarker levels and performance in identifying Aβ‐PET‐positivity in CU and MCI ADNI participants.

Method

The study included 417 participants (Table1) with known Aβ‐PET status and plasma Aβ42/Aβ40 (IP‐LC‐MS/MS), and pTau181, tTau and NfL (Simoa HD‐X). We used ANCOVA to examine the effect of age, sex and APOEε4 on plasma biomarkers, and the interactions between sex, APOEε4 and age. ROC analyses were performed to determine the added value of each plasma biomarker, alone or in combination, to a base model of risk factors age and APOEε4 in the entire sample. The models were then applied to subsets of women and men separately, and the AUCs were compared with DeLong test. The same models were run separately for CU and MCI individuals, and Random Forest (RF) analyses were performed to assess each variable’s importance.

Result

In CUs, women had higher Aβ deposition but lower plasma pTau181 than men. In contrast, MCI men had lower plasma Aβ42/40 than MCI women. In CU men, there was a steeper increase of pTau with age (Figure1), whereas APOEε4 had a stronger effect on pTau in MCI women. ROC analyses indicated that in CUs, addition of Aβ42/40 to risk factors performed better than using risk factors alone for both sexes. In MCIs, the addition of any plasma biomarker improved the base model in men, but not in women (Figure2). In RF analyses, plasma Aβ42/40 had the strongest importance for model accuracy in CU men and women. In women with MCI, Aβ42/40 and tau have similar importance and were only slightly superior to risk factors, while in men, Aβ42/40 had the strongest importance.

Conclusion

Sex differences were observed in plasma Aβ42/40 and pTau, and in the impact of risk factors, which varied by clinical stage. In MCIs, the classification performance varied by sex, with a greater added value of plasma biomarkers, particularly Aβ42/40, in men. These findings emphasize the need to consider sex differences when using plasma biomarkers for clinical trials, especially in MCIs. Further studies are necessary to elucidate the underlying mechanisms and implications of these observations.
The case for low‐dose BACE inhibition
Authors: Watkins Elyse , Vassar Robert J.
Published: December 2023

Background

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Positive trials of anti‐amyloid‐β immunotherapy have confirmed that amyloid contributes to cognitive deficits in patients. However, these therapies are costly and require monthly or bi‐weekly infusions. Furthermore, in their current state, anti‐amyloid immunotherapy is approved for treatment of AD once symptoms have already appeared, which may be late in the cascade of neuronal damage. There is substantial need for an inexpensive and minimally invasive preventative therapy that could be taken during the pre‐symptomatic stage of AD, or in combination with amyloid immunotherapy to be taken after amyloid clearance to prevent the reemergence of plaques. Small‐molecule inhibitors of β‐site amyloid precursor protein (APP)‐cleaving enzyme 1 (BACE1) reduce the production of amyloid‐β peptide, are taken orally, and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment primarily in memory domains, and trials that have conducted follow‐up testing after study completion suggest that the cognitive impairment is reversible. In this talk, I discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors.

Method

N/A

Result

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Conclusion

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Preliminary validation of the Stress and Adversity Inventory for Adults (Adult STRAIN) in Dutch and its associations with in‐vivo locus coeruleus integrity
Authors: Engels Nina , Riphagen Joost M. , Van Egroo Maxime , Spahr Chandler M. , Slavich George M , Jacobs Heidi I.L.
Published: December 2023

Background

The Stress and Adversity Inventory (STRAIN) systematically assesses lifetime stressor exposure, but its validity has yet to be established in The Netherlands. This work aims to validate the Dutch translation of STRAIN and its association with key biological correlates: cortisol measures and the locus coeruleus (LC), a brainstem nucleus involved in stress responses and accumulating phosphorylated tau early in adulthood.

Methods

Eighty‐seven cognitively unimpaired Dutch participants (31‐81 years; ∼45% female; Table 1) completed stress‐ and affective‐related questionnaires, cognitive testing, salivary and plasma cortisol measurements, and 7T‐MRI. The STRAIN was administered after translation into Dutch. LC MRI signal intensity was extracted from an MT‐TFL sequence by normalizing LC signal against the pontine tegmentum (reference region) and creating a sample‐specific LC template. Pearson correlation models assessed associations between STRAIN summary scores (total stressor count and severity), and stress‐related (MIA‐Anxiety, PSS, DASS‐Stress, NEO PI‐R‐Neuroticism), affective (DASS‐Anxiety‐Depression, HDRS), cognitive (WLTDR, LDST, STR3), stress‐related biological (salivary‐, plasma cortisol), and LC measures (Table 1). HDRS models employed Spearman correlations. Age and sex were included as covariates, additionally including education for cognitive measures. Analyses were FDR‐corrected and conducted based on complete cases.

Results

Overall, the sample had relatively low lifetime stressor counts (M = 14.08; Figure 1A). When assessing concurrent validity, the STRAIN was positively associated with other stress measures (r = .21,.36; pFDR
<.05; Figure 1B,C). Models including cortisol revealed that less stressor exposure and severity were associated with higher cortisol levels (r = ‐.22,‐.23; pFDR
<.05). Affective and cognitive measures were investigated for discriminant validity. STRAIN was not associated with DASS, but was positively associated with HDRS (r = .17,.28; pFDR
<.05). Generally, greater stressor exposure was related to poorer cognitive performance (r = .13,‐.19; pFDR
<.05), except for a positive association between WLTDR and stressor severity (r = .18; pFDR
<.05). No significant associations were found with LC MRI signal intensity (Figure 1B).

Conclusion

This study demonstrates preliminary good concurrent and discriminative validity for the Dutch STRAIN translation, even among individuals with low‐to‐moderate self‐reported stress levels. We found no direct associations between LC integrity and lifetime stressors. Future research will investigate associations with other STRAIN domains and potential moderating effects of Alzheimer’s Disease‐related biomarkers on the relationship between cumulative stressor exposure and LC integrity.
A novel automated multiplex immunoassay for the ultrasensitive detection of blood‐based biomarkers for neurodegenerative diseases
Authors: Ma Xiao‐Jun , Ariyapala Ishara , Alganem Khaled , Hao Qinyu , Feng Wei , Zhang Bingqing , Blennow Kaj , Luo Yuling , Zetterberg Henrik
Published: December 2023

Background

Efforts to identify accurate blood biomarkers for neurodegenerative disease hallmarks have been hampered by the lack of a proteomic tool that has the required sensitivity to detect very low concentrations of brain‐derived proteins in plasma or serum and the ability to multiplex many analytes in a single assay. Here we evaluated NULISA™, a recently developed novel immunoassay with attomolar level sensitivity and high multiplex capability1, for its ability to detect serum biomarkers associated with Alzheimer’s disease.

Method

Serum samples from 31 Alzheimer’s disease (AD) patients and 31 non‐AD controls were analyzed using NULISA with a 200plex inflammation panel targeting a broad spectrum of inflammation‐related cytokines, chemokines and other proteins. Five samples failed quality control and were excluded from further analysis, resulting in 28 AD and 29 control samples in the final dataset. Linear model analysis, including age and sex as covariates, was performed for each target for differential expression between AD patients and controls.

Result

Two significant proteins were identified. The level of glial fibrillary acidic protein (GFAP) was 1.84‐fold higher in AD patients (adjusted p‐value = 0.00014), whereas the level of S100 calcium‐binding protein A12 (S100A12) was 2‐fold higher in non‐AD controls (adjusted p‐value = 0.031). GFAP serum levels correlated strongly with total tau (Spearman rho = 0.69, p = 1.7e‐09), p‐tau181 (rho = 0.69, p = 1.7e‐09) and amyloid beta 42 (rho = ‐0.71, p = 4.7e‐10) levels in cerebrospinal fluid (CSF). S100A12 levels also correlated significantly with total tau (rho = ‐0.39, p = 0.0031), p‐tau181 (rho = ‐0.36, p = 0.0053) and amyloid beta 42 (rho = 0.38, p = 0.0067) CSF levels. Receiver operating characteristic analysis demonstrated that GFAP strongly discriminated AD from controls with an area under the curve (AUC) of 0.93 (95% CI 0.87‐1.0), and S100A12 also exhibited good discrimination with an AUC of 0.72 (95% CI 0.59‐0.86).

Conclusion

This exploratory study identified serum GFAP levels as a strong discriminatory biomarker for AD, consistent with previous studies. S100A12 also demonstrated significant associations with AD and CSF biomarkers and thus warrants further study. NULISA holds great promise for the discovery and validation of blood‐based biomarkers for the early detection and monitoring of neurodegenerative diseases.

1. Feng, W. et al. bioRxiv 2023.04.09.536130 (2023) https://doi.org/10.1101/2023.04.09.536130.
In vivo [18F]SMBT‐1 imaging of reactive astrocytes in mouse models of Alzheimer’s disease ‐ temporospatial relationship with amyloid, tau and microgliosis
Authors: Kong Yanyan , Maschio Cinzia , Yao Bolin , Shi Kuangyu , Rominger Axel , Xiao Jianfei , Huang Qi , Guan Yihui , Ni Ruiqing
Published: December 2023

Background

Reactive astrocytes play an important role in the pathogenesis of Alzheimer’s disease (AD). Here, we aim to investigate the temporospatial relationship between reactive astrocytes, microgliosis, tau and amyloid‐β by using in vivo multitracer imaging in AD transgenic mouse models.

Method

Positron emission tomography (PET) imaging with [18F]SMBT‐1 (monoamine oxidase‐B for reactive astrocytes), [18F]DPA‐14 (translocator protein for microgliosis), [18F]PBB3 (tau), and [18F]florbetapir (Aβ) was carried out in 5‐ and 12‐month‐old APP/PS1, 12‐month‐old 3×Tg mice, and aged‐matched wild‐type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as reference region. Immunofluorescence staining was performed with antibodies against monoamine oxidase‐B, astrocytes, translocator protein, microglia, tau, and amyloid in mouse brain slices.

Result

[18F]SMBT‐1 SUVRs were higher in the cortex and hippocampus of 12‐month‐old APP/PS1 mice than age‐matched wild‐type mice. [18F]DPA‐14 SUVRs were higher in the brain stem and amygdala of 5 and 12‐month‐old APP/PS1 mice than in age‐matched wild‐type mice. [18F]PBB3 were higher in the cortex, striatum and hippocampus of APP/PS1 mice than in 5‐month‐old APP/PS1 mice and wild‐type mice. [18F]florbetapir SUVRs were higher in the brain stem, thalamus and midbrain of APP/PS1 mice at 5 months than in age‐matched wild‐type mice. No significant difference in the regional [18F]SMBT‐1, [18F]DPA‐14, [18F]PBB3, [18F]florbetapir or [11C]PIB SUVR was observed in 12‐month‐old 3×Tg mice compared to age‐matched wild‐type mice, which is validated by the limited 6E10‐positive amyloid plaques and AT8‐positive tau deposits.

Conclusion

The findings provide in vivo evidence for different regional distribution of reactive astrocytes and microgliosis in animal models of AD.
Value of blood‐based biomarkers for differential diagnosis of Alzheimer’s disease: the ActiGliA cohort
Authors: Kurz Carolin Isabella , Carli Laura , Guersel Selim Üstün , Schrurs Isabelle , Jethwa Alexander , Carboni Margherita , Bittner Tobias , Rauchmann Boris‐Stephan , Brendel Matthias , Burow Lena , Haeckert Jan , Tato Maia , Utecht Julia , Papazov Boris , Pogarell Oliver Michael , Palleis Carla , Weidinger Endy , Stöcklein Sophia , Haass Christian , Levin Johannes , Höglinger Günter , Perneczky Robert
Published: December 2023

Background

Cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of Alzheimer’s disease (AD), ß‐amyloid (Aß) and tau, can identify early disease stages with high accuracy. However, this approach is not suitable for routine clinical care because of the high costs and invasiveness. Implementation of blood‐based biomarkers (BBBM) in the diagnostic process may facilitate the identification of persons with AD in the earliest stage possible and may reliably differentiate AD from healthy aging and other non‐AD dementias like corticobasal syndrome (CBS).

Method

From the prospective ActiGliA study we included 27 participants with probable AD (including participants with mild cognitive impairment [n = 16] and AD‐related dementia [n = 11]), 17 age‐matched controls with subjective cognitive impairment, 9 participants with corticobasal syndrome and underlying Aß‐pathology (Aß[+]CBS), and 26 participants with Aß[‐]negative CBS. The diagnostic value of different BBBMs in differentiating amyloid‐positive from ‐negative cases was examined. All participants underwent a thorough diagnostic work‐up, including CSF and blood sampling, neuropsychological tests, amyloid‐PET, and magnetic resonance imaging. Blood biomarkers (Aß1‐40, Aβ1‐42, apolipoprotein E4 [ApoE4], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], and phosphorylated‐tau181 [pTau181]) were measured using Elecsys® plasma prototype immunoassays.

Result

In amyloid‐positive cases, plasma concentrations of Aβ1‐42/1‐40 ratio were decreased while ApoE, GFAP, and pTau181 levels were elevated. In the entire cohort, blood and CSF levels of both Aß1‐42/Aß1‐40 ratio and pTau181 were significantly positively correlated. ApoE4, GFAP, and particularly pTau181 levels showed a strong negative association with neuropsychological performance. A positive association between NfL levels and hippocampal atrophy was demonstrated. pTau181 levels revealed an are under the curve (AUC) of 0.885 in the discrimination between amyloid‐positive and ‐negative cases, plasma ApoE4 levels and Aß1‐42/Aß1‐40 ratio showed an AUC of 0.774 resp. 0.815. Regarding differentiation of AD from healthy aging and other dementias, elevated NfL levels were associated with a diagnosis of CBS and Aß[+]CBS, while elevated pTau181 and ApoE4 levels indicated a diagnosis of AD.

Conclusion

BBBMs may be useful in differentiating amyloid PET‐positive from amyloid PET‐negative cases and in differentiating AD from healthy aging and non‐Alzheimer dementias. These results must be validated in a larger cohort.
Blood‐derived extracellular vesicles phosphoproteome as a resource of biomarker candidates for Alzheimer’s disease
Authors: Martins Tânia Soares , Rosa Ilka Martins , da Cruz e Silva Odete , Henriques Ana Gabriela
Published: December 2023

Background

Protein phosphorylation plays a crucial role in cell communication, signaling and by extension is relevant to Alzheimer´s disease (AD) pathogenesis. Extracellular vesicles (EVs) are recognized as important mediators in intercellular communication and can be isolated from peripheral biofluids, where the content reflects the cellular origin. EVs’ role in AD pathophysiology and their value as biomarker resources is being unraveled. However, little is known regarding EVs’ phosphoproteome in AD and it has still to be determined if blood‐derived EVs are suitable for phosphoproteome profiling. Hence, this work aimed to characterize plasma‐derived EVs (pdEVs) and plasma supernatant EVs free (plasma‐depleted EVs) phosphoproteomes, to potential unravel disease mechanisms and/or new biomarker candidates for AD.

Method

A pool of human plasma was used for pdEVs isolation using a precipitation‐based methodology. Both pdEVs and plasma‐depleted EVs samples were analyzed using an antibody‐based phosphospecific microarray. Characterization of the phosphoproteomes obtained was achieved by Gene Ontology enrichment analysis and the most relevant Reactome pathways associated, using ClueGo and CluePedia plugins from Cytoscape v3.9.1. In addition, protein‐protein interaction network of the pdEVs phosphoproteome was retrieved from STRING database and analyzed using Cytoscape “Network Analyzer”, employing the betweenness centrality option to highlight central nodes. Further, the pdEVs phosphoproteome (corresponding gene names) was overlapped with a list of genes associated with AD, collated from DisGenet database.

Results

More than 70 proteins were enriched ≥40% in bdEVs when compared to plasma‐depleted. Top biological processes were mainly related to cell proliferation/division, apoptosis and phosphorylation. Reactome pathways analysis revealed terms associated to toll like receptor cascade and MAPK signaling. In the network constructed for the pdEVs enriched proteins, PTEN appeared as a central node. Additionally, overlap with AD gene list from DisGenet revealed that 60% of the pdEVs phosphoproteome is AD‐related. Among these, several kinases already described in senile plaques and/or neurofibrillary tangles were identified.

Conclusion

In sum, bdEVs phosphoproteome is enriched in AD‐related targets, exhibiting potential as a biomarker candidate resource for AD diagnosis.

This work was funded by the Alzheimer’s Association under Grant 2019‐AARG‐644347, supported by iBiMED‐UIDB/04501/2020,iBiMED‐UIDB/04501/2020,ADPro‐SAICT‐45‐2021‐02 and TSM individual PhD grant SFRH/BD/145979/2019. Health Ethics Committee ARS Centro(No.012804‐04.04.2012) and CNPD(No.369/2012).
Topline results of INTERCEPT‐AD: A phase I trial of Aβ oligomer‐targeting ACU193 in early Alzheimer’s disease
Authors: Siemers Eric R , Feaster Todd , Skljarevski Vladimir , Sundell Karen L , Sethuraman Gopalan , Johnson Kimball ,   INTERCEPT‐AD Study Group
Published: December 2023

Background

ACU193 is a humanized IgG2 subclass monoclonal antibody targeting soluble amyloid‐beta oligomers (sAβOs). Growing evidence supports the view that sAβOs may be the most toxic and pathogenic form of Aβ relative to Aβ monomers and amyloid plaques and are one of the primary drivers of Alzheimer’s disease (AD) neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 is a promising approach for treating AD.

Method

INTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐ ascending dose (SAD/MAD) study of the safety, tolerability, and pharmacokinetics (PK) of intravenous ACU193 in participants with early AD, i.e., mild cognitive impairment or mild dementia due to AD. Key inclusion criteria are 55‐90 years of age, confirmation of amyloid pathology with a PET scan, MMSE score of 18‐30, and CDR‐Global score (CDR‐GS) of 0.5 or 1.0. The MAD portion of the study includes three administrations of ACU193 at doses of 10, 25, or 60 mg/kg. In addition to standard safety measures, MRI is assessed periodically. Cerebrospinal fluid is collected to assess PK and evidence of target engagement. The study also includes exploratory measures such as standard cognitive and functional assessments, a computerized cognitive test battery, measures of cerebral blood flow via arterial spin labeling on MRI, and various plasma biomarkers.

Result

Sixty‐five participants from 17 U.S. study sites were randomized to INTERCEPT‐AD, with 53% female and baseline age of 72.1 ± 7.8 years (mean ± SD). The baseline MMSE was 24.2 ± 3.6, CDR‐GS was 0.64 ± 0.27, and CDR‐Sum of Boxes was 3.5 ± 1.8. In addition to baseline characteristics, the presentation will provide topline safety results, frequency of amyloid‐related imaging abnormalities (ARIA), PK assessments, and evidence of target engagement. Some exploratory measures including cognitive and functional assessments, computerized cognitive testing, and endpoint florbetapir PET results will also be presented.

Conclusion

We will present topline results, along with key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. The data generated from this trial will guide further development of ACU193 in a subsequent trial to test the novel mechanism of action of ACU193 in the treatment of early AD.
Longitudinal robustness of resting‐state functional connectivity signatures across different stages of the Alzheimer’s disease continuum
Authors: Behjat Hamid , Strandberg Olof , Binette Alexa Pichet , Spotorno Nicola , Vogel Jacob W , Ossenkoppele Rik , Hansson Oskar
Published: December 2023

Background

A growing number of resting‐state fMRI (rs‐fMRI) studies report changes in network activity to be a frequent and often early pathological feature in many neurodegenerative conditions. The majority of studies have primarily focused on changes in group averages, failing to account for individual functional connectivity (FC) idiosyncrasies that have been shown to provide a unique identifier or “fingerprint” in healthy individuals (Finn et al., 2015). It thus remains unclear to what extent FC‐signatures are stable in the context of cognitive decline and Alzheimer’s Disease (AD) pathology (e.g., β‐amyloid [Aβ] and tau). We studied the robustness of subject‐specific FC in a longitudinal cohort covering the AD spectrum.

Method

275 participants with longitudinal rs‐fMRI data—baseline plus a follow up after approximately two‐years—were selected from the Swedish BioFINDER‐2 cohort, split into six groups: cognitively normal (CN) Aβ‐, subjective cognitive decline (SCD) Aβ‐, SCD Aβ+, mild cognitive decline (MCI) Aβ‐, MCI Aβ+, and AD Aβ+. FC matrices were derived from each subject rs‐fMRI session using the Schaefer cortical parcellation (200 and 400 ROIs), and consequently, a 275×275 identifiability matrix (IM) was derived; see Fig. 1B. For each subject, two fingerprinting measures were extracted from the IM: self identifiability (I‐self) and differential identifiability (I‐diff); see Fig.1B.

Result

I‐self and I‐diff show varied distributions across the six groups, but values remain notably high even within the AD Aβ+ (Fig.2A). Both I‐self and I‐diff show significant differences between CN Aβ‐ and AD Aβ+ (Fig.2B). SCD Aβ‐ not only show a greater difference to AD Aβ+, but also to SCD Aβ+ and MCI Aβ+; see Fig.2B. Baseline tau‐PET was associated with I‐self (r = ‐0.1928,p = 0.0014) and to a lesser degree with I‐diff (r = ‐0.1293, p = 0.0334), whereas baseline MMSE was only found associated to I‐self (r = 0.1671,p = 0.0055); neither I‐self nor I‐diff were associated with age (Fig.3).

Conclusion

Our results suggest that resting‐state FC is mostly stable under cognitive decline and presence of AD pathology. FC was most notably differentiable for SCD Aβ‐, suggesting it as a potential signature to decipher underlying cognitive status and to predict likelihood of future conversion to AD.
Comparing feature selection methods to improve the classification of Mild Cognitive Impairment patients based on Magnetoencephalography data
Authors: Martínez‐Évora Adelia‐Solás , Carrasco‐Gómez Martín , Shpakivska‐Bilán Danylyna , Nebreda Alberto , García‐Colomo Alejandra , Maestú Fernando
Published: December 2023

Background

Machine learning (ML) algorithms are generating great interest for early diagnose of Alzheimer’s disease (AD). Despite several approaches have been developed, limited research has been conducted on the impact of feature selection in classification performance. In this study we compare two feature selection methods, LASSO and Elastic Nets (EN), applied to ML algorithms based on magnetoencephalography (MEG) data from mild cognitive impairment (MCI) patients.

Method

An eyes‐closed resting‐state MEG recording was performed by 262 participants (117 healthy controls and 145 MCI). Functional connectivity measures were estimated for all classical frequency bands using the Phase‐Locking Value. To develop the ML algorithms, specific regions of interest from the default mode network, based on the Automatic Anatomical Labelling atlas, were selected, resulting in a total of 325 features. After dividing the dataset into training (80%) and test (20%) sets, feature selection with 10000 iterations and five‐fold cross validation was performed independently for each band using LASSO and EN algorithms. Afterwards, several classification models were trained with a five‐fold cross validation and then validated on the test set, over 500 iterations.

Result

The classifier showing the best performance was the linear Support Vector Machine for the beta frequency band (12‐30 Hz). Given the similarity of the training and test performance values, the results reveal that overfitting was avoided when using the 45 features selected by LASSO instead of the 47 features selected by EN, reaching a validation accuracy of 77%. Additionally, LASSO consistently identified three functional connectivity links as relevant in all frequency bands but alpha: right superior frontal gyrus & right superior frontal gyrus orbital, left posterior cingulate cortex & left hippocampus, right posterior cingulate cortex & right precuneus.

Conclusion

ML algorithms applied to MEG data can successfully discriminate MCI patients from healthy controls. In addition, LASSO algorithm applied for feature selection leads to better classification performance. Moreover, the resulting relevant functional connectivity links involve areas affected by AD pathology even in early stages of its development (López‐Sanz et al., 2019). Further exploration of this methodology is needed, combining this data with structural neuroimaging or complementary biomarkers.
A novel fluid biomarker for TDP‐43 loss of function
Authors: Irwin Katherine E , Jasin Pei , Braunstein Kerstin E , Sinha Irika , Bowden Kyra D , Moghekar Abhay , Oh Esther S , Raitcheva Denitza , Bartlett Dan , Berry James D , Traynor Bryan J , Ling Jonathan P , Wong Philip C
Published: December 2023

Background

TDP‐43 nuclear clearance and cytoplasmic aggregation occur in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD), Alzheimer’s disease (AD), and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). Nuclear clearance of TDP‐43 leads to its failure to repress splicing of nonconserved cryptic exons. This loss of TDP‐43 splicing repression is well‐documented in postmortem tissues, but there is currently no method of detecting TDP‐43 dysfunction in living patients. As some cryptic exons are spliced in‐frame and translated into proteins carrying novel epitopes, we hypothesize that these “cryptic peptides” may be found in patient CSF as biomarkers of TDP‐43 dysfunction.

Method

We generated novel monoclonal antibodies against several TDP‐43 cryptic exon targets and then developed a sandwich ELISA using the Meso Scale Discovery (MSD) platform, which we validated in cells deficient in TDP‐43 for the cryptic exon target in HDGFL2. We then screened CSF samples of C9ORF72‐mutation carriers with or at risk of ALS‐FTD and control individuals for the presence of this cryptic peptide.

Result

The MSD signal for cryptic HDGFL2 was elevated in CSF of C9ORF72‐mutation carriers with ALS (n = 5, mean = 1601) compared to those of controls (n = 5, mean = ‐64.10; p<0.013), so we examined a larger cohort of C9ORF72‐mutation carriers. In symptomatic individuals (n = 27), cryptic peptide levels showed a correlation nearing significance with symptom duration (r = ‐0.368, p = 0.059), suggesting that levels of the cryptic peptide tend to be higher during the earlier symptomatic phase. We also found elevated cryptic peptide levels in CSF of several pre‐symptomatic individuals. To clarify cryptic peptide dynamics during disease progression, we began to assess longitudinal CSF samples and found that in 82.35% (14/17) of symptomatic individuals, levels of the cryptic peptide decreased with disease progression.

Conclusion

Our findings indicate that loss of TDP‐43 splicing repression occurs early in disease progression in ALS‐FTD, even pre‐symptomatically, and that detection of HDGFL2’s cryptic neoepitope may facilitate earlier diagnosis of TDP‐43‐related diseases. Further efforts linking the presence of cryptic HGDFL2 to TDP‐43 co‐pathology in AD may help expand biomarker development in AD. Additionally, evaluating dynamics of these biomarkers could provide a way of measuring target engagement for new therapeutics aimed at restoring TDP‐43 function.
The tauopathy‐associated PERK variant, PERK‐B, induces maladaptive translation and reveals novel pathogenic mechanisms of PSP
Authors: Lessard Christian B , Tolton Samantha G , McFarland Karen , Criado‐Marrero Marangelie , Bagchi Pritha , Seyfried Nicholas T , Abisambra Jose F. F
Published: December 2023

Background

A major challenge in the field is identification of molecular mechanisms driving pathological tau accumulation in tauopathies such as progressive supranuclear palsy (PSP). The largest GWAS for PSP identified a protein kinase endoplasmic reticulum kinase haplotype B (PERK‐B) hypomorph as a risk factor for the disease. This variant is less effective at reducing translation as its counterpart, PERK haplotype A (PERK‐A) and promotes the accumulation of pathological hyperphosphorylated tau species. However, the functional differences between PERK‐A and ‐B remain unknown, and this is partly due to the need for chemical induction of ER stress with compounds that provoke pleiotropic effects.

Method

To address these gaps in knowledge and overcome technical issues, we developed novel molecular tools and models to study PERK function. Using CRISPR/Cas9, we generated PERK‐KO HEK cells, transfected them with newly designed PERK plasmids, ER stress sensors, and markers of cap‐dependent translation. We also measured changes in tau accumulation and insolubility because of PERK‐B. In addition, we performed transcriptomic and puromycin proteomics to specifically identify the transcriptome and the nascent proteome resulting from PERK‐B expression.

Result

We established that expression of both PERK variants equally induced ER stress and reduced cap‐dependent translation. In addition, the PERK‐A and ‐B transcriptomes were virtually identical. However, while PERK activity was protective, PERK‐B less effectively cleared tau, leading to accumulation of insoluble pathological hyperphosphorylated tau. SUnSET proteomics revealed four proteins that were only present in the PERK‐B translatome. Given that these proteins had not been previously associated with PSP, we measured their levels in human brains and identified that at least one of them was significantly increased in PSP cases.

Conclusion

Our data suggest that the PERK‐B variant promotes accumulation of specific proteins associated with PSP. The new link between these proteins and PSP may reveal novel pathogenic mechanisms and could uncover new and effective therapeutic targets. Efforts to establish the role of these proteins in PSP is underway.
NeuroAI: AI‐based prediction model of Amyloid PET positivity using MR images and APOE genotype
Authors: Park Jun Young , Kim Byeong‐Chae , Ha Jung‐Min , Chong Ari , Lee Kun Ho
Published: December 2023

Background

Since acquiring amyloid PET data is costly and long waiting period due to the inaccessibility of PET machine, predicting positivity of amyloid PET data has many benefits. Therefore, we aimed to develop an artificial intelligence (AI) model for predicting amyoloid PET positivity for mild cognitive impairment (MCI) subjects with MR images and APOE genotype.

Method

A total 1,742 MCI subjects were enrolled in the Gwangju Alzheimer’s and Related Dementia cohort registry, Korea. We trained the deep learning model using MR images (T1 and Flair) and their APOE genotyping data. Finally, we conducted an external validation with 227 MCI subjects (118 with Aβ(+) and 109 with Aβ(‐)) from Chonnam National University Hospital and Chosun University Hospital in Korea.

Result

With independent test set, our model had the great performance with an AUC of 0.84 (0.78‐0.89), Accuracy of 78% (72‐83%), Sensitivity of 73% (64‐81%), and Specificity of 83% (74‐89%). The Korea Ministry of Food and Drug Safety granted clearance for the Phase III clinical trail of our model (NeuroAI) in March 2023 (NCT05383053).

Conclusion

Our model could help reduce the need for costly and time‐consuming amyloid PET scans, while also improving the accuracy of Alzheimer’s Disease diagnosis.
Plasma oligomeric amyloid‐β and the correlation with cognitive function across the clinical spectrum of Alzheimer’s disease
Authors: Min Jin‐Young , Min Kyoung‐bok , Ha Sang‐Won , Kang Min‐Ju , Jeong Da‐Eun , Lee Ryan
Published: December 2023

Background

The amyloid hypothesis linking amyloid β protein (Aβ) to Alzheimer’s disease (AD) is the key pathological event. It has shifted in recent years to suggest Oligomeric Amyloid‐β (OAβ) as a promising candidate for AD diagnosis. We aimed to depict the plasma levels of OAβ across a spectrum of cognitive stages and to explore the correlation between OAβ and specific cognitive domains.

Method

In this single‐center observational study, we included 494 individuals who had normal cognition (NC), mild cognitive impairment (MCI), and AD. Cognitive function was assessed across four cognitive domains (language and related functions, visuospatial functions, memory, and frontal/executive functions) and with the Mini‐Mental State Examination (MMSE). Participants were defined as: 1) NC with a percentile >16th in all sub‐tests of the SNSB‐C, 2) MCI with a percentile >16th in one or more sub‐tests of the SNSB‐C and K‐IADL < 0.43, and 3) AD with a percentile >16th in one or more sub‐tests of the SNSB‐C and K‐IADL ≥ 0.43. The MDS‐AD assay kit (PeopleBio Inc., Gyeonggi‐do, Republic of Korea) was used to quantify the levels of OAβ in the plasma.

Result

The plasma OAβ levels gradually increased among different cognitive stages of AD, with the lowest concentration in the NC (0.72 ng/ml), an increase in the MCI (0.76 ng/ml), and the highest concentration in AD (1.08 ng/ml). The plasma OAβ levels were significantly correlated with MMSE scores (r = ‐0.119, P‐value = 0.0083), the Korean‐Boston Naming Test (r = ‐0.090, P‐value = 0.0464), and the Trail Making Test‐Elderly (TMT‐E) (r = ‐0.146, P‐value = 0.0012). After adjusting for confounding variables, the elevated plasma OAβ were associated with worse performance on MMSE (Adjusted beta = ‐0.691; SE = 0.27, P‐value = 0.0100) and TMT‐E (Adjusted beta = ‐7.721; SE = 2.33, P‐value = 0.0100) as frontal/executive functions.

Conclusion

Plasma OAβ has correlated with language and related functions and frontal/executive functions, suggesting its potential biomarker for clinical manifestations of AD.
Digital Cognitive Assessment Leveraging the Boston Process Approach Can Flag Emergent Cognitive Decline in Individuals with Subtle and Mild Functional Disability
Authors: Libon David J , Swenson Rodney , Gomes‐Osman Joyce Rios , Banks Russell E , Jannati Ali , Higgins Connor , Tobyne Sean , Bates David , Pascual‐Leone Alvaro
Published: December 2023

Background

Early detection of Mild Cognitive Impairment (MCI) and Alzheimer’s Disease and Related Dementias (ADRD) is key to optimal management. Digital tests allow for the reliable capture of meaningful, process‐based neuropsychological test parameters that traditional paper/pencil measures fail to detect, thus enabling earlier detection. We assessed how subtle functional decline relates to process features extracted from the digital Clock Drawing Test (dCDT) and the digital Trail Making Test‐Part B (dTrB).

Methods

629 community dwelling participants (58.5% female) were assessed with the Functional Assessment Questionnaire (FAQ), the MMSE, the digital clock drawing test (dCDT) and the digital Trail Making Test‐Part B (dTrB). Three FAQ groups were constructed: FAQ = 0‐2 (minimal functional disability, n = 490); FAQ = 3‐5 (subtle functional disability, n = 90); FAQ = 6‐8 (mild functional disability, n = 49).

Results

Participants with minimal functional disability were younger (p = 0.027) and scored better on the MMSE (p = 0.001) than other groups. Groups were equated for education. dCDT command/copy component placement was more accurate among participants with minimal functional disability compared to other groups (command dCDT p = 0.001 versus mild functional disability; copy dCDT p = 0.006 versus both subtle and mild functional disability). On the dTrB, participants with minimal disability drew faster than those with subtle or mild disability (mean stroke velocity, p = 0.001). Analyses for percent pen lift time found no difference between participants with minimal versus subtle disability; however, both groups differed from participants with mild disability (p = 0.001). Optimal group classification using stepwise nominal regression with the minimal functional disability group as the reference was achieved using dCDT copy component placement and dTrB mean stroke velocity (X
2 = 28.37, p = 0.001), where dTrB mean velocity entered first (X
2 = 17.73, p = 0.001) followed by dCDT copy component placement (X
2 = 11.19, p = 0.004). Both variables contributed comparably to group classification (Wald statistic range 5.82‐8.88, p = 0.012, respectively).

Conclusions

The digital assessment described above, targeting executive, scanning, visuoconstructional and motor domains, captures highly nuanced, discrete behaviors with precision/ operationalism heretofore unattainable. Consequently, it is reasonable to posit that digital cognitive assessments leveraging the Boston Process Approach can both objectively detect emergent cognitive impairment and infer its likely impact on functional activities, critical for practical assessment in clinical care.