bluuebunny/crossref_metadata_2025 huggingface dataset:
Lysosomal ion homeostasis as a novel biomarker for Alzheimer's disease
Authors: Connolly Owen , Wahdan Malak , Deivasigamani Senthilkumar , Krishnan Yamuna , Modi Souvik
Published: December 2022

Background

Protein clearance and neuronal homeostasis critically depend upon normal functioning of autophagy and endo‐lysosomal pathways (Nixon, 2020; Usenovic & Krainc, 2012). Multiple studies show that lysosomal dysfunction is associated with Alzheimer’s disease (AD), since impaired degradation of aggregate‐prone proteins can lead to pathological accumulations of Aβ plaques and neurofibrillary tau tangles (Baranello et al., 2015; Rajendran & Annaert, 2012). To leverage this paradigm shift in our understanding of AD pathology, we have invented a pioneering, ion‐imaging technology using DNA nanodevices to non‐invasively map lysosomes for early AD detection.

Method

Our lysosomal ion reporters are short DNA duplexes that simultaneously measure the concentrations of two ions ratiometrically, such as H+ and Ca2+. We used dermal skin fibroblasts from a clinically diagnosed cohort of 120 samples comprising healthy individuals, AD, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s and Huntington’s disease patients. Using our lysosome mapping technology, we identified five distinct, AD‐related lysosomal features. A model probability score of predicting AD was calculated using a logistic binary regression.

Result

Lysosomal ion profiles in age‐matched control groups showed significant differences compared to AD patients. Firstly, lysosomes from AD samples were found to be significantly more acidic and harbored more calcium than healthy samples. Secondly, resolving lysosomes into populations based on their pH and Ca2+ levels revealed that two distinct lysosomal populations are significantly altered in AD. Our assay is 88% accurate (AUC: 0.91, 95% CI :0.84‐0.97) at identifying AD from other healthy and non‐AD related individuals with dementia. Further, we could detected AD‐related lysosomal dysfunction more than 19 years prior to symptom manifestation.

Conclusion

Our novel ion‐mapping technology reports the ionic composition of single lysosomes of cultured cells. This enables early detection of AD in individuals who are either pre‐symptomatic, AD symptomatic, or suffer from other non‐AD dementia. This unique technology will allow us to build a drug discovery pipeline where we can specifically monitor the effect of pharmacological interventions and their impact on selective lysosomal populations, enabling personalized medicine for AD and other neurodegenerative diseases.
Quantum Dot loaded BQCA‐Octadecylamine conjugate nanosystems for theranostic applications in Alzheimer’s Disease.
Authors: Chintamaneni Pavan Kumar , Krishnamurthy Praveen Thaggikuppe , Pindiprolu Saikiran S.S , Sathyamoorthy NandhaKumar
Published: December 2022

Background

Alzheimer’s Disease (AD) is one of the most common types of dementias in the world and is characterized by progressive, irreversible neurodegeneration. Benzyl quinolone carboxylic acid was shown to have beneficial in management of AD. The current challenge with BQCA is its low brain half‐life, permeability and rapid elimination. The above challenge can be answered by formulating lipid drug conjugates of BQCA, with octadecyl amine (BQCA‐ODA). Quantum dots (QDs) with their unique optical properties, with high sensitivity and stability emerging as theranostic agents in several neurodegenerative diseases. Hypothesizing the co‐delivery of QDs and BQCA for the effective treatment of AD, in the present study we have formulated lipid nano carriers loaded with quantum dots (QDs) surface modified with Polysorbate 80, called PS80‐QD‐BQCA‐ODA‐NPs, for integrating imaging and therapy for effective management of AD.

Method

BQCA was conjugated to Octadecyl amine (ODA), to form BQCA‐ODA LDC conjugate. The amphiphilic nature of the BQCA‐ODA conjugate allows the formation of self‐assembled nanoparticles. Here, we have employed solvent injection method followed by sonication, while addition of QDs in the organic phase and P80 in the aqueous phase to form PS80‐QD‐BQCA‐ODA‐NPs . The optimized formulation was evaluated for physicochemical properties (particle size, zeta potential and polydispersity index) surface morphology and in vitro drug release. The in vitro biocompatibility of the PS80‐QD‐BQCA‐ODA‐NPs was assessed on RBC and SHSY‐5Y cell lines. Further the application of PS80‐QD‐BQCA‐ODA‐NPs was assessed by in vivo imaging and behavioural studies on STZ induced mice models of AD.

Result

The formation of BQCA‐ODA conjugate formation was confirmed 13C‐NMR, 1H‐NMR, LC‐MS. The optimized PS80‐QD‐BQCA‐ODA‐NPs were found to have a near spherical shape with a particle size (PS) of 152.62 ± 1.82 nm, zeta potential (ZP) of 18.59 ± 0.56 mV and polydispersity index (PDI) of 0.214±0.08. PS80‐QD‐BQCA‐ODA‐NPs. The NPs shown improved brain permeability, with greater fluorescence intensity in mouse brains when compared to free QDs. In the in vivo efficiency studies PS80‐QD‐BQCA‐ODA‐NPs shown a significant improvement in memory in mice models.

Conclusion

The PS80‐QD‐BQCA‐ODA‐NPs nanomedicine was successfully prepared, thoroughly characterized and has shown theronostic benefits in AD mice models.
Information Communication Technology as Instrumental Activities of Daily Living for Aging‐in‐Place in Chinese Older Adults with and without Cognitive Impairment
Authors: Ho‐yin Lai Frank
Published: December 2022

Background

The capability in applying information communication technology (ICT) is crucial to older peoples’ functional independence of community living nowadays. The proper assessment of individuals’ capability of ICT application is the corner stone for the future development of telemedicine in our aging population.

Method

With recruitment of 300 participants of different functional and social background in home‐living, hostel‐living and care‐and‐attention home living; and through assessing individuals’ ability in instrumental activities of daily living and cognitive assessments, this study aimed at capturing the content validity and construct validity of the Advanced Instrumental Activities of Daily Living (AIADL scale) and to assess the ability of older peoples’ in applying ICT and how the functional and social background affects their independence in aging‐in‐place.

Result

The AIADL scale showed good test‐retest reliability and good‐to‐excellent internal consistency. In determining if the AIADL scale’s items measure various aspects of community living, exploratory factor analysis revealed a two‐factor structure with “home living and management” and “community living”. Validity analysis with the known‐groups method showed a high overall accuracy of prediction of individuals’ capability of independent living in the community.

Conclusion

The AIADL scale is a valid and reliable instrument to assess older adults’ ability in handling ICT as part of their instrumental activities in daily living. The scale can reflect older peoples’ capability in applying ICT. This instrument can serve as a reference in measuring individuals’ readiness in receiving tele‐medicine and their ability of aging‐in‐place.
Improving Early Detection of White Matter Degeneration in Aging and Dementia along the AD continuum
Authors: Moody Jason F , III Douglas C Dean , Kecskemeti Steven R , Johnson Sterling C. , Alexander Andrew L , Bendlin Barbara B.
Published: December 2022

Background

Diffusion tensor imaging (DTI) has been commonly used to characterize microstructural changes associated with aging and Alzheimer’s disease (AD) dementia. However, DTI ignores non‐Gaussian diffusion, which limits its ability to describe the more restricted diffusion present within cellular structures. Neurite Orientation Dispersion and Density Imaging (NODDI) and Mean Apparent Propagator (MAP) MRI are two alternative diffusion MRI (DWI) models which can be used to calculate parameters that better characterize alterations observed in tissue microstructure.

To investigate the sensitivity of DTI, NODDI, and MAP to white matter changes associated with aging and dementia, we examined the relationship between 15 DWI parameters, age, and AD clinical status in 418 aging adults along the AD continuum.

Methods

418 participants (328 cognitively unimpaired [CU], 60 Mild Cognitive Impairment [MCI], 30 AD) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged with multi‐shell DWI (Table 1). 15 DWI parameters were extracted from the cingulum, including 4 DTI (FA, MD, RD, AxD), 3 NODDI (ODI, NDI, ISO) and 8 MAP (RTOP, RTAP, RTPP, MSD, QIV, NG, NG||, NG⊥) metrics. All measures were fit to the following linear model:

Diffusion Metric = β0+β1
*(age)+ β2
*(sex)+β3
*(status)+β4*(age*status)+Ε

Results

DWI age trajectories and model parameters are provided in Figures 1‐2 and Tables 2‐4, respectively. 12 of 15 DWI metrics were significantly associated with age, including all 8 MAP measures. Additionally, 6 metrics were associated with AD and 8 were associated with MCI. The interaction between age and AD was significant for RTOP, NDI, FA, and AxD, while the interaction between age and MCI was significant for RTOP, RTPP, MSD, NG, NG⊥, ISO, MD, RD, and AxD (Pcorr = 0.05).

Conclusion

The significant effects of clinical status and interactions between age and clinical status, may indicate that these metrics are sensitive to microstructural alterations specific to dementia. Furthermore, the meaningful interactions between age and MCI in 5 of 8 MAP parameters suggests that MAP MRI may be particularly useful for detecting early WM degeneration along the AD continuum. Future work will translate this analysis to larger cohorts and assess MAP parameters in gray matter.
Speed of cognitive decline in biomarker stratified SCD subgroups
Authors: Jessen Frank , Kleineidam Luca , Wolfsgruber Steffen , Spottke Annika , Brosseron Frederic , Laske Christoph , Perneczky Robert , Schneider Anja , Wiltfang Jens , Teipel Stefan , Bürger Katharina , Priller Josef , Peters Oliver , Ramirez Alfredo , Boecker Henning , Heneka Michael T. , Wagner Michael , Duzel Emrah
Published: December 2022

Background

Subjective cognitive decline (SCD) is associated with an increased risk of cognitive decline and dementia, specifically in cases in the Alzheimer’s continuum (amyloid positive, A+). In the present study we tested, if further stratification with additional markers is useful for identifying fast progressors within SCD‐A+.

Method

The analysis is based on 170 SCD case of the multicenter memory clinic based DELCODE study in Germany. The following markers were used as predictors of cognitive decline: number of SCDplus criteria, CSF Aß42/Aß42, tTau, pTau181, APOE status and hippocampal volume. The outcome was the preclinical Alzheimer’s cognitive composite 5 (PACC5) over up to 5 years. Univariate and multivariate hierarchical regression models were calculated with continuous (a) and dichotomized (b) variables.

Result

In the univariate analyses significant or close to significant associations of Aß42/Aß42 (a:p = 0.012; b:p = 0.040), tTau (a:p = 0.034; b:p = 0.053) and pTau181 (a:p = 0.057; b:p = 0.019) with cognitive decline were observed. In the hierarchical model with continuous variables, only Aß42/Aß40 reached significance (p = 0.016); while dichotomized variables Aß42/Aß40 (p = 0,074) and pTau181 (p = 0.068) reached trend level significance.

Conclusion

Within SCD‐A+, those who are also pTau positive show greatest decline. This finding is in agreement with the concept of A+ and T+ indicating full Alzheimer’s disease pathology and is important for the design of clinical trials in SCD.
Impact of background strains and diet on metabolic profile in mouse model of Alzheimer’s disease
Authors: Kaur Harpreet , Dai Miko , Dunn Amy R , O'Connell Kristen MS , Hoffmann Brian , Kaczorowski Catherine C.
Published: December 2022

Background

Genetic background is known to significantly affect the behavioral and molecular phenotypes in mice and has been well documented over many disease areas including Alzheimer’s disease (AD). However, how different background strains and their interaction with environmental factors such as high fat diet (HFD) could have an impact on metabolic phenotypes in AD not known.

Method

To determine how genetic background, diet, sex and age contributes to the metabolic profile in AD, 2.5 months old male and females 5xFAD mice on C57BL/6J (B6) and B6D2 background were fed either normal chow diet, or 45% high‐fat diet till 6 or14 months of age and compared to their age matched non‐transgenic littermate controls. Blood plasma samples were collected and a four‐mode discovery metabolomics approach on a Q‐Exactive Orbitrap coupled to an ultra‐high‐performance liquid chromatography (UHPLC) system was used to analyze metabolic changes.

Result

Following the quality assessment of spectral data, the dataset contained a total of 21,746 features across C18 and HILIC columns run with negative and positive ionization. After further filtering for named metabolites, removing duplicates, and a Fragment Ion Search (FISh) Score > 10, a total of 3,199 unique metabolites with high confidence MS2 fragmentation remained. Using linear regression analysis on these unique metabolites, we found that diet has a substantial impact (of all the factors tested including diet, sex, age, background strain, genotype) on plasma metabolites in both the strains with and without 5XFAD genotype, both in positive and negative mode of C18 and HILIC columns. Further on examining the interactive effects of different factors, we found a stronger interaction effect of sex by diet on metabolic phenotype. Interestingly, background strain had a moderate influence on collective metabolites irrespective of sex and age of mice.

Conclusion

Our initial results suggest that HFD is a major factor in defining the metabolic profile in AD mice above background strain, that could affect AD pathophysiology. We are currently looking into various classes of metabolites altered following HFD feeding and performing metabolic pathway analysis to understand the underlying disease mechanisms.
Association Between Neuropsychiatric Symptoms and Blood‐Based Autoantibody Biomarkers
Authors: Emrani Sheina , DeMarshall Cassandra , Viviano Jeffrey , Godsey George , Sarkar Abhirup , Belinka Benjamin , Libon David , Nagele Robert
Published: December 2022

Background

Neuropsychiatric symptoms are frequently observed along the Alzheimer disease (AD) continuum. Recent research has shown that blood‐based biomarkers are able to identify early AD‐related pathological changes associated with (1) preclinical AD (before the onset of clinical/functional symptoms), (2) mild cognitive impairment (MCI; with clinical symptoms and relatively spared functional decline), and (3) AD (obvious clinical and functional symptoms). Evidence for the potential diagnostic utility of serum autoantibodies has been extensively studied. The purpose of this study is to explore whether blood levels of specific autoantibodies used in the diagnostic biomarkers panels are linked with specific behavioral changes observed along the AD continuum.

Method

Using a customized panel of three AD‐specific autoantibody biomarkers and Luminex xMAP® technology, sera from patients (n=46; female = 30, mean age = 73.4) from the Memory and Aging Program at Rowan University were analyzed. All patients, irrespective of diagnosis (cognitively normal, MCI, AD) were included. The Neuropsychiatric Inventory (NPI) was used to gather data pertaining to neuropsychiatric symptoms. Partial correlations, controlling for age and education, for each neuropsychiatric symptom was employed.

Result

Two of the three autoantibody biomarkers showed an association with neuropsychiatric symptoms. Biomarkers 2 and 3 both showed a significant correlation with total neuropsychiatric score (r= .255, p= .047; r= .345, p= .01, respectively). Delusions, hallucinations, depression, anxiety, and irritability symptoms were not associated with either biomarker. Biomarker 2 was associated with apathy (r= .365, p=.007), agitation (r= .345, p= .011), disinhibition (r=.316, p=.018), and appetite changes (r= .302, p= .023). Biomarker 3 was associated with elation (r= .328, p= .015), aberrant motor behaviors (r= .331, p=.014), sleep behaviors (r= .483, p=.001), and appetite changes (r= .372, p=.006).

Conclusion

Results demonstrate an association between neuropsychiatric symptoms often observed in the AD continuum and specific blood‐based autoantibody biomarkers using Luminex xMAP® bead‐based technology. The autoantibody biomarker panel serves as an accurate, non‐invasive, and inexpensive diagnostic screener for preclinical AD, MCI, and AD. These biomarkers can not only distinguish different stages of AD, typically diagnosed using cognitive/functional assessments, increased blood levels of specific autoantibody biomarkers are also associated with commonly observed neuropsychiatric features.
Automated Analysis of Written Language in the Three Variants of Primary Progressive Aphasia
Authors: Josephy‐Hernandez Sylvia E. , Rezaii Neguine , Jones Amelia , Hochberg Daisy , Quimby Megan , Wong Bonnie , Dickerson Bradford C.
Published: December 2022

Background

Despite the important role of written language in everyday life, abnormalities in functional written communication have been sparsely investigated in PPA.

Method

We developed a Python program which uses a language parser and quantifies content units (CU) and total utterances in language samples. The program was used to analyze written descriptions of the WAB Picnic scene, based on a pre‐defined CU corpus, from a cohort with 95 participants (20 controls, 28 nonfluent variant Primary Progressive Aphasia (nfvPPA), 30 logopenic variant (lvPPA), 17 semantic variant (svPPA)). We then compared written functional communication between the three PPA variants and controls. We analyzed the measurements in relation to aphasia severity (Progressive Aphasia Severity Scale Sum of Boxes (PASS SoB) and Clinical Dementia Rating Supplemental Language (CDR‐L) scores), and dementia severity (Clinical Dementia Rating Sum of Boxes (CDR SoB)).

Result

The reliability of the automated analysis was high as compared to manual scoring of 239 samples (99.6%). One‐way ANOVAs revealed patients with lvPPA and svPPA wrote fewer CU than controls (mean+/‐SD 11.97+/‐7.87 and 10+/‐4.5, vs 18.5+/‐9.32) (F(3, 91)=[4.897], p=0.003). There was a trend towards a decrease in CU in nfvPPA (13.89+/‐6.33) (p=0.144). Patients with all PPA subtypes (nfvPPA mean+/‐SD 34.64+/‐18.89; lvPPA 38+/‐24.54; svPPA 28.88+/‐20.36) wrote fewer total utterances than controls (61.7+/‐27.86) (F(3, 91)=[7.778], p<0.001). The CU/utterance ratio was higher in nfvPPA and svPPA than in controls and lvPPA (0.42+/‐0.14 and 0.43+/0.22 vs 0.3+/‐0.05 and 0.32+/‐0.12 respectively) (F(3, 91)=[5.592], p=0.001). Considering all PPA samples, regression analysis showed a decrease in CU relative to an increase in PASS SoB (R=0.24, p=0.04), CDR‐L (R=0.22, p=0.06), and CDR SoB (R=0.34, p=0.004).

Conclusion

As expected, we found impairments in informative written language in patients with PPA. Automated CU analysis is a tool that can improve assessment of functional written communication, and may be an objective tool to track aphasia progression. More studies are required to assess individual changes over time and whether these findings could be extrapolated to other forms of cognitive impairment.
Plasma pTau181 is associated with impaired cognition in the Old Order Amish and adds additional information beyond the known genetic risk factors for AD
Authors: Prough Michael B. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Dorfsman Daniel A. , Adams Larry D. , Laux Renee A. , Song Yeunjoo E. , Lynn Audrey , Fuzzell M. Denise , Fuzzell Sarada L. , Miller Sherri D. , Miskimen Kristy L. , Main Leighanne R. , Osterman Michael D. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Haines Jonathan L. , Scott William K. , Pericak‐Vance Margaret A.
Published: December 2022

Background

As plasma biomarker assays have become more widely available, they are increasingly being used to characterize AD and related dementias. The Old Order Amish are a cultural and genetic isolate in the US that have participated in genetic studies for decades. This study investigated plasma phosphorylated tau at threonine‐181 (pTau181) in an Old Order Amish cohort to determine if the association with cognitive status is reproducible in this population.

Method

Old Order Amish individuals over age 65 (n=467, mean age = 81.3, 60.6% female) in Indiana and Ohio were examined using a modified Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery. Each individual was assigned Impaired (n=155, mean age = 82.5, 56.8% female) or Unimpaired (n=312, mean age = 80.8, 62.5% female) cognitive status via consensus review of these examination results. The level of plasma pTau181 was measured using the pTau181 Advantage V2 assay from Quanterix. Genetic Risk Scores (GRS) were calculated using genome‐wide significant variants from Kunkle et al. (2019), weighted by log odds ratio estimates. A t‐test was used to compare plasma pTau181 levels between the Impaired and Unimpaired groups. Logistic regression was then used to model the contribution of age, sex, GRS, and plasma pTau181 on cognitive status.

Result

We found that the average level of plasma pTau181 was significantly higher in the Impaired group (2.46 pg/mL) compared to the Unimpaired group (2.01 pg/mL) at p<0.0001. A multivariable model found increasing age (OR=1.10, p=0.0002), male sex (OR=1.60, p=0.04), increasing GRS (OR=1.97, p<0.0001), and increasing plasma pTau181 (OR=1.46, p=0.001) associated with impaired cognitive status. The effect of GRS is mostly attributable to APOE.

Conclusion

The result of these analyses indicates that pTau181 is associated with impaired cognitive status in the Old Order Amish, adding additional information beyond the known genetic risk factors for AD.
Role of Vitamin D on cognitive performance among healthy volunteers of SANSCOG cohort
Authors: Lingegodwa Abhishek Mensegere , Giridhar Varsha , Bota Ragasudha , Ravindranath Vijayalakshmi
Published: December 2022

Background

Nutrients such as vitamin D play an important role in aging and dementia and evidence on the effect of vitamin D on cognition among healthy aging adults especially in rural India is sparse. Our aim was to observe the effect of vitamin D on cognition.

Method

Using a cross‐sectional study design we examined cognitive performance between vitamin D sufficient, vitamin D insufficient and vitamin D deficient groups among the cognitively healthy volunteers of SANSCOG cohort.

Result

Our analysis revealed that two thirds (74.5%) had suboptimal vitamin D levels (Insufficiency: 38.3% and Deficiency: 36.2%) and women were more affected than men. Vitamin D levels affected subject’s depression scores and diabetes status negatively, however no effect was found on cognitive performance.

Conclusion

It may be postulated that vitamin D plays an indirect role on cognitive performance. Large proportion of suboptimal vitamin D levels in the rural population warrants proactive public health measures.
Translational potential of JAX humanized APOE mice: Peripheral biomarkers of pathology
Authors: McLean John W. , Reyes‐Reyes Elsa M. , Bhattrai Avnish , Wiegand Jean‐Paul L. , Raikes Adam C. , Rodgers Kathleen E. , Brinton Roberta Diaz
Published: December 2022

Background

Alzheimer’s Disease (AD) drives the global rising incidence of neurodegenerative dementia. Disease progression includes cerebral aggregation of amyloid‐beta plaques and immune activation. Many AD animal models carry mutations that cause an early onset of these phenotypes, but the mutations are rare in human populations; most cases are idiopathic and late‐onset AD (LOAD). Another approach utilizing a transgenic APOE animal model may better model clinical populations. APOE4 is the predominant genetic risk factor for LOAD and confers increasing risk for LOAD in allelic fashion, relative to normative APOE3. This study investigates the JAX humanized APOE knock‐in mouse model of LOAD’s translational potential for peripheral biomarkers of pathology in aged, male and female mice.

Method

Aged mice of both sexes (23‐25 months old; 39M/37F) with APOE3/3,APOE3/4, andAPOE4/4 genotypes underwent blood plasma amyloid‐beta (Aß) measurement. A subset of these animals (30M/28F) additionally received peripheral immunophenotyping of whole blood via flow cytometry. Two‐way ANOVA and post‐hoc t‐tests were conducted to determine data significance.

Results

Female mice had lower Aß42 plasma levels as well as a decreased Aß42/40 ratio, suggesting higher levels of the aggregate‐prone Aß42 protein in the brain, but there were no observed APOE genotype effects. Blood plasma Aß40 levels did not differ by genotype or sex. Whole blood flow cytometry showed an elevation in CD8+ memory T cells in APOE4/4 mice relative to APOE3/3 andAPOE3/4 mice. Aged female mice had a peripheral immune cell profile consistent with a more reactive and dysfunctional immune system than genotype‐matched aged males: higher levels of CD11b+ B cells, CD4+ helper T cells, and CD8+ cytotoxic T cells along with a lower percentage of naïve CD4+ and CD8+ T cells.

Conclusion

In mice aged to resemble a ∼70‐year‐old human population, these results suggest increased brain levels of the aggregate‐prone Aß42 isoform and a reactive peripheral immune system in female APOE mice. This sex difference is consistent with the increased prevalence of LOAD in women. However, the specificity of APOE4 genotype effects may define the translational potential of this humanized APOE mouse model of late‐onset Alzheimer’s Disease.

Research supported by T32AG061897, R01AG057931, and RF1AG059093 to RDB.
Differential properties of Early vs. Late 18F‐Florbetaben imaging acquisition time frames
Authors: Johnson Aubrey S. , Smith Anna C. , Tomljanovic Zeljko , Ziaggi Galen , Roetman Andrew E. , Klein Julia , Keegan Richard , Honig Lawrence S , Kreisl William Charles
Published: December 2022

Background

18F‐Florbetaben (FBB) is a PET radioligand approved for determining binary amyloid status. According to the product label, FBB images may be acquired anytime 45‐130 minutes post injection. Protocols vary in the acquisition of FBB with respect to use of Early (50‐70 minutes‐post‐injection) or Late (90‐110 minutes‐post‐injection) frames. Identifying differences between Early and Late acquisitions of FBB data could aid in image interpretation and inform efforts towards harmonization across cohorts. We evaluated inter‐rater agreement of visual reads (VR) and differences in SUVR thresholds to characterize Early vs. Late frames.

Method

Fifty‐three subjects were studied including 23 patients meeting clinical criteria for amnestic mild cognitive impairment or mild Alzheimer’s disease and 30 cognitively normal controls. FBB images were acquired 50‐110 min post‐injection in 5‐min frames. Images were corrected for subject motion and separated into 50‐70 and 90‐110 min time windows. Three certified readers blind to cognitive status and time window provided a binary VR for each of the 106 data sets. Global standardized uptake value ratios (SUVRs) were calculated using a cerebellar gray matter reference. An ROC‐derived SUVR cut‐off value was determined for each window using a preliminary cohort (n=23) and evaluated in a larger cohort (n = 53).

Result

Inter‐reader agreement was similar in 50‐70 min and 90‐110 min scans, (Fleiss Kappa= 0.597 and 0.598). SUVRs from 50‐70 min and 90‐110 min scans were highly correlated (r = 0.99, p<0.0001). SUVRs were greater in visually positive than in visually negative scans for both time windows (Fig. 1; p<0.0001). SUVRs were still increasing at 50‐70 min but became but plateaued at 90 min. ROC‐derived SUVR cut‐off values (Fig. 1; SUVR50‐70=1.342, SUVR90‐110=1.524) largely agreed with the majority consensus VR (49/53; 92.5%) across both time frames.

Conclusion

Early and Late frame data were highly correlated, and both provided robust quantitative differences between visually positive and negative Ab groups. However, imaging at 90‐110 min provides more stable SUVRs and therefore is preferred for measuring longitudinal change in amyloid burden.
Assessing periadolescent memory ability and characterizing the development of a functional brain network vulnerable to Alzheimer’s disease
Authors: Behm Lillian , Phipps Connor J , Ramirez Meghan K , Sexton Jennifer N , Heller Abi M , Zatkalik Abigail L , Nickolas Kristen , DeCesare Thomas A , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E
Published: December 2022

Background

In typically presenting Alzheimer’s disease (AD), pathological changes to the hippocampus (Hc) and its associated functional brain networks result in impaired declarative/relational memory. While it is known that risk factors for AD (genetic, environmental, etc.) can impact hippocampal resting‐state functional connectivity (RSFC) later in life, the development of the hippocampus and its connections to other brain regions may also be influenced by such risk factors. The goal the current study was to characterize the neurodevelopmental changes in this hippocampal network during the periadolescent epoch and determine whether the observed changes were associated with declarative/relational memory ability. Therefore, we utilized a cross‐sectional approach to test whether individual differences in hippocampal RSFC covary with outcomes on a test of relational memory ability in periadolescent children.

Method

Data were drawn from an ongoing NIA‐funded project: the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. Our analysis was carried out using data from healthy periadolescent participants (N=90; age 8‐13 years). We assessed declarative/relational memory with Cambridge Cognition’s Paired Associates Learning (PAL) task. To conduct the resting‐state functional MRI analyses, we used a seed‐based approach with the bilateral hippocampus as the seed region of interest. We then analyzed the hippocampal RSFC data to and assessed covariance of individual patterns of hippocampal RSFC with memory performance measured with the PAL task.

Result

Our preliminary findings, largely consistent with previous work, demonstrate patterns of hippocampal RSFC sharing territory with the ventral and lateral portions of the default mode network (DMN). In addition, we observed evidence of regional covariance between hippocampal RSFC and PAL task performance.

Conclusion

The preliminary findings of the ongoing PRANK study indicate that hippocampal RSFC covaries regionally with hippocampal‐dependent memory ability in periadolescent children. Future work from the PRANK study aims to understand whether genetic and polygenic risk factors for AD influence this hippocampal network development. To do so, we will utilize participants’ AD polygenic risk scores, and determine whether those scores are related to individual differences in hippocampal RSFC.
Antisense oligonucleotides targeting miR‐29b binding site increase translation of progranulin protein: potential therapeutic strategy for progranulin‐deficient frontotemporal dementia
Authors: Aggarwal Geetika , Banerjee Subhashis , Jones Spencer A. , Pavlack Monica , Benchaar Yousri , Bélanger Jasmine , Sévigny Myriam , Smith Denise M. , Niehoff Michael L. , de Vera Ian Mitchelle S. , Petkau Terri L. , Leavitt Blair R. , Ling Karen , Jafar‐nejad Paymaan , Rigo Frank , Morley John E. , Farr Susan A. , Dutchak Paul A. , Sephton Chantelle F. , Nguyen Andrew D.
Published: December 2022

Background

GRN mutations cause frontotemporal dementia (FTD) due to haploinsufficiency of progranulin. Several microRNAs (miRs), including miR‐29b, have been reported to negatively regulate progranulin protein levels. Here, we tested if antisense oligonucleotides (ASOs) – which are versatile modulators of target mRNA/protein levels – can be used to increase progranulin levels by sterically blocking the miR‐29b binding site.

Method

We designed 48 ASOs targeting the miR‐29b binding site in the 3’ UTR of the human GRN mRNA. We treated H4 neuroglioma cells and iPSC‐derived neurons with these ASOs and subsequently measured progranulin protein levels by western blot and ELISA. We performed further studies to determine the mechanism of action of these ASOs using ribosomal profiling, metabolic labeling, and FRET assays.

Results

We identified 16 ASOs that increased progranulin protein levels in a dose‐dependent manner. Ribosomal profiling experiments revealed that cells treated with ASOs had marked enrichment in GRN mRNA in heavy polyribosome fractions, compared to cells treated with a scrambled control ASO, suggesting that the ASOs increase the rate of progranulin translation. Consistent with this, ASO treatment resulted in increased levels of newly synthesized progranulin protein. FRET‐based assays showed that ASOs can effectively compete miR‐29b from its binding site in the GRN 3’ UTR RNA under in vitro conditions.

Conclusions

Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This strategy may be therapeutically feasible for progranulin‐deficient FTD as well as other conditions of haploinsufficiency.
Non‐invasive quantification and SUVR validation of [18F]‐florbetaben with total‐body EXPLORER PET
Authors: Holy Emily Nicole , Fan Audrey P. , Alfaro Evelyn Rebekha , Fletcher Evan , Spencer Benjamin A. , Cherry Simon R. , DeCarli Charles S.
Published: December 2022

Background

Kinetic modeling of brain amyloid deposition with [18F]‐florbetaben more accurately quantifies the binding density to amyloid plaques compared to standardized uptake ratios (SUVR) (Becker, JNM2013). The total‐body EXPLORER PET scanner with an axial field of view of 194cm supports the acquisition of a full human body in one scan and permits noninvasive Image‐Derived Input Functions (IDIFs) as an alternative to arterial blood sampling (Badawi, JNM 2019). Our aim is to quantify amyloid buildup with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and validate with SUVR in an elderly cohort.

Method

Twelve adults aged 66‐86 underwent dynamic total‐body 18F‐florbetaben PET for 110min, spatial resolution = 2.344mm, average tracer dose = 299.70 MBq. 8 cognitively‐normal, 3 Mild Cognitive Impairment (MCI), and 1 Alzheimer’s disease (AD). Regions of interests were drawn in the middle descending aorta and eroded to exclude the vessel walls to derive IDIFs (Fig.1). Next, regional brain analysis including PET image matching to previously acquired T1‐weighted MRI, normalization, and segmentation were performed in PMOD (v4.2) using the AAL atlas. PET SUVR (90‐110min) means were calculated from 7 index regions (lateral frontal, medial frontal, anterior cingulate, posterior cingulate, lateral temporal, lateral parietal, and precuneus) and the cerebellar gray matter. Dynamic time activity curves (TACs) from the same brain regions were fit to the two‐tissue compartment model (2TCM) using population metabolite‐corrected IDIFs; and the Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).

Result

Amyloid‐positive patients showed the highest SUVR in brain index regions (Fig.2). High quality dynamic kinetic modeling was achieved (Fig.3), with high SUVR accumulation in index regions compared to cerebellum at later time points in amyloid‐positive cases. SUVR and DVR from kinetic models were strongly correlated; with slight overestimation of SUVR compared to DVR (Fig.4). DVR values from the MRTM were lower than (86.7% of) DVR quantified by 2TCM.

Conclusion

Absolute quantification of amyloid binding from total‐body [18F]‐florbetaben PET data is feasible using aorta IDIFs with high agreement between dynamic binding parameters compared to SUVR in discriminating positive and negative scans.
Fine‐mapping of chromosome 9p21 linkage in Puerto Rican Alzheimer disease families.
Authors: Celis Katrina , Rajabli Farid , Simon Shaina A , Wang Liyong , Hamilton‐Nelson Kara L. , Adams Larry D. , Mena Pedro Ramon , Whitehead Patrice L. , Van Booven Derek , Feliciano‐Astacio Briseida E. , Chinea Angel , Feliciano Nereida I , Acosta Heriberto , Dalgard Clifton L. , Haines Jonathan L. , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A.
Published: December 2022

Background

We previously reported strong linkage on chromosome 9p21 in multiplex Alzheimer disease (AD) families from Puerto Rico. Nine families had the highest linkage contribution. 3/9 families shared seven coding variants with displayed evidence for AD association in similar ancestral. Although these variants reside in genes with neuronal expression and functionality, they do not explain the linkage signal in all families. Here, we performed a fine‐mapping analysis to identify non‐coding variants that can contribute to the AD trait previously observed.

Method

We analyzed whole genome sequencing (WGS) from 9 families, 43 AD and 15 cognitively intact individuals. Chromatin interaction and cis‐regulatory element (CREs) were used to prioritized relevant non‐coding variants. Induced pluripotent stem cells (iPSC) derived neurons were generated from five individuals for characterization.

Result

We found an average of 300,000 non‐coding variants per family. Following filtering steps including segregation, allele frequency and chromatin association, we identified ∼400 variants per family. These variants were analyzed using the CREs derived from ENCODE, which left us with 31 (8%) variants falling in promoters. 5/31 variants were shared among four or more families, and fall in the promoter of genes FBXO10, ACO1, NDUFB6 and DNAJA1. Six families shared variants in FBXO10 making it our top candidate gene, a F‐box protein family with a role in apoptosis and immunity. Interestingly, another F‐box protein (FBXL7) has been associated with AD in a Caribbean Hispanic population.

Conclusion

These results reiterate the importance of family‐based studies and fine‐mapping as a resourceful tool to identified functional variants in AD. Transcriptomic profile and functional characterization of iPSC derived neurons will aid to understand the implication of prioritized genes in the linkage association previously observed.
Identifying context‐specific genetic variants and molecular pathways associated with resilience to Alzheimer’s disease in the induced immune response
Authors: Mustafa Yousef , Naj Adam C. , Bush William S. , Below Jennifer
Published: December 2022

Background

Neurodegenerative pathologies consistent with Alzheimer’s disease (AD) are common in older adults even among those without cognitive symptoms. Genome‐wide association studies (GWAS) have identified loci associated with better‐than‐predicted cognitive performance for a given level of neuropathology, described as resilience to AD symptoms. Transcriptome‐wide association studies (TWAS) provide powerful mechanistic insights bridging the association between loci and phenotype by implicating genes. We hypothesize that genetic variants influence resilience phenotypes by altering the function and response of monocytes, one of the premier immune cells involved in neuroinflammation. Moving to test this hypothesis, we have developed monocyte TWAS reference panels based on expression from a naïve state and following in vitro stimulations which can reveal important associations only seen in an inflammatory context.

Methods

Genetic data of monocytes produced by Fairfax et. al 2014 were obtained and SNPs imputed on the Michigan Imputation Server using samples available on the Haplotype Reference Consortium. Plink 1.9 was used for standard quality control. Corresponding monocyte expression data was downloaded from ArrayExpress, and a custom script was used to extract probes not overlapping with regions containing common SNPs (MAF > 0.05) and mapping to single genes. Cis‐eQTL analysis was then performed using the MatrixeQTL R package, and final gene expression prediction panels constructed by fitting elastic‐net regularized regression models using the PredictDB pipeline.

Results

Our pipeline has been validated through showing concordance between our results and those of the Fairfax group with respect to the rs1179625 SNP and its context‐specific direction of effect on the gene expression of HIP1. Further, genotype imputation enabled the identification of thousands of additional eQTLs and response‐eQTL’s (re‐eQTL’s) across the genome—illustrating the importance of studying these cells in an appropriate environment. TWAS analyses of their collective impact on resilience phenotypes are ongoing.

Conclusion

We expand the available tissues and cell types for TWAS of AD by generating reference panels that account for the dynamic biology of monocytes in different states. These panels enable analyses that may have specific importance for cognitive resilience, and may provide concrete biological mechanisms as to how some individuals can manifest the neuropathology of AD and yet remain asymptomatic.
Association of Retinal Nerve Fiber Layer Thickness with Plasma pTau181 and Aβ42/Aβ40 ratio
Authors: Mathew Sunu , WuDunn Darrell , Mackay Devin , Dage Jeffrey L. , Russ Kristen A , Blennow Kaj , Zetterberg Henrik , Vosmeier Aaron , Tallman Eileen F. , Deardorff Rachael , Harris Alon , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. , Risacher Shannon L.
Published: December 2022

Background

The eye has been considered a ‘window to the brain’ and to several neurodegenerative brain disorders including Alzheimer’s disease (AD) that display alterations in the eye, especially the retina. Plasma levels of AD biomarkers, including pTau181 and Aβ42/Aβ40 ratio are significantly altered in AD patients. We sought to evaluate the association of peripapillary retinal nerve fiber layer (RNFL) thickness measured using optical coherence tomography (OCT) with plasma levels of pTau181 and the Aβ42/Aβ40 ratio.

Method

Participants (78; 21 mild cognitive decline/AD, 27 subjective cognitive decline and 30 cognitively normal) underwent ophthalmological evaluation including OCT and a blood sample. Single molecule array (Simoa) assays were used to measure plasma concentrations of pTau181, Aβ42, and Aβ40 at the University of Gothenburg. Partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary retinal nerve fiber layer (RNFL) with plasma level of pTau181 and the ratio of Aβ42/Aβ40.

Result

Plasma pTau181 was significantly associated with RNFL thickness in the superior quadrant of the retina in the right eye (rp=‐0.300, p=0.025) and showed a trend towards an association with mean RNFL thickness of the right eye (rp= ‐0.226, p=0.094). Plasma Aβ42/Aβ40 showed a significant positive association with nasal RNFL of the right eye (r=0.312, p=0.027), as well as a negative association with RNFL thickness in the temporal quadrant of both eyes (right: r=‐0.324, p=0.022; left r=‐0.325, p=0.021).

Conclusion

The majority of the sample was cognitively normal or mildly impaired, suggesting that RNFL thickness may be a useful tool for early diagnosis of AD‐related pathophysiology. Future longitudinal studies in larger samples and evaluating the utility of combining retinal and plasma biomarkers for predicting future progression to AD are needed.
Analysis of Alzheimer Disease Plasma Biomarker pTau‐181 in Individuals of Diverse Admixed Ancestral Backgrounds
Authors: Grimmer Timo , Rajabli Farid , Garcia‐Serje Catherine , Arvizu Jamie , Larkin‐Gero Emma , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Adams Larry D. , Contreras Maricarmen , Sanchez Jose Javier , Tejada Sergio , Mena Pedro Ramon , Starks Takiyah D. , Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela , Silva‐Vergara Concepcion , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E. , Byrd Goldie S. , Beecham Gary W. , Haines Jonathan L. , Pericak‐Vance Margaret A.
Published: December 2022

Background

Plasma proteins, including phosphorylated threonine‐181 of Tau (pTau181) are used as biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, observation and measurement of these biomarkers are mostly from individuals of non‐Hispanic, European ancestry. Given differences in AD risk, generalizability of these findings is not assured in individuals of diverse ancestry. This study evaluates the utility of plasma pTau181 in discriminating clinically diagnosed AD from cognitively intact, age‐matched controls in ancestrally diverse, admixed cohorts.

Method

We measured pTau181 with Simoa chemistry using the pTau181 AdvantageV2 on the Quanterix HD‐X. Our cohorts consisted of 642 African Americans (162 AD and 480 controls), 906 Puerto Ricans (385 AD and 521 controls), 149 Peruvians (49 AD and 100 controls), 60 Cubans (26 AD and 34 controls), 246 individuals of non‐Hispanic, European ancestry (22 AD and 224 controls), and 58 autopsy confirmed AD cases of European ancestry with plasma isolated from EDTA blood tubes. Samples were randomized, measurements performed in duplicate, and non‐parametric Kruskal‐Wallis tests used to detect differences in biomarker concentrations between cases and controls in each cohort.

Result

Median pTau levels in cases was higher than controls in all cohorts assayed: African Americans (2.30±1.14pg/mL vs 1.15±2.99pg/mL, pcorr=2.0x10‐27); Puerto Ricans (2.33±1.82pg/mL vs 1.44±1.21pg/mL, pcorr=8.2x10‐32); Peruvians (2.63±1.64pg/mL vs 2.13±1.42pg/mL, pcorr=0.02); Cubans (2.09±1.16pg/mL vs 1.35±0.67pg/mL, pcorr=0.02); and European ancestry (2.40pg/mL±0.78pg/mL vs 1.54pg/mL ±1.44pg/mL, pcorr=0.02). The pTau levels in the autopsy confirmed cases (2.96±2.29 pg/mL) were not significantly higher than AD cases in the other ancestries.

Conclusion

This study suggests pTau181 as a biomarker is generalizable across genetic ancestries, though potential sex and age effects remain to be determined. Ultimately, combining genomic and biomarker data, including pTau181 and other AD related plasma biomarkers such as Aβ40 and Aβ42, from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries.