bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of mild cognitive impairment of Alzheimer’s disease and tauopathy differentiation by phospho‐tau396
Authors: Wang Shih‐Hsiu Jerry , Wu Ling , Ervin John F. , Gilyazova Nailya , Xu Bin
Published: December 2023

Background

In recent years, CSF and blood‐based biomarkers have been developed for premortem diagnosis of AD. However, no well‐established biomarkers are currently available for early detection of AD in patients with mild cognitive impairment (MCI), a transitional stage between normal cognition and dementia. As tau aggregates in AD brains are highly phosphorylated, we sought to develop novel biomarkers for early diagnosis of AD and differential diagnosis of tauopathies by detecting site‐specific phospho‐tau (p‐tau) epitopes.

Method

A panel of site‐specific p‐tau antibodies were screened for their ability to detect high molecular weight “smear‐like” tau aggregates from brain extracts of AD, PSP, CBD, and Pick’s disease patients by Western blotting. Selection of tau phosphorylation sites is based on the high frequencies of these sites reported in AD patients from recent high‐resolution quantitative post‐translational modification mapping. Selected candidates were further tested for their ability to differentiate subjects with AD vs. other tauopathies and MCI vs. cognitively normal controls by ELISA assays and immunohistochemical staining of postmortem brain tissue followed by machine learning‐based image analysis.

Result

Among the antibodies screened, p‐tau396 was able to differentiate between AD vs. controls (AUC: 0.983, P<0.0001), AD vs, CBD (AUC: 0.986, p = 0.0001), and AD vs. PSP (AUC: 0.967, p<0.0001). More importantly, ptau396 was able to detect subjects with MCI vs. cognitively normal controls (AUC: 0.835, p = 0.0032). Immunohistochemical staining of postmortem brain tissue with p‐tau396 antibody also showed increased neurofibrillary tangle pathology in the hippocampus and temporal cortex of subjects with MCI. Machine learning‐based image analysis reliably detected more severe tau burden in subjects with MCI vs. cognitively normal controls, even among subjects with the same Braak stages.

Conclusion

p‐tau396 is a promising novel biomarker for early detection of AD and differential diagnosis of AD from other tauopathies. Ongoing work is aimed at developing ultrasensitive assays, such as SIMOA, to detect p‐tau396 from patient blood and CSF.
Neurophysiological activity linked to Alzheimer’s disease pathology relates to longitudinal cognition and progression to mild cognitive impairment.
Authors: Rudolf Jonathan E Gallego , Wiesman Alex I , Baillet Sylvain , Villeneuve Sylvia ,   the PREVENT‐AD research group
Published: December 2023

Background

Alzheimer’s Disease (AD) is defined by the pathological accumulation of amyloid‐beta (Aβ) and tau in the brain. Regional deposition of these proteins is associated with changes in frequency‐defined neurophysiological activity that can be detected using non‐invasive magnetoencephalography (MEG). Here we examined whether these neurophysiological alterations were associated with participants’ demographics and longitudinal changes in cognition. Additionally, we addressed the clinical utility of MEG to predict progression to mild cognitive impairment (MCI), as compared to other established AD imaging biomarkers.

Methods

We used Positron Emission Tomography (PET) to measure the deposition of whole‐brain Aβ ([18F]NAV4694) and tau ([18F] Flortaucipir), Magnetic Resonance Imaging (MRI) to measure hippocampal volume and resting‐state MEG to capture neurophysiological activity in a group of clinically unimpaired older adults with family history of AD (PREVENT‐AD cohort; n = 103). We implemented a multivariate partial least squares (PLS) analysis to test the association between imaging markers (i.e., neurophysiological activity and AD proteinopathy) and participants’ clinical profiles (i.e., demographic‐clinical variables and longitudinal cognition data). For the second analysis we used logistic regression models to assess the added value of neurophysiological activity to predict MCI progression compared to established MRI/PET imaging markers (n = 100; 14 MCI progressors).

Results

The PLS analysis identified significant latent variables that linked proteinopathy‐related neurophysiological activity slowing to older age, lower education, positive APOE ε4 status and longitudinal deficits in cognition across multiple domains (Figure 1). The initial logistic regression model included demographic and clinical variables and had an AUC = 0.772, which increased to 0.794 after adding the MRI hippocampal volume. Incorporating MEG spectral power from temporal regions where tau accumulates resulted in a considerable increase in accuracy with an AUC = 0.873. The model including Aβ and tau PET on top of MRI and MEG markers reached an AUC = 0.905 (Figure 2).

Conclusion

Our results show that the neurophysiological changes linked to AD pathology are associated with longitudinal cognitive impairment across multiple domains. MEG spectral power from early tau accumulating regions improved the accuracy for predicting MCI progression, contributing information beyond traditional demographic/clinical variables and structural MRI and representing a more accessible and less invasive alternative compared to PET imaging.
A population‐based investigation of brain changes related to Alzheimer’s disease in middle‐aged adults in Brazil
Authors: Leite Renata Elaine Paraizo , Rodriguez Roberta Diehl , Socher Karen L R , Suemoto Claudia Kimie , Brucki Sonia Maria Dozzi , de Lucena Ferretti‐Rebustini Renata Eloah , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Grinberg Lea T. , Nitrini Ricardo
Published: December 2023

Background

Given the progressive nature of neurodegenerative pathologies, great effort has been made to create diagnostic tools for detecting neurodegenerative changes in their early stages. However, the lack of information about the frequency of neurodegenerative changes in mid‐age adults impacts biomarker interpretation and sensitivity improvement. In addition, recent clinicopathological studies have shown than even a low Alzheimer’s disease (AD) neuropathological burden can significantly impact neuropsychiatric function. Finally, clinicopathological studies point to a role of small cerebrovascular changes in the cognitive decline of individuals with zero or low neurodegenerative burden; however, it remains unclear if small vascular brain lesions can impact cognition in younger mid‐age individuals.

Method

We evaluated the presence of AD neuropathological changes and their relationship with cognitive impairment, neuropsychiatric symptoms and risk factors in a multiethnic and heterogeneous group under 65 years of age at the moment of death, most of them with low educational level (Table 1). A semi‐structured interview with an informant was performed to obtain socioeconomic and clinical data. Internationally accepted neuropathological criteria were used for pathologic diagnosis.

Result

Some degree of neurofibrillary pathology was found in 53% (n = 145) of the individuals, while neuritic plaques were found in 10% (n = 26) of the cases, regardless of the presence of cognitive impairment or neuropsychiatric symptoms. AD‐type pathology burden was similar among individuals with and without cognitive impairment. However, a higher frequency of vascular pathology (p<0.001) was found in individuals with cognitive impairment (Table 2). Some degree of neuropsychiatric symptoms was noted in 59% (n = 160) of the cases. High frequency of cerebrovascular risk factors such as hypertension (63.9%), smoking (58.5%) and alcohol intake (27.5%) was also observed in the entire sample (n = 275) (Table 1).

Conclusion

Our data shows that AD neuropathological changes can begin in mid‐age and corroborates findings from other series with predominantly older Caucasians of high scholarity that have demonstrated the role of vascular pathology in cognitive impairment. As vascular risks are preventable, aggressive measures to reduce these factors may impact the prevalence of cognition‐related dysfunction.
Glutamate Release and Uptake in CNS of Young and Aged Mice Compared to a Knock‐In Mouse Model of Alzheimer’s Disease
Authors: Sulkowski Brittany A. , Suhail Cocanut , Pomerleau Francois , Huettl Peter , Murphy Paul , Gerhardt Greg A
Published: December 2023

Background

Alzheimer’s disease (AD) and aging of the CNS are complex, heterogenous processes involving both structural and functional changes to neuronal and glial elements. While neuronal cell loss is well known, issues surrounding how age impacts both AD development and dementia and the metabolic and pathological changes that concomitantly occur are unclear. Major gaps in knowledge in aging of the CNS and AD involve changes in the excitatory/inhibitory balance between glutamate and GABA release and regulation with prior research supporting either elevated or reduced levels of resting glutamate.

Method

Tonic and phasic glutamate release were measured in real time in vivo through the utilization of enzyme‐based microelectrode arrays (MEAs). Young adult male and female C57BL6 mice (5‐8 months old) were the wild‐type (WT) control group and were compared to male and female old APP/PS1 knock‐in mice (13‐24 months old) and age matched WT controls. Glutamate was recorded in the hippocampus, frontal cortex, and striatum. Following recordings of basal glutamate levels, DL‐threo‐beta‐hydroxyaspartate (TBOA), was locally injected (100 nl/ 50mg/ml) in the brain to study glutamate uptake.

Result

There was a trend for basal glutamate levels to be increased in the hippocampus of both aged APP/PS1 and aged WT mice when compared to young WT animals with highest levels in the aged WT group. In both the frontal cortex and striatum, there was a trend for decreased basal glutamate levels in aged APP/PS1 and WT mice when compared to young WT animals with lowest levels seen in the aged WT group for both brain regions.

Conclusion

There were differences in glutamate extracellular regulation seen within the hippocampus, frontal cortex, and striatum of all animal groups and ages. In addition, we see evidence for age‐related increases in glutamate within the hippocampus of the aged animal groups. These data support that glutamate regulation is not homogenous in the CNS and that aging of the CNS may result in the greatest effect on glutamate regulation in the CNS, rather than genes that are implicated in the etiology of AD such as the APP and PS1 genes.

Support provided by NIH grants RF1AG070952 and 1P01AG078116.
Strategies for recruiting African Americans into aging research: The Health and Aging Brain Health Disparities (HABS‐HD) Study.
Authors: Munoz Haydee Izurieta , Large Stephanie E , Bailey Patricia , O'Bryant Sid E. , Johnson Leigh
Published: December 2023

Background

Despite the increase in Alzheimer’s disease (AD) research among ethnic and racial minority populations, they are underrepresented in research and successful recruitment of diverse cohorts remains challenging. Culturally specific recruitment strategies and community engagement are needed to increase diverse participant enrollment in aging research. In 2020, we designed and implemented a strategy to recruit 1,000 African Americans (AA), 50 years and older into the Health & Aging Brain Study‐ Health Disparities (HABS‐HD) project. In this study, we examined the effectiveness of recruitment strategies among this group.

Method

HABS‐HD is an epidemiological study of cognitive aging among diverse communities. The team recruited an initial cohort of 1,000 non‐Hispanic whites and 1,000 Mexican Americans using a community‐based approach. This foundation was expanded to reach the AA community through the engagement of key stakeholders and the use of an integrated marketing and outreach strategy. Recruitment methods included an integrated approach combining traditional marketing (print, radio); social media (influencers and online ads), and in person community recruitment and education events at local churches, barbershops, health fairs, etc. The reach and enrollment data were collected and analyzed.

Result

Out of 4066 participants that were interested in HABS‐HD, 1362 (33.5%) identified as AA. While recruiting the AA cohort outreach team participated in over 140 community events, ranging from state fairs, barbershops, and church events. Enrollment data indicated participants heard of us through word of mouth (35%); community events (21.6%); news (12.7%); refer a friend program (6.8%); print media (6.4%) radio (4%); and social media (3.6%). In terms of traditional marketing and overall general study awareness, the social media approach reached 179,200 individuals. Of this number12.1% of people interacted with the landing site and then a further 747 clicked to sign up. The reach of our radio advertising was 2,200,000 listeners.

Conclusion

Recruiting diverse communities into research involves targeting the recruitment techniques and materials to the target population. The creation of a culturally appropriate media campaign and utilizing community based methods such as outreach, engagement, and collaboration between the research team and key stakeholders in the community led to the successful recruitment of AA into our study.
Investigating Potential Racial Differences in Dementia‐Related Plasma Biomarkers
Authors: Pettway Erika C , Labonte Jacob , II Robert W Turner , Bragg Tahlia , Turner Arlener , Banks Sarah J , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J. , Karikari Thomas K , Tripodis Yorghos , Martin Brett M , Palmisano Joseph N , Stern Robert A , Killiany Ronald J , Aparicio Hugo J , Goldstein Lee E , Qiu Wendy , Budson Andrew E , Mez Jesse B. , Alosco Michael L
Published: December 2023

Background

Black self‐identified individuals are disproportionately affected by dementia, a phenomenon best attributable to differences in social determinants of health (SDOH). Plasma protein levels can serve as antemortem indicators of dementia pathology; recent findings indicate potential race‐specific differences in these biomarkers of tau and non‐tau pathologies between Black self‐identified or White individuals.

Methods

This sample included 568 participants (77, 13.56% Black self‐identified, Table 1) from the Boston University Alzheimer’s Disease and Research Center (BUADRC). Participants completed a battery of neuropsychological tests and cognitive diagnoses were made during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using ELISA methods for YKL‐40 levels and using Simoa platform for phosphorylated tau (p‐tau 181, p‐tau231), total‐tau, glial fibrillary acidic (GFAP), and neurofilament light chain (NfL) levels. ANCOVAs tested for a cross‐sectional association between racial identity and each plasma biomarker and stratified by cognitive impairment status with covariates for age, education (in years), sex assigned at birth, and APOE ε4 carrier status. Cox proportional‐hazards models were used for longitudinal analyses of the interaction effect between racial identity and plasma biomarkers in the risk for conversion from normal cognition (NC) to mild cognitive impairment (MCI) and reversion from MCI to NC.

Results

Baseline YKL‐40 was lower among Black self‐identified participants (adjusted mean diff = 0.37 SD, p<.001); this association was particularly salient within the MCI group (adjusted mean diff = 0.62 SD, p<.001). The longitudinal analysis revealed interaction effects between race and GFAP for risk for conversion from NC to MCI and reversion from MCI to NC. Among White participants, higher GFAP predicted increased risk for conversion from NC to MCI and lower levels predicted reversion. However, no significant effects were found among Black self‐identified participants; these findings might be limited by sample size (n = 18) resulting from the high occurrence of baseline MCI diagnoses and subsequent lack of conversion or reversion among Black self‐identified participants.

Conclusion

In the context of an unrepresentative sample, we found trivial differences in plasma biomarkers between Black self‐identified and White participants. Recruitment of Black self‐identified participants representative of the population and further exploration of SDOH is essential in understanding the disproportionate risk for dementia carried by Black self‐identified individuals.
Differential diagnosis of Lewy body dementias using multivariate EEG classifiers
Authors: Yoder Keith J , Brookshire Geoffrey , Gerrol Spencer , Quirk Colin , Lucero Ché
Published: December 2023

Background

Lewy body dementia (LBD) results from pathology in ɑ‐synuclein and is the second most common cause of dementia. LBD has two manifestations: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). There is currently no non‐invasive, fast, reliable way to distinguish between early‐stage PDD, DLB, and Alzheimer’s disease (AD). Although previous traditional EEG visual rating methods have not been useful in delineating dementia subtypes, resting‐state electroencephalography (rsEEG) is a promising method for differential diagnosis of dementia, because it is inexpensive, non‐invasive, and widely available for clinical use. Here, we demonstrate how a multivariate classifier using rsEEG as input can differentiate PDD, DLB, and Alzheimer’s disease.

Method

We analyzed rsEEG data from older adults (N = 133, age 59‐89) with AD (n = 33), DLB (n = 27) or PDD (n = 45). We computed the aperiodic and periodic parameterization of brain activity, along with metrics of variation in fractal dimension within specific frequency bands. We then used these features, along with age and sex, to develop XGBoost machine‐learning models to predict patient diagnoses. Models were evaluated using cross‐validation with balanced accuracy, weighted sensitivity, and weighted specificity.

Result

The first task was a two‐way classification: Control vs Dementia (accuracy = 86%, sensitivity = 93%, specificity = 79%, p < .001). The second task was a three‐way classification: AD vs DLB vs PDD (accuracy = 66%, sensitivity = 70%, specificity = 82%, p < .001). We also evaluated two‐way models distinguishing between AD vs DLB (accuracy = 86%, sensitivity = 87%, specificity = 86%, p < .001), AD vs PDD (accuracy = 84%, sensitivity = 85%, specificity = 83%, p < .001), AD vs LBD (combined DLB and PDD; accuracy = 82%, sensitivity = 85%, specificity = 78%, p < .01), and DLB vs PDD (accuracy = 68%, sensitivity = 71%, specificity = 65%, p < .05).

Conclusion

Machine‐learning and rsEEG are capable of distinguishing between AD and LBD. Moreover, machine‐learning combined with spectral and fractal features can distinguish between DLB and PDD, despite both forms of dementia arising from ɑ‐synuclein pathology.
Diagnostic Challenges in Progressive Supranuclear Palsy: Early Identification and Mimics
Authors: Taiwo Tolulola O
Published: December 2023

Background

Progressive supranuclear palsy (PSP) is an often‐undiagnosed neurodegenerative disorder. There are often delays in diagnosing PSP.

Method

Retrospective chart review of all newly diagnosed PSP patients referred to an outpatient clinic. We conducted a review of all initial/new PSP cases in our geriatric clinic. The most common preliminary diagnosis the patients had been given included was idiopathic Parkinson’s disease. Other common diagnoses were vascular Parkinson’s, frontal lobe dementia, psychotic depression and late life psychosis.

Clinical records with the subjective accounts, cognitive assessments and brain imaging reports of 23 PSP patients were reviewed.

Results

The most common cognitive deficits were visuospatial changes (100%), semantic fluency deficits (80.4%), dysexecutive function. Sleep disruption with insomnia with intermittent awakening was also commonly reported.

A propensity for falls and multiple falls were also reported. The interval from the onset of symptoms and initial presentation to a clinical provider to diagnosis ranged from 1 ‐ 7 years.

Conclusion

A high index of suspicion and recognition that PSP might not be as uncommon as previously thought is needed. A timely diagnosis and recognition of the various cognitive and behavioral changes is important.
Association Between Age and Cognitive Severity in Participants from the Longitudinal Early‐Onset Alzheimer’s Disease Study
Authors: Hammers Dustin B. , Eloyan Ani , Thangarajah Maryanne , Taurone Alexander , Kirby Kala , Polsinelli Angelina J , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G.
Published: December 2023

Background

Age‐related cognitive declines are well‐documented in cognitively normal adults (van der Willik et al., 2021), as are greater cognitive impairments with advancing age in traditional‐ (or “late‐”) onset Alzheimer’s disease (LOAD; Davis et al., 2018). Early‐onset Alzheimer’s disease (EOAD; diagnosis ≤65 years old) possesses a unique disease course and underlying pathology relative to LOAD (Mendez, 2012), consequently it is unknown if the association between age and cognitive severity is similar. The objective of the current study is to examine the relationship between cognition and age‐at‐baseline in participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019).

Method

Cross‐sectional cognitive data from 371 participants (aged 40‐64) enrolled in the LEADS protocol were analyzed, using composites for the domains of Episodic Memory, Speed/Attention, Visuospatial skills, Language, and Executive skills. Relationships between age‐at‐baseline and cognition were examined using linear regression based on diagnostic group classification (cognitively normal [CN], amyloid‐positive EOAD, and amyloid‐negative Early‐Onset non‐Alzheimer’s disease [EOnonAD]), controlling for the effects of age and education years.

Result

Demographic characteristics for each group are shown in Table 1. Across cognitive domains, the CN group displayed either non‐significant or negative relationships (Executive skills; r = ‐0.30, p = .006) between age‐at‐baseline and cognitive performance (Figure 1 and Table 2). Conversely, the EOAD group showed consistent positive relationships for domains of Speed/Attention (r = 0.23, p<.001), Visuospatial Skills (r = 0.19, p = .01), and Episodic Memory (r = 0.16, p = .02). A similar non‐significant trend was observed for the EOnonAD group for Speed/Attention (r = 0.17, p = .19). When considering those with amnestic‐variant early‐onset dementia across diagnostic groups, positive relationships between age‐at‐baseline and cognition were observed for Speed/Attention (r = 0.19, p = .006) and Visuospatial skills (non‐significant trend; r = 0.14, p = .05), but not for Episodic Memory (r = ‐0.06, p = .35).

Conclusion

Worse cognitive severity was associated with younger age‐at‐baseline for EOAD participants in LEADS. Similar trends were observed for EOnonAD participants, though to a lesser magnitude. These results were counter to those observed for CN participants, and to what is known about cognitive trajectories in normal aging or LOAD. These findings further support previous suggestions that EOAD appears to be a distinct entity relative to LOAD.
Sex‐ and APOE‐Specific Transcriptomic Signatures in Alzheimer’s Disease: An AZ‐ADRC‐Research Education Scholars Team Science Project
Authors: Vitali Francesca , Raikes Adam C. , Hernandez Gerson D , Yin Fei
Published: December 2023

Background

Age, female sex and APOEε4 allele are among the top risk factors for developing late‐onset Alzheimer’s disease (LOAD). To enable Precision medicine for AD drug development, it is crucial targeting specific biological pathways driving AD pathology. While individual effects of sex or APOE have been studied, genes and biological pathways commonly or uniquely altered by these two factors are less understood.

Method

ROSMAP RNA‐Seq data were obtained from AMP‐AD including 369 frontal cortex samples from APOEε3/ε3 and APOEε3/ε4 individuals. Of these, 209 had an AD diagnosis and 160 were controls. Differentially expressed genes (DEGs, pvalue<.05) between LOAD and cognitively normal individuals were identified using a generalized linear regression model. Gene Set Enrichment Analysis (GSEA) was performed using Gene Ontology Biological Processes (GOBP). Redundant GOBP enriched terms were removed computing semantic similarity measures (adjusted pvalue<.05). Comparison analyses were conducted to identify common and unique DEGs and enriched GOBPs across sex‐genotype conditions.

Result

APOEε3/ε3 female brains exhibited the greatest DEG number (n = 11,851) while APOEε3/ε3 males exhibited the least (n = 714). Nine DEGs were shared across all comparisons, which were involved in metabolic processes, synaptic function, myelination, and GPCR signaling. GSEA revealed comparable numbers of LOAD‐enriched pathways in all female groups and male APOEε3/ε4s (n = 144‐155 GOBP terms), whereas APOEε3/ε3 males exhibited the fewest enriched terms (n = 13). Identified GOBP terms included pathways related to metabolism, cellular responses and regulation, and immune response regulation. However, there were no common GOBP terms across all sex‐genotype conditions.

Conclusion

Our analyses provide evidence of sex‐ and APOE‐ specific transcriptomic signatures and biological processes altered in LOAD brains. The findings suggest significantly greater transcriptomic dysregulation in female APOEε3/ε3 brains despite the similar extent of affected biological pathways as other sex‐APOE conditions. In contrast, a significantly smaller number of affected biological processes were identified in male APOEε3/ε3s despite having comparable transcriptomic dysregulation as the male APOε4 carriers but less than the female groups. These analyses provide rationale to develop risk factor‐specific therapeutics for the prevention and treatment of LOAD by considering the interaction between biological sex and APOE genotype.
Dysphagia in people with dementia
Authors: Opritoiu Bianca , Ungureanu Larisa , Ciopleias Bogdan , Diaconu Stefania , Irincu Laura , Despa Irina , Falup‐Pecurariu Oana , Kakucs Cristian , Cusnir Malina , Falup‐Pecurariu Cristian
Published: December 2023

Background

Dysphagia is a common complication in multiple neurodegenerative disorders, influencing quality of life and long term prognosis. In dementia, data regarding prevalence of dysphagia and secondary complications such as aspiration pneumonia is not well understood.Aim of the study: to assess the prevalence of dysphagia and aspiration pneumonia in patients with dementia.

Method

Cross‐sectional study that included patients previously diagnosed with dementia, evaluated in the outpatient clinic or admitted in the Department of Neurology, County Clinic Hospital Brasov. We evaluated the patients using a standardized protocol that included the MMSE, MoCA scale, Gugging Swallowing Screen, fiberoptic evaluation of swallowing and FEDSS scale.

Result

there were 42 patients with dementia included in the study (57,14% females) with a mean age of 69.7 ±9,1 years. The mean MMSE score was 16.8 ± 4.4. Dysphagia was present in 9 patients (21.42%). Pneumonia was encountered in 33.3% of the dysphagic patients, and it was associated with high mortality. The major secondary risk factors for pneumonia were older age, obesity, smoking and diabetes. Patients with a lower score on the MMSE/MoCA scale had a higher risk of developing dysphagia and aspiration pneumonia. Mortality in the dysphagic group was higher when compared with the non‐dysphagic group (44.2% vs. 21.2%).

Conclusion

Dysphagia has an important impact on the clinical outcome of the patients with dementia, increasing the risk of institutionalization and mortality and being associated with dependency and poor quality of life.
Esya AD360: A multi‐parametric platform for establishing a novel lysosome‐based biomarker for Alzheimer’s Disease
Authors: Connolly Owen , Deivasigamani Senthilkumar , Wahdan Malak , Venkat Dhivya , Krishnan Yamuna , Modi Souvik
Published: December 2023

Background

Biomarker development in Alzheimer’s Disease (AD) relied on techniques such as neuroimaging, and proteomics to investigate tauopathy and amyloidosis (Musiek & Holtzman, 2015). However, multiple studies show that lysosomal dysfunction is associated with Alzheimer’s disease (AD) by regulating both the formation and degradation of Aβ (van Weering & Scheper, 2019). To leverage this paradigm shift in our understanding of AD pathology, we describe a method using lysosomal two ion‐mapping (2‐IM) technology in addition to RNA panel for early detection of AD.

Method

Esya’s diagnostic (Esya AD360) is a multiparameter platform incorporating 1) 2‐IM probes that ratiometrically measure concentrations of ions such as H+ and Ca2+ with single lysosome resolution 2) ApoE genotyping and, 3) a panel comprising 12 RNA targets identified through RNA‐Seq. The diagnostic utility of Esya AD360 was assessed through application to fibroblasts from a clinically diagnosed cohort comprising healthy individuals and patients diagnosed with AD, frontotemporal dementia (FTD), Parkinson’s, and Huntington’s disease. A model probability score of predicting AD was calculated using a logistic binary regression.

Result

The diagnostic power of Esya AD360 is improved by addition of a custom RNA panel and ApoE genotyping to our pre‐existing 2‐IM model. Logistic regression demonstrates that the assay is >96% accurate in differentiating AD from HI (specificity of >99% and sensitivity of 92.3%). This was further validated using a small validation sample set comprising 12 autopsy confirmed AD samples. Esya AD360 successfully identifies all 12 samples as AD patients, independently validating assay accuracy. After combining the validation data, we find the specificity of Esya AD360 to be >99%, and 96% sensitive. We also demonstrate that Esya AD360 can successfully differentiate between AD and non‐AD dementias (FTD, Huntington’s and Parkinson’s), with an AUC of 0.99 between HI and AD, and an AUC of 0.99 between AD and non‐AD dementias.

Conclusion

The incorporation of three independent features has resulted in an accurate, specific, and sensitive assay at identifying AD and differentiating it from healthy and non‐AD dementias. This technology can be further optimised and applied to other neurological disorders and will allow Esya to develop a more accurate platform for personalized medicine in neurology.
Understanding the protective effect of the PLCG2 P522R variant in human microglia
Authors: Frik Jesica , Robert Aiko , Koppes Sascha , Erlebach Lena , Kronenberg‐Versteeg Deborah , Giera Martin , Kant Rik
Published: December 2023

Background

Although recent advances in the field suggest significant involvement of the shared pathway between the proteins ApoE and TREM2 in the pathogenesis of late onset Alzheimer’s disease (LOAD), the direction that disease‐modifying interventions targeting this pathway should take are still under debate.

Interestingly, a variant of the Phospholipase C Gamma 2 (PLCG2), a downstream effector of the TREM2 receptor, has been associated with a reduced risk of developing dementia. This variant results in a single amino acid change, which was reported to increment enzyme activity. However, mutations in this same enzyme (S707Y, L848P), which also result in hyperactivity, were found to lead to auto‐inflammatory immune diseases or increased AD risk (M28L), suggesting that there may be specific modulatory effects of the P522R variant. Alternatively, the existence of diverging downstream signaling pathways may explain its protective potential.

Method

We have generated a complete set of human isogenic iPSCs derived from the Bioni037A parental line using Crispr/Cas9 edition to introduce the mutations for the different PLCG2 variants. We obtained homozygous and heterozygous clones with the protective P522R mutation, the immune disease related S707Y or L848P. We also acquired ApoE4 isogenic iPSCs. Microglia differentiation was induced from these iPSCs using a protocol involving embryoid bodies. Our approach includes lipidomics and proteomics analyses, with focus on microglial lipid metabolism.

Results

Here, we show the generation of new human isogenic iPSC lines to study PLCG2 mutations. Preliminary results from the characterization of human iPSC‐derived ApoE4 microglia employing this multi‐omics approach shows a reduced expression of TREM2 pathway components including the tyrosine kinases SYK and BTK. Since BTK and SYK are both PLCG2 kinases that result in enzyme activation, we are expanding this analysis to PLCG2 mutants and base our working hypothesis on the possibility that PLCG2 hyperactive variants show a reverse phenotype compared to ApoE4 microglia.

Conclusion

We present new tools and a rationale to explore the protective effect of the PLCG2 P522R variant against LOAD in human microglia.
To Assess Mediation Effects of BIN1 Risk Variant rs6733839 and APOE4 on Alzheimer’s disease Pathology
Authors: Hooli Basavaraj , Rathore Saima , Wang Jian , Morris Amanda , Lu Ming , Sabourin Jeremy , Shcherbinin Sergey
Published: December 2023

Background

Alzheimer’s disease (AD) patients carrying T‐allele in the single nucleotide polymorphism rs744373 show higher levels of misfolded tau protein levels, as well as faster accumulation of neurofibrillary tangles (Franzmeier‐2019; Franzmeier‐2022), in addition to established risk gene apolipoprotein E (APOE4). Here we conduct pathway analysis to understand the direct and indirect effects, mediated through amyloid levels, of the rs6733839 T‐allele and APOE e4‐allele on tau.

Method

Amyloid‐positive (florbetapir PET) placebo‐arm patients with a clinical diagnosis of AD dementia from four clinical trials (NCT01900665, NCT02791191, NCT02245737, NCT02016560, Table.1) underwent baseline (N = 547) and follow‐up (N = 230) flortaucipir PET scans. Tau burden was assessed using standardized uptake value ratio (SUVr) in AD‐specific region (MUBADA; Devous‐2018) with respect to cerebellum‐crus. We tested direct and indirect effects of BIN1 (rs6733839) and APOE4 on baseline SUVr and change‐from baseline (CFB) in tau‐PET mediated by baseline florbetapir signal. Unstandardized indirect effects were computed for each of 1,000 bootstrapped samples, and the 95% confidence interval was computed by determining the indirect effects at the 2.5th and 97.5th percentiles.

Result

BIN1 and age showed significant association with the baseline tau‐PET level (BIN1: ßeta = 0.05, P = 0.05; Age: ßeta = ‐0.03, P<0.001), whereas APOE4 association with the baseline tau‐PET levels was not statistically significant (ßeta = 0.006, P = 0.81). The bootstrapped unstandardized indirect effect of BIN1, age, and APOE4 mediated via baseline amyloid levels was insignificant (BIN1: ßeta = 0.0002, P = 0.92; Age: ßeta = 3.82e−05, P = 0.74; APOE4: ßeta = ‐0.0003, P = 0.86). When evaluated on longitudinal tau measures, the direct effect of APOE4 on CFB in tau‐PET SUVr was significant (ßeta = 0.02; P = 0.01). The direct and indirect effects (mediated via baseline amyloid levels) of BIN1 (Direct: ßeta = ‐0.007, P = 0.215; Indirect: ßeta = ‐0.0007, P = 0.58) and Age (Direct: ßeta = ‐0.0009, P = 0.26; Indirect: ßeta = 0.0001, P = 0.32) were insignificant.

Conclusion

BIN1 showed significant association with the baseline tau‐PET level whereas APOE‐e4 allele directly affected longitudinal tau buildup independent of amyloid levels. These observations require additional validation using larger datasets and further optimization of the applied methodology is warranted.
Sex and aging signatures in human CSF proteomics and their link to neurologic diseases
Authors: Sung Yun Ju , Seo Da Hun , Lee Cheol Min , Timsina Jigyasha , Wang Lihua , Ruiz Agustin , Pastor Pau , Park Taesung , Cruchaga Carlos
Published: December 2023

Background

Sex and age are major risk factors for several chronic diseases. Recent human and mouse studies of age‐related molecular changes in blood provided new insights into age‐related disease biology. Cerebrospinal fluid (CSF) is more closely related to brain than blood and can provide additional insights to sex and age‐related brain diseases.

Method

We measured over 7000 proteins in CSF from 998 healthy individuals representing middle and old age (43‐91) across four multiple cohorts. After stringent QC, we performed weighted gene co‐expression network analysis (WGCNA) to group CSF proteins with similar sex and age trajectories. Each cluster was then tested for aging and sex differences. Cell‐type enrichment and disease ontology enrichment was also performed.

Result

Co‐expression network analysis identified 24 modules for CSF 4926 proteins. Sex difference was detected for 2949 proteins (1730 were higher in females; 1219 were higher in males). Aging signature was detected for 4480 proteins (2999 increasing; 1481 decreasing with age). The pink module (containing SERPINA3, TREML2, and additional 197 proteins) had proteins higher in males and increasing with ages and were enriched in endothelial cell (P = 0.04). Cardiovascular diseases (FDR = 2.6E‐9), ischemic stroke (FDR = 1.7E‐7) and Alzheimer’s disease (AD) (FDR = 7.3E‐3) were significantly enriched in this module. The blue module (containing APOE, APP and additional 681 proteins) had proteins higher in females and decreasing with ages, were enriched in microglia and macrophage (P = 0.01). AD (FDR = 0.043) and vascular dementia (FDR = 0.025) were enriched. The yellow module (containing SMPD1, GNS, CTSB and additional 331 proteins) had proteins higher in females and non‐linear aging trajectory (increasing until 70 years old and decreasing) were enriched in neurons (P = 4.6E‐9). Lysosomal storage diseases (FDR = 3.4E‐03) showed enrichment for them. Among the 46 plasma proteins showing conserved aging signature in mice and humans (Lehallier et al 2019), 20 proteins including TNFSF15 and PPBP were also conserved in CSF. In addition, nine of them show the sex‐specific signature conserved across all three datasets.

Conclusion

Our study in CSF proteomic signatures identified clusters of proteins in distinct patterns and their relation to Alzheimer’s disease and other neurodegeneration. More detailed characterization of proteomic signatures for other age‐related chronic diseases is underway.
Reduction of apathy and caregiver distress using a combination of tetrahydrocannabinol and melatonin in dementia due to Alzheimer’s disease
Authors: Gutierrez Evelyn , Sanchez Laura Tatiana , Arbelaez María Juanita , Tangarife Maria Alejandra , Delgado‐Murillo Laura , Rodriguez‐Soacha Diego , Shahnawaz Saadia S , Ghazaryan Varduhi , Naranjo Maria Paula , Venegas Margarita , Silva‐García David , Pujals Karen Y , De Jesus William Julio , Grimaldi Claudia , Mukunda Ram , Hong L Elliot , Lanctôt Krista L.
Published: December 2023

Background

Apathy is one of the most frequent and long‐lasting neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD). Up to 78% of AD patients exhibit apathy, which is related to caregiver distress, decreased quality of life, and increased morbidity. While many medications and behavioral interventions are used to treat apathy, the effects are often limited and lack in‐depth research to support these approaches. We present preliminary data for improvement in NPI‐apathy (NPI‐ap) scores and NPI Caregiver Distress (NPI‐D) scores using IGC‐AD1, a tetrahydrocannabinol (THC) and melatonin combination.

Method

Twelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort, Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts‐2 and 3, one ml BID and TID were administered respectively, with a minimum of 4‐days washout between Cohorts. Solicited and non‐solicited adverse events (AEs) were monitored daily.

In each Cohort, seven participants (5‐active, 2‐placebo) had apathy at baseline, as rated by the NPI‐ap. They were administered the NPI‐ap at EOT and the Wilcoxon matched pairs signed‐rank test (R‐Studio, dplyr) was used to compare the difference in NPI‐ap scores between baseline and EOT. A similar analysis was carried out for NPI‐D.

Result

In Cohort‐1 mean NPI‐ap at baseline and EOT was 5.4 and 3 respectively (mean difference = ‐2.4, v = 6, p = 0.091). In Cohort‐2 mean NPI‐ap at baseline and EOT was 5.2 and 2.4 respectively (mean difference = ‐2.8, v = 6, p = 0.087). In Cohort‐3 mean NPI‐ap at baseline and EOT was 5.2 and 2.6 respectively (mean difference = ‐2.6, v = 6, p = 0.087). Results for NPI‐D: (Cohort‐1:mean difference = ‐0.6, 37.5%, v = 6, p = 0.075; Cohort‐2:mean difference = ‐1.8, 69.2%, v = 15, p = 0.028; Cohort‐3:mean difference = ‐0.2, 12.5%, v = 2, p = 0.5). No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were observed.

Conclusion

As IGC‐AD1 contains THC, the results are intriguing because cannabis use has been associated with apathy but also increased empathy and sociality. In Cohort‐1, Cohort‐2, and Cohort‐3 NPI‐ap was reduced 44.44%, 53.85%, and 50% respectively. These results, while not statistically significant (p>0.05), appear clinically significant (reduction≥30%). A larger placebo‐controlled study is warranted.
Maya Angelou Center for Health Equity Caregiver College: a culturally‐relevant training for African American Alzheimer’s disease caregivers
Authors: Caban‐Holt Allison M , Starks Takiyah D. , Lloyd Shawnta' , Ford Anita , McCall Sole' , Eale Samuela B. , Fuller Lori , Byrd Goldie S.
Published: December 2023

Background

African American (AA) caregivers of patients with Alzheimer’s disease (AD) and related disorders can play a critical role in maintaining patient health. The Maya Angelou Center for Health Equity at Wake Forest University School of Medicine Caregiver College (MC2) aims to (1) improve informal caregivers’ knowledge of AD and related disorders, (2) enhance the quality of life for AD patients and caregiver’s by providing awareness of and access to resources that can help reduce caregiver burden, (3) provide strategies to effectively manage patient symptoms associated with AD, and (4) fill gaps in culturally relevant health education and awareness on AD, brain health, and dementia caregiving skills for AAs.

Method

The 40‐hour inaugural session of MC2 was conducted in‐person in October 2022. Educational sessions were facilitated by experts in various fields including AD, social work, nursing, aging, nutrition, and pharmacy. Topics covered over the course of the educational week included: Alzheimer’s Disease Overview, Health Disparities in AAs, Risk Factors for AD, End of Life Planning, and Caregiver Health. The 21‐item Dementia Knowledge Assessment Tool (DKAT), version 2 (Toye, et al. 2013) was used to track changes in AD knowledge and awareness. A DKAT pre‐test was administered before the educational sessions began on Day 1, and a post‐test assessment was administered at the end of the last educational session on Day 5.

Result

Attendees (N = 21) are African American (100%), primarily female (90.48%), with an average age of 66.8 years (range 42‐82 years, 1 missing value). DKAT assessments from the week‐long educational training, showed an 8% increase in knowledge about AD in this sample of dementia caregivers based on a 5.7 percentage point increase on the DKAT from an average of 71.4% correct pre‐training to an average of 77.1% correct post‐training.

Conclusion

Findings suggest that community‐based educational training is a useful strategy for improving AD knowledge and resource awareness for AA informal caregivers. Results will be used to expand this training to include community members who will be engaged through presentations by attendees of the MC2.
Correlations between [18F]flutemetamol PET and region‐matched postmortem integrated density measures of cyano‐flutemetamol signal in Aβ plaques
Authors: Abrahamson Eric E , Buckley Christopher , Pemberton Hugh , Farrar Gill , Smith Adrian , Ikonomovic Milos D
Published: December 2023

Background

The binding substrates of [18F]flutemetamol and [11C]PiB PET consist of fibrillar amyloid‐β (Aβ) aggregates in morphologically and structurally distinct diffuse plaques (DP) and cored plaques (CP) which are present at different proportions across brain regions in Alzheimer’s disease (AD). To account for this heterogeneity, an unbiased quantitative measure integrating plaque size and density of amyloid‐β (Aβ) fibrils in plaques could help avoid false positive results, improve imaging‐to‐autopsy correlations, and further advance our understanding of pathological substrates for binding of amyloid PET tracers.

Method

Sixteen subjects underwent [18F]flutemetamol PET imaging in the pivotal Phase III end‐of‐life study (Study GE067‐007 and GE067‐026) and later came to autopsy (mean imaging‐to‐autopsy interval was 111 ± 87.6 days). [18F]flutemetamol SUVRpons values in four neocortical regions were correlated with region‐matched postmortem measures of cyano‐flutemetamol labeling of all plaques, as well as CP and DP separately, using percent area coverage, mean grayscale intensity of fluorescence, or a combination of the two measures referred to as integrated density.

Result

In the analysis of all cyano‐flutemetamol‐labeled plaques, [18F]flutemetamol SUVRpons values were more closely associated with integrated density measures than percent area coverage and mean grayscale values. Similarly, when CP and DP were analyzed separately, the integrated density values showed the closest association with neocortical region‐matched [18F]flutemetamol SUVRpons values. When area coverage of CP and DP were each expressed as a fraction of total plaque area coverage with or without integrating fluorescence intensity values, [18F]flutemetamol SUVRpons values within each region of interest were associated with the DP, but not the CP, area coverage measure.

Conclusion

The association of antemortem [18F]flutemetamol PET and region‐matched postmortem integrated density measurements of cyano‐flutemetamol labeled plaques further supports the hypothesis that amyloid PET signal is influenced both by plaque size and Aβ fibril density within DP and CP. Further elucidating the relative contributions of each plaque type to the retention of amyloid PET radioligands could influence how a positive amyloid PET signal is interpreted in relation to postmortem pathology data.