bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative stress biomarkers and longitudinal changes in human brain imaging across the Alzheimer’s disease continuum
Authors: Willette Auriel A , Li Tianqi , Willette Sara A , Larsen Brittany A , Pollpeter Amy , Klinedinst Brandon S , Moody Shannin , Barnett Neil , Parvin Mohammadiarvejeh , Pappas Colleen , Jonathan Mochel , Allenspach‐Jorn Karin , Wang Qian
Published: December 2022

Background

Oxidative stress is critical for Alzheimer’s disease (AD) pathophysiology. Brain mitochondrial function, proteins, and lipids are susceptible to oxidative damage caused by reactive oxygen species. In turn, this damage leads to key AD‐like changes in the brain, such as impaired glucose metabolism (i.e., lower fluorodeoxyglucose, or FDG‐PET) and gray matter volume atrophy in AD‐sensitive regions. It is unknown if oxidative stress biomarkers like superoxide dismutase (SOD) proteins track these changes using longitudinal brain imaging data, and what mechanisms may be at work (Figure 1).

Method

Using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, 192 aged adults (75 unimpaired, 48 MCI, 69 AD) had annual CSF and FDG data available for over 6 years. A two‐phase MRM targeted proteomics panel was used to gauge CSF SOD1 levels from serum. Standard assays in CSF determined Aβ, p‐tau‐181, and total tau. Brain glucose uptake was determined using FDG SUVR calibrated to the pons. Brain volume was examined longitudinally using FreeSurfer.

Result

Longitudinally, among SOD1 quartiles (Figure 2), the lowest SOD1 group showed marked hypometabolism among older adults at baseline (R2=0.528, p<.001, “blue line”), but 6 years later instead predicted hypermetabolism (R2=0.389, p<.001). The highest SOD1 group showed no association at baseline but at 6 years later predicted hypometabolism among older adults (R2=0.151, p<.05, “dotted red line”). CSF Aβ and p‐tau‐181 fully mediated these effects (ps<.01), such that lower Aβ and higher p‐tau‐181 over time resulted in higher SOD1 predicting less glucose uptake. Similarly, higher SOD1 was not related to atrophy in AD‐sensitive regions like parahippocampus at baseline, but 5 years later was strongly related to more brain atrophy (R2=0.207,p<.001) (Figure 3), which was mediated by higher CSF total tau (p<.001).

Conclusion

Like previous reports, we found that SOD1 initially showed neutral or ameliorative patterns, reflecting its classical role in reducing oxidative stress. With increased Aβ or p‐tau‐181 deposition over time, however, SOD1 became a marker of the degree of oxidative damage that may have occurred in neural tissue due to Aβ or tau.
Non‐invasive brain stimulation causes anxiolytic effect in intracerebroventricular streptozotocin injected rats through prevention of serotonergic fibres in dorsal hippocampus
Authors: Roy Avishek , Sharma Binney , Nag Tapas Chandra , Gupta Yogendra Kumar , Jain Suman
Published: December 2022

Background

Intracerebroventricular streptozotocin (ICV‐STZ) injection at 3mg/kg of b/w is reported to induce sporadic Alzheimer disease (sAD) like pathology, where it causes an insulin resistance brain state. Synaptic dysfunction along with glial aggravation poses major risk factor for sAD. Brain stimulation evinced to be promising in AD patients, however, mechanism of the same in the form of magnetic field (MF) stimulation are elusive.

Method

Total 55 rats were recruited and randomly divided into five groups: Control, Sham, AD, Sham+MF, AD+MF. Animals were provided with ad libitum food and water, experiments were performed under permission from IAEC (file no. 937/IAEC/2016). Rats were exposed to 17.96µT for 2hr/day for 30 days and at end elevated plus maze task was performed. Next, transmission electron microscopy(TEM), Golgi‐Cox staining was done on hippocampal sample. In addition, GPx activity and serotonin was measured in hippocampal homogenate.

Result

Reduction in ratio of time spent in close versus open arm in AD group as compared to Sham (p<0.001), Sham+MF (p<0.01) and AD+MF (p = 0.008). In continuation, head dipping duration was also reduced significantly in AD group as compared to control (p = 0.008), Sham+MF (p = 0.03) and AD+MF (p = 0.001). We found a loss of spine density in apical dendrite of with invasion of ramified microglia in neurovascular‐unit in dCA1 layer of AD group versus control (p<0.0001) and AD+MF(p = 0.004). TEM examination of hippocampal samples, we found invasion of ramified microglia in NVU as well as loss of synaptic density. Furthermore, GPx activity was found to be decreased in AD group (p<0.05) versus other counterparts on 30th day post‐injection of STZ. Similarly, serotonin was depleted in AD group as compared to other groups (p<0.05). In addition, results showed a strong correlation between head dipping duration and serotonin level in AD group on 30th day post‐injection of STZ (r = 0.7;p = 0.02).

Conclusion

Hence, this work reveals that MF stimulation to have anxiolytic effect through replenishing the synaptic dysfunction and serotonin loss in dorsal CA1 pyramidal cells of hippocampus in ICV‐STZ model of sAD.
Potential Bio‐signal Links between Alzheimer’s Disease and Osteoporosis
Authors: Lee Ji‐Won , Lee In‐Hee , Iimura Tadahiro , Kong Sek Won
Published: December 2022

Background

Low bone mineral density is associated with the development of Alzheimer’s disease (AD). The patients with AD have an early‐onset bone loss with a rapid progression before cognitive symptoms appear. Yet the pathophysiological relationship is not well understood between two clinical conditions. Microglia and osteoclasts share developmental origins and are commonly classified as tissue‐specific macrophages in brain and bone, and are responsible for pathological changes in AD and osteoporosis, respectively. Interestingly, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), caused by mutations in TREM2 or DAP12 genes, present bone pathology followed by presenile dementia.

Method

To further discover genetic correlations between AD and osteoporosis, we constructed comprehensive network of signaling pathways for microglia and osteoclasts.

Result

We discovered that an intracellular kinase, Pyk2 encoded by the PTK2B gene in microglia and osteoclasts in brain and bone, respectively, is a pleiotropic mediator of shared genetic risk factor for AD and osteoporosis. Pyk2, a non‐tyrosine kinase that regulates cytoskeleton rearrangement, is one candidate that is potentially related to both the progression of both AD and osteoporosis, as it is specifically expressed within the central nervous system and in bone tissue.

Conclusion

Our findings indicate that Pyk2 may be eligible for horizontal pleiotropy as genetic variants in PTK2B increase the risk of two traits, and thus we suggest that Pyk2 has potential as a novel diagnostic and therapeutic biomarker for AD.
A transcriptomic study reveals beneficial effects of HsTX1[R14A] on the cognition of a mouse model of sporadic Alzheimer’s disease
Authors: Pan Yijun , Sun Jiaqi , Deveson Deanna , Mamo John CL , Takechi Ryu , Norton Raymond , Jin Liang , Nicolazzo Joseph
Published: December 2022

Background

Neuroinflammation is a key pathological feature of Alzheimer’s disease (AD), which can be partly attributed to the chronic activation of microglia. The voltage‐gated potassium channel 1.3 (Kv1.3) is selectively upregulated in pro‐inflammatory microglia, making it an ideal therapeutic target to modulate microglia‐mediated neuroinflammation. A highly potent and selective Kv1.3 blocker (HsTX1[R14A]) developed in our laboratory can effectively suppress neuroinflammation. More importantly, chronic subcutaneous dosing of HsTX1[R14A] (1 mg/kg every 2 day) over 8 weeks improved cognitive function in a mouse model of sporadic AD, senescence accelerated mouse‐prone 8 (SAMP8). The current transcriptomic study is to explore the therapeutic benefits in the SAMP8 mouse brains from chronic dosing of HsTX1[R14A].

Method

Subcutaneous dose of HsTX1[R14A] (1mg/kg every 2 day) or PBS was administered to 4‐month‐old SAMP8 mice for 8 weeks (n = 6 each). At the conclusion of treatment, mice were euthanized and RNA from the brains were extracted using RNeasy Lipid Tissue Mini Kit (Qiagen). RNA samples were processed using an MGI RNA Directional Library Preparation Set V2. Fastq files were processed using the Laxy tool and the NfCore/RNAseq (v3.2) pipeline. Reads were aligned to the Mus musculus GRCm38 reference using STAR aligner and quantified using Salmon producing the raw genes count matrix. Raw counts were then analyzed with Degust and functional enrichment analysis was performed using R packages.

Result

Functional enrichment analysis indicated an upregulation of genes associated with 1) synapse assembly, neuronal synaptic plasticity for biological process; 2) postsynaptic neurotransmitter receptor activity, glutamate receptor activity for molecular function; 3) presynaptic active zone, NMDA selective glutamate receptor complex for cellular component. A downregulation of genes associated with 1) oxidative phosphorylation, ATP synthesis coupled electron transport for biological process; 2) chemokine activity for molecular function; 3) mitochondrial proton transporting ATP synthase complex for cellular component have also been highlighted.

Conclusion

Overall, the transcriptomics data indicated beneficial effects of HsTX1[R14A] on cognition in a mouse model of sporadic AD, possibly achieved by improving synaptic function, altering cellular metabolism, and reducing inflammation. Further experiments are required to confirm the current transcriptomics study.
Prevalence of Suspected non‐Alzheimer’s disease pathophysiology across the Alzheimer’s disease clinical spectrum: a meta‐analysis
Authors: Vos Stephanie J. B. , Delvenne Aurore , Visser Pieter Jelle
Published: December 2022

Background

Suspected non‐Alzheimer’s disease pathophysiology (SNAP) is a heterogeneous biomarker‐based concept that describes individuals with neurodegeneration without amyloid pathology. Our aim was to perform a meta‐analysis of all available SNAP studies to better estimate the prevalence of SNAP based on different definitions across the Alzheimer’s disease (AD) clinical spectrum.

Method

A search in PubMed was performed to identify all papers on SNAP. From these papers, we extracted the prevalence of persons with SNAP, biomarker negative persons and amyloid positive persons. We performed a meta‐analysis on overall SNAP prevalence by cognitive status and compared different SNAP definitions according to ATN biomarker classifications. In persons without dementia, we examined SNAP prevalence based on imaging versus CSF definitions and investigated differences in sex and APOE‐e4 carriership. We used R packages meta and metafor.

Result

We included 47 papers with SNAP across the AD clinical spectrum. Table 1 presents SNAP prevalence by cognitive status, compared to the prevalence of other biomarker groups. Overall prevalence of SNAP was 19.6% (95% CI 16.3‐23.2) in persons with normal cognition (NC), 15.6% (12.3‐19.3) in persons with mild cognitive impairment (MCI), and 10.1% (5.5‐15.8) in persons with dementia. In persons with NC, SNAP based on tau only (A‐T+N‐) was most common (36%) and SNAP based on both tau and neurodegeneration (A‐T+N+) least common (21%). In persons with MCI or dementia, SNAP based on neurodegeneration only (A‐T‐N+) was most common (MCI 39%, dementia 34%) and SNAP based on tau only least common (MCI 20%, dementia 7%). In persons without dementia, a similar SNAP prevalence was observed between imaging and CSF biomarker definitions (NC 19 vs. 20%, MCI 18 vs. 12%). Yet, persons with NC‐SNAP using imaging‐based definitions were more often male and less often APOEe4 carrier as compared to NC‐SNAP using CSF‐based definitions (imaging: male 54% and APOEe4 16%; CSF: male 41% and APOEe4 34%).

Conclusion

SNAP is common across the AD clinical spectrum. In persons without dementia, CSF and imaging definitions of SNAP resulted in a similar prevalence but in differences in sex and APOE‐e4 carriership in NC‐SNAP. Findings are valuable for AD trial design and clinical diagnostics.
Developing a bioprinted scaffold‐based model of neurodegeneration for high throughput screening in Drug Development
Authors: Whitehouse Chloe Ann , Corbett Nicola J
Published: December 2022

Background

A major component of the failure to bring novel drugs for Alzheimer’s disease (AD) to market is the translational gap between in vitro, animal and human studies. Using the novel technology of 3D bio‐printing, this project aims to develop a scaffold‐based 3D quad‐culture model of AD for drug screening using human induced pluripotent stem cells.

Method

A cell‐hydrogel suspension is “printed” onto 96‐ and 394‐well plates using a 3D bioprinter, which uses drop‐on‐demand technology to allow high resolution placement of the cells. The culture is suspended in a hydrogel of extracellular matrix proteins, which has been modulated to mimic brain biomechanics.

Result

Protocols to differentiate human neural progenitor cells into cortical neurons, astrocytes and oligodendrocytes have been established from AD mutation lines and healthy controls which express desired markers. These cell types, alongside iPSC‐derived microglia, will form the quad‐culture of cells within the model.

Conclusion

This model will exercise the benefits of a 3D model, while maintaining the benefits of 2D systems, including reproducibility, reliability, and suitability for high throughput screening.
Intrathecal pseudodelivery of Ab‐mAb alleviates pathology in an Alzheimer’s disease model
Authors: Menendez‐Gonzalez Manuel , Vilcapoma Almudena Coto , Silgado Juan Castilla , Alvarez‐Vega Marco , Antuña‐Ramos Aida , Fernandez‐Garcia Benjamin , Prado Catuxa , Alvarez Gabriel , Rodriguez Maria , Perez Ester , Tomas‐Zapico Cristina
Published: December 2022

Background

Intrathecal pseudodelivery is a new route of drug delivery to the CNS based on an implantable device endowed with a smart system of nanoporous membranes. We have developed a miniaturized prototype of the device for rodents. Here we present preliminary results on the use of antiAbeta mAbs intrathecally pseudodelivered in the APP/PS1 mouse model of Alzheimer’s disease.

Method

28‐week‐old male mice, APP/PS1 and non‐transgenic were used. The device was implanted subcutaneously in the back of the mouse and connected to one of the lateral ventricles via a catheter, also subcutaneous. The reservoir of the devices was filled with artificial CSF (aCSF) or with a solution of anti‐amyloid beta (Ab) antibody (clone 6E10, Biolegend) in aLCR. The infusion period was three weeks, during which animal welfare aspects were assessed. After this time, the mice were sacrificed for histopathological evaluation. All procedures were performed in accordance with institutional guidelines approved by the Ethical Committee in Research of Universidad de Oviedo.

Result

Safety: The device was successfully implanted in a total of 18 mice. Three mice showed complications 3 days after surgery, including lethargy and significant weight loss. This could be due to the surgery itself or to the post‐operative medication. The rest of the mice recovered perfectly and returned to normal activity 4 days after surgery.

Efficacy: Immunohistochemistry was performed to assess the size of Ab plaques, using a rabbit polyclonal anti‐Ab antibody (Invitrogen). The surface area occupied by the plaques in each of the APP/PS1 mice was determined. The results show a decrease in the area occupied by Ab‐positive plaques in the mice treated with the antibody. Although not statistically significant, there is a tendency for treated mice to have a smaller area occupied by plaques.

Conclusions

Our results show that:

• Intrathecal pseudodelivery of mAbs is a feasible route of drug delivery for neurodegenerative diseases.

• Intrathecal pseudodelivery of Ab‐mAb alleviates pathology in an Alzheimer’s disease model.

• Albeit preliminary efficacy and safety results are promising, further studies are needed.
Building a Dementia‐Capable Nursing Workforce
Authors: Vasquez Lyndsy , Schultz Melinda , Ishado Emily , Borson Soo , Sadak Tatiana
Published: December 2022

Background

Today’s undergraduate nursing students will play a pivotal role in caring for the rising numbers of older adults and people living with dementia (PLWD). Because current nursing training does not require dementia care competencies, new graduates may not be adequately prepared to care for this population.

Objective

This study aimed to capture students’ interest and intention to work with older adults and PLWD as a career path, and elicit their feedback on how best to structure educational and clinical training offerings that would attract them to this field. Long‐Term care (LTC) settings blend clinical and residential features in a comprehensive setting uniquely suited for teaching nursing students about dementia. Hence, we evaluated students’ interest in enrolling in a new elective rotation, the LTC Externship.

Methods

We designed and administered a survey and conducted a focus group. The survey consisted of 20 questions modified from the Dementia Attitude Scale and eight questions related to respondents’ health care experience and attitudes about nursing care for older adults, comfort working with PLWD, and willingness to further develop geriatric and dementia care skills. Focus group enrollment was limited to the first 8 participants who expressed interest and completed preliminary questionnaires.

Participants

First and second‐year Bachelor of Science in Nursing students at the University of Washington School of Nursing (SoN).

Results

Seventy Six of 223 (34%) students responded to the survey. The majority expressed low interest in working with older adults, as evidenced by the low survey response rate, low self‐reported knowledge of nursing care for PLWD, and a lack of desire to work with older adults after graduation. Among the eight focus group participants, six expressed interest in acquiring additional knowledge and hands‐on learning opportunities. Participants identified three specific training components that could attract students to geriatrics and LTC education: weekly structured seminars that reflect the depth of relevant scholarship; access to interactive, relevant pre‐study materials developed by clinicians; and 4‐6 hours per week of supervised paid, clinical training in hands‐on skills.

Conclusions

The findings informed the development of a LTC Externship at the UW SoN that is currently being piloted and evaluated.
Highly specific plasma β‐amyloid assays on the fully automated platform predict brain β‐amyloid pathology determined by a Centiloid threshold of amyloid PET
Authors: Yamashita Kazuto , Miura Masahiro , Watanabe Shunsuke , Ishiki Kengo , Arimatsu Yuji , Kawahira Junoko , Kubo Toshiko , Sasaki Katsutaka , Arai Takayuki , Hagino Kei , Irino Yasuhiro , Nagai Kota , Verbel David , Koyama Akihiko , Dhadda Shobha , Niiro Hayato , Iwanaga Shigeki , Sato Toshiyuki , Yoshida Tomokazu , Iwata Atsushi
Published: December 2022

Background

The U.S. Food and Drug Administration approved aducanumab for the treatment of Alzheimer’s disease (AD) under the accelerated approval pathway and several new drug candidates are currently in development or have been submitted for marketing authorization in the U.S. and other countries. Consequently, the necessity of pathological diagnosis of AD by confirming brain β‐amyloid (Aβ) pathology in routine clinical practice is increasing to ensure that appropriate AD patients can access these drugs. We reported the development of the fully automated plasma Aβ40 and Aβ42 immunoassays that showed high performance for predicting brain Aβ pathology defined by amyloid PET. Here, we present the effect of several markers on the performance of our plasma Aβ assays.

Methods

Plasma Aβ40 and Aβ42 levels were measured using a fully automated platform (HISCLTM series). To assess the performance of plasma Aβ42/Aβ40 ratio for predicting brain Aβ pathology, two studies (discovery and validation studies) were performed using plasma samples obtained from the elenbecestat phase 3 program. Brain Aβ pathology was determined by amyloid PET Centiloid scale. A cut‐off of Centiloid unit was determined as 32.21 by performing a receiver operating characteristic (ROC) analysis and determination of the Youden Index using visual reads as the standard. To evaluate the clinical performance of our assays, area under the curve (AUC) was obtained by performing a ROC analysis. The model, incorporating age and APOE ε4 status, was also evaluated.

Results

Plasma Aβ42/Aβ40 ratio predicted brain Aβ pathology defined by amyloid PET with AUCs of 0.93 and 0.92 in the discovery and validation studies, respectively. The sensitivity and specificity were calculated as 97.5% and 80.8% in the discovery study and 94.5% and 78.0% in the validation study. The model incorporating age and APOE ε4 status didn’t show significant improvement for predicting brain Aβ pathology.

Conclusions

Plasma Aβ42/Aβ40 ratio measured by our immunoassays achieved high accuracy to predict brain Aβ pathology, and age and APOE ε4 status didn’t contribute to improve the accuracy unlike most past reports from other groups. Our assays may contribute to a high‐throughput, less invasive diagnostic method for detecting brain Aβ pathology in routine clinical practice.
Sex and APOE‐ε4 carrier effects on early‐onset Alzheimer’s disease pathology
Authors: Logan Paige E. , Nemes Sára , Iaccarino Leonardo , Mundada Nidhi S. , La Joie Renaud , Aisen Paul , Dage Jeffrey L. , Eloyan Ani , Fagan Anne M. , Foroud Tatiana M. , Gatsonis Constantine , Hammers Dustin B. , Jack Clifford R. , Kramer Joel H. , Koeppe Robert , Saykin Andrew J. , Toga Arthur W. , Vemuri Prashanthi , Atri Alireza , Day Gregory S. , Duara Ranjan , Graff‐Radford Neill R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Sha Sharon , Turner Robert W. , Womack Kyle B. , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Bradford C. , Apostolova Liana G.
Published: December 2022

Background

Previously, we found that female sex is associated with greater pathology burden in early‐onset Alzheimer’s disease (EOAD) in the Longitudinal EOAD Study (LEADS). Here, we have expanded our analyses by adding APOE‐ε4 carrier status as a further predictor of EOAD pathologic burden.

Method

We included 180 EOAD LEADS participants with available APOE genotype, Flortaucipir PET, Florbetaben PET, and MRI data. Demographic and biomarker differences were analyzed using ANOVA. EOAD participants were split by sex and APOE‐ε4 carrier status. Box plots were created in R and a voxel‐wise multiple linear regression in SPM12 yielded statistical brain maps of gray matter density (GMD), amyloid and tau burden.

Result

Compared to males, EOAD females showed significantly greater global amyloid uptake (mean SUVR, p=0.002) and greater tau SUVR in the MetaROI, Braak 3&4 and 5&6 regions (p=0.0007, p=0.001, p=0.01, resp., Table 1). Female APOE‐ε4 carriers showed greater tau SUVR in Braak regions 1&2 than female non‐carriers (p<0.01, Figure 2B). Male APOE‐ε4 carriers showed trend‐level thinner entorhinal cortex than male non‐carriers (p=0.06, Figure 1). Interestingly however, femaleAPOE‐ε4 non‐carriers showed greater global amyloid SUVR than female carriers (p<0.01, Figure 2A). Further, APOE‐ε4 non‐carriers showed significantly thinner medial temporal cortices than carriers in both sexes (M, p<0.05; F, p<0.01). Male APOE‐ε4 non‐carriers also showed significantly lower mean cortical thickness than male carriers (p<0.05, Figure 1). Female APOE‐ε4 non‐carriers showed trend‐level lower mean cortical thickness than female carriers (p=0.06, Figure 1). The FWE corrected SPM12 maps showed significantly greater GM atrophy in the right temporal lobe and greater amyloid burden in a right lateralized occipitoparietal pattern in female APOE‐ε4 non‐carriers compared to female carriers. Further, male APOE‐ε4 non‐carriers showed greater tau uptake in the left frontal lobe than male carriers (Figure 3).

Conclusion

These results suggest that APOE‐ε4 non‐carrier status is associated with greater atrophy, amyloid and tau deposition in EOAD. This might be due to the presence of other strong genetic drivers of disease pathology in EOAD.
The feasibility of Goal Attainment Scaling in adults with Down syndrome: early results from the LIFE‐DSR‐GAS sub‐study
Authors: Dunn Taylor , Britton Angela , Chicoine Brian , Costa Alberto , Hendrix James A , Knox Kari , Lai Florence , Mobley William C , Rockwood Kenneth , Rosas H. Diana , Network The Down Syndrome Clinical Trials
Published: December 2022

Background

Adults with Down syndrome (DS) face a markedly increased risk of Alzheimer’s disease (AD). LIFE‐DSR is a 32‐month longitudinal study of adults with DS aiming to characterize and assess change in cognition, behaviour, function, and health. Goal Attainment Scaling (GAS) is a patient‐centric outcome measure. It evaluates change in goals that are meaningful to participants/caregivers and has proven a valuable and sensitive instrument in dementia clinical trials. To assess the feasibility of using GAS in the DS population and to better understand what is most important to them, the LIFE‐DSR‐GAS sub‐study is enrolling and following participants and their caregivers over 16 months.

Method

Participants with DS and their caregivers who consented to the LIFE‐DSR‐GAS sub‐study took part in an initial goal‐setting interview with a trained GAS rater to identify meaningful goal areas related to the participant’s condition. Change in these goals was then rated at two follow‐up interviews at 3 and 16 months. To aid in goal setting, a menu of 58 common DS‐AD goal areas was developed pre‐study through interviews with expert clinicians and caregivers. A secondary objective is to evaluate this menu in both its comprehensiveness and usefulness as a resource to improve GAS implementation in DS‐AD studies.

Result

To date, 31 (of 45) participants with DS and their caregivers have enrolled across three U.S. study sites. All participants have set three goals (the recommended minimum). The mean (standard deviation) time to conduct the interviews was 43.2 (7.5) minutes. 20 participants have completed a 3‐month follow‐up interview; the mean time taken was 18.2 (10.4) minutes. Most goals (83/93) set to date were selected from the DS‐AD menu. The most frequent goals concerned aspects of daily function: Household Chores (8 goals), Personal Care and Hygiene (8), and Meal‐Time Preparation and Activities (7).

Conclusion

Evaluating health outcomes in people with DS is challenging due to varying levels of baseline cognition and function, further complicated by the onset of dementia. There is a critical need for sensitive and valid measures that capture this heterogeneity. Our early data suggest that GAS may offer a feasible solution.
Preliminary results of computer‐based multimodal training in Alzheimer’s disease over six months – the multimodAAL study
Authors: Berger Martin , Schüssler Sandra , Zuschnegg Julia , Russegger Silvia , Paletta Lucas , Fellner Maria , Strobl Bernhard , Ploder Karin , Hofmarcher‐Holzhacker Maria , Stögerer‐Oberschmid Eva Maria , Guttmann‐Lattmanig Alexandra , Koini Marisa
Published: December 2022

Background

Alzheimer’s disease (AD) is associated with cognitive decline and limited therapeutic interventions to maintain cognitive function. The present study investigates the effectiveness of a computer‐based cognitive and physical training (CCPT) on a tablet device in patients with AD and aims to present preliminary results of the multimodAAL project (project number: FFG 875345).

Method

Twenty‐three patients were randomly assigned to intervention and control group (randomized controlled trial). The intervention group received weekly multimodal CCPT with a trainer and were encouraged to train as often as possible alone or with a caregiver over six months. At the time of data analysis 14 subjects had a 6‐month follow‐up with comprehensive pre and post neuropsychological assessment including tests on global cognitive functions (Mini Mental Status Examination, MMSE), memory, working memory, executive function and verbal fluency. Repeated measures ANOVA comparing neuropsychological test performance over time was calculated to determine the between‐group difference. Analyses were corrected for disease duration. Paired t‐test was used for post‐test analyses.

Result

In this preliminary analysis six subjects from the intervention group (4 female, age: x̅ = 75.4, disease duration: x̅ = 30.3 months) and eight subjects from the control group (7 female, age: x̅ = 74.8, disease duration: x̅ = 30.75 months) were included. The results showed a significant interaction effect considering global cognition and group with a high effect size (MMSE: F(1,11) = 7.503, p = 0.019, ηp
2 = 0.405). Post‐tests revealed a maintenance of performance in the intervention group (+0.68 points in the MMSE over 6 months, t(5) = ‐1.2, p = 0.300) and a significant decrease in the performance of the control group (‐1.34 points in the MMSE over 6 months; t(7) = 2.5, p = 0.041). The other cognitive domains did not show significant results.

Conclusion

These preliminary results indicate that CCPT over six months has the potential to maintain global cognitive functions in Alzheimer patients.
Plasma ratio of phospho‐ to non‐phospho‐tau at threonine 217 identifies brain amyloid burden as measured by quantitative amyloid PET in the PARIS sub‐study of IDEAS
Authors: Meyer Matthew R. , Kirmess Kristopher M. , Wente‐Roth Traci L. , Irvin Faith , Holubasch Mary S. , Verghese Philip B. , Monane Mark , Bateman Randall J. , Holtzman David M. , Venkatesh Venky , Fogelman Ilana , Yarasheski Kevin E. , Braunstein Joel B. , West Tim
Published: December 2022

Background

Accumulation of amyloid beta plaques and tau tangles in the brain are sequential pathological hallmarks of Alzheimer’s disease. Specific measurement of tau phosphorylation sites in plasma samples can be used to investigate the presence of both amyloid plaque and tau tangle brain pathology.

Method

A tandem mass spectrometry assay that quantifies phosphorylation of tau at threonine residues 181 and 217 in plasma was developed. Both phosphorylated (phospho) and non‐phosphorylated (non‐phospho) peptides containing tau residues 181 and 217 as well as the ratio of phospho to non‐phospho at each of these phosphorylation sites can be calculated from a blood sample. We tested the concordance between these measures and brain amyloid burden in PARIS study participants, an IDEAS sub‐study in patients with mild cognitive impairment or dementia. K2EDTA plasma samples from PARIS participants (n=221) were analyzed for tau phosphorylation and Aβ42/40.

Results

The amount of phosphorylation at both 181 and 217 sited were significantly higher in patients who were amyloid PET positive, while PET negative patients showed very low amounts of phosphorylation at 217 (1.2 pg/mL vs. 4.9 pg/mL; p <2e‐16). The ratio of phospho‐tau to non‐phospho‐tau 217 showed high correlation (Spearman’s rank correlation r=0.78; p <2e‐16) with quantitative amyloid PET, demonstrating that phosphorylation of tau on threonine‐217 can quantitatively identify the amount of amyloid burden. This ratio of phospho‐tau to non‐phospho‐tau also correlated better with amyloid status than the concentration of phospho‐tau alone, with area under the curve (AUC) for detecting brain amyloid burden improving from 0.74 (95%CI 0.67‐0.82) to 0.81 (95%CI 0.75‐0.88) for 181 and from 0.92 (95%CI 0.88‐0.96) to 0.95 (95%CI 0.92‐0.98) for 217. Combining the phospho‐tau‐217 with the Aβ42/40 ratios for the same sample further increased the AUC to 0.96 (95%CI 0.93‐0.99).

Conclusion

This novel mass spectrometry‐based quantitative assay for plasma phospho‐tau and non‐phospho‐tau species has excellent analytical and clinical validity performance characteristics. Combining the ratio of tau phosphorylation at 217 with plasma Aβ42/40 can help identify brain amyloid pathology with a performance that rivals that of CSF or PET tests.
Human nasal beta‐amyloid 42 reflects cognition decline in Alzheimer’s disease
Authors: Jung Da Hae , Son Gowoon , Wang Shengmin , Lim Hyun Kook , Moon Cheil
Published: December 2022

Background

The key in Alzheimer’s disease (AD) therapy is a timely and accurate diagnosis for prompt drug intervention. However, due to the high cost and invasiveness of conventional biomarker analyses, including brain positron emission tomography (PET) imaging and cerebrospinal fluid (CSF)‐based assays, easy accessibility to these screening tests is often hindered. There is, therefore, a great need to develop a more accessible biomarker screening test using less invasive and cost‐effective peripheral body fluid biomarkers. Previous studies examined the non‐quantitative expression of beta‐amyloid (Aβ) in normal and AD patients' nasal discharge fluid. They identified higher expression of oligomeric Aβ in AD patients, showing a correlation with cognitive decline. However, the quantitative measurements of nasal Aβ42 levels, including the full AD continuum, remain unknown. Here, we assessed whether quantified human nasal Aβ42 levels could identify patients with AD and differentiate them from non‐AD patients.

Method

161 subjects (cognitively normal (CN), n=32; preclinical, n=29; mild cognitive impairment (MCI), n=73; AD, n=27) underwent neuropsychological battery tests. Their nasal discharge samples were collected, and nasal Aβ42 levels were measured via enzyme‐linked immunosorbent assay (ELISA).

Result

We found that the second‐highest quartile (Q3) group of nasal Aβ42 constituted the majority of patients with AD diagnosis (p=0.036). The Q3 group also outnumbered the other groups in the most cognitively impaired subjects in all three neuropsychological battery tests (p=0.033; p=0.0212; p=0.0147).

Conclusion

Quantified nasal Aβ42 is strongly associated with cognition measurements. Nasal Aβ42 suggests the possibility for discriminating AD from non‐AD.
Cell‐type Specific Effects of AD Mutations on Hippocampal Intrinsic Firing Properties in Genetically Diverse Mice
Authors: Berchulski Mariah R , Funke Jonathan R , Hadad Niran , O'Connell Kristen MS , Kaczorowski Catherine C.
Published: December 2022

Background

Cognitive resilience to Alzheimer’s disease (AD) is a phenomenon whereby individuals with known AD mutations or high levels of pathology exhibit better than predicted cognitive performance. Identification of the factors governing resilience may lead to novel therapeutic interventions to treat AD. Analysis of hippocampal transcriptional profiles from susceptible and resilient AD‐BXD strains indicates that transcriptomic changes in excitatory neurons in CA1 and dentate gyrus (DG) are associated with resilience and we now seek to examine physiological changes.

Method

We adapted the Patch‐Seq method (Cadwell et al., 2017) to investigate cell type‐specific transcriptional and electrophysiological changes associated with AD using the AD‐BXD genetic reference panel (Neuner et al., 2019). Whole‐cell patch clamp was used to evaluate intrinsic excitability of neurons within the DG and CA1 of 14m old mice with cognitive deficits compared to age matched controls; their cellular contents, including the nucleus, were collected after each recording to characterize the transcriptome.

Result

Comparison of the intrinsic properties of DG and CA1 neurons of hippocampal slices from 5XFAD mice and their non‐transgenic (Ntg) counterparts revealed that DG granule cells from 5XFAD mice have a lower input resistance and an increased sag ratio in response to hyperpolarizing current injections. Pyramidal neurons from the CA1 of 5xFAD mice exhibit significantly more depolarized action potential thresholds, a significant increase in the medium afterhyperpolarization (mAHP) and sag ratio compared to Ntg controls. While these intrinsic properties are proxy measures for neuronal excitability, we did not observe a significant effect of genotype on firing rate in response to 1s and 15s depolarizing current steps.

Conclusion

Our findings newly demonstrate disease related changes to intrinsic firing properties of DG granule cells at 14mo indicating that these neurons may be hypoexcitable. Also found, CA1 neurons from AD mice exhibit an increased mAHP and changes to sag ratio and AP threshold, indicating they too become less excitable. Future work will add additional AD‐BXD strains characterized as resilient or susceptible to the AD transgene to discover changes in intrinsic properties that could underlie resilience. We will also use an integrated analysis of transcriptomic and electrophysiological data to identify relevant functional targets for validation.
Multimodal Imaging Analysis for Brain Clearance: PET Imaging Based Clearance Slope, FASTT2 MRI‐based Parenchyma CSF fraction, and DTI‐based ALPS‐index
Authors: Zhou Liangdong , Nguyen Thanh D , Wegiel Jarek , de Leon Mony J. , Li Yi
Published: December 2022

Background

Glymphatic clearance is important to maintain brain health, which depends on two interconnected fluid systems: the novel glymphatic system and the traditional well‐characterized CSF system1. There are several imaging tools have been developed to evaluate the glymphatic function in the human brain, however each method providing only a limited perspective into glymphatic system2. A proper imaging tool should consider both circulation pathway of the bulk CSF flow, and a complex PVS network parallel to the microvascular structure. We developed and tested an imaging package including vCSF, CSFF, and DTI‐ALPS, to investigate the ventricular CSF turnover rate, perivascular CSF flow and brain parenchymal CSF fraction.

Method

A total of 23 subjects (F=16, M=7, NL=17, MCI=6) age from 63 and 82 years (mean=69.3, std=5.1). PET MK6240 was acquired for lateral ventricle CSF clearance measure3 (vCSF), and MRI FASTT2 and DTI was acquired for CSF fraction4 (CSFF) and diffusion tensor imaging along perivascular spaces5 (DTI‐ALPS) index, respectively. Precisely, vCSF was calculated as the slope of 10 to 30min lateral ventricle TAC normalized by 1‐4min whole brain AUC. CSFF was fitted using three compartment model with 6 TEs = 0, 7.5, 17.5, 67.5, 147.5, 307.5 ms. DTI‐ALPS was calculated by mean(D𝑥_𝑝𝑟𝑜𝑗,D𝑥_𝑎𝑠𝑠𝑜𝑐)/mean (D𝑦_𝑝𝑟𝑜𝑗, D𝑧_𝑎𝑠𝑠𝑜𝑐), where Dx, Dy and Dz are the diffusivity along x‐, y‐ and x‐axis, and the projection, association regions.

Result

Figure 4 shows Parenchymal CSFF negative correlates with DTI‐ALPS (r = ‐.51; p=.01 n=23), suggesting link between glymphatic system dysfunction and increased cerebral CSFF. 4 NL subjects with high CSFF and low DTI‐ALPS are amyloid positive. Figure 5 shows ventricular CSF turnover rate (vCSF) negative correlates CSFF (r = ‐.53; p=.01 n=23).

Conclusion

Our preliminary results showed that ventricular CSF turnover rate (vCSF), perivascular CSF flow (DTI‐ALPS) and brain parenchymal CSF fraction (CSFF) are correlated to each other and indicate the connection between the glymphatic system and the traditional CSF system. The complementary imaging approaches could lead to a much greater understanding of glymphatic clearance, and facilitate a more complete perspective on both glymphatic pathology and function alterations.

Reference: 1. JM. Wardlaw,2020. 2. M. Niazi,2018. 3. Y. Li, 2022. 4. L. Zhou, 2021. 5. T. Taoka, 2017
Synaptic dysfunction reflected in CSF: serial CSF sampling reveals trajectories of potential synaptic biomarkers in early AD stages
Authors: Duits Flora H. , Nilsson Johanna , Teunissen Charlotte E. , Zetterberg Henrik , Blennow Kaj , Scheltens Philip , van der Flier Wiesje M. , Brinkmalm Ann
Published: December 2022

Background

Synaptic dysfunction plays an important role in Alzheimer’s disease (AD) and cognitive decline. Using serial CSF sampling we investigated longitudinal trajectories of synaptic proteins, including SYT1, SNAP25, neurogranin, synucleins, neuronal pentraxins (NPTX) and three 14‐3‐3 proteins, in AD.

Methods

We included 150 subjects with subjective cognitive decline (SCD; 62±7 years), mild cognitive impairment (MCI; 66±8 years) or AD dementia (64±7 years) from the Amsterdam dementia cohort, based on availability of CSF at two time points and clinical follow‐up of more than one year (median[interquartile range] 3.3[2.1‐5.1] years). Synaptic proteins were analyzed using two different mass spectrometry‐based assays. We used linear mixed models to assess whether baseline protein levels and slopes over time differed between groups (first analysis), and to assess associations of protein levels with cognitive function at baseline and decline over time, measured by repeated MMSE (second analysis). We first compared groups according to baseline diagnosis. Secondly, non‐demented subjects were compared based on CSF AD profile (i.e. abnormal Ab42 and tau levels; 60 AD‐ and 40 AD+ subjects). All protein levels were transformed to Z‐scores for comparison of effect sizes and were evaluated in separate models.

Results

At baseline levels of SNAP25, neurogranin, beta‐synuclein and 14‐3‐3 proteins were higher in AD dementia than in SCD and MCI (figure 1), and in non‐demented AD+ versus AD‐ subjects. NPTX‐2 levels were lower in AD compared with SCD. Over time SYT1, NPTX‐1, NPTX‐2 and NPTX‐receptor decreased in AD dementia patients (st.B between ‐0.10 and ‐0.15; figure 2A), while 14‐3‐3 zeta/delta increased in MCI subjects (st.B[SE] 0.08[0.03]). Similar changes were seen in non‐demented AD+ subjects (Figure 2B). In SCD subjects lower baseline levels of NPTX‐2 were associated with lower baseline MMSE. In SCD and MCI subjects higher levels of SNAP25, Ng, synucleins and 14‐3‐3 proteins were associated with faster cognitive decline.

Conclusion

CSF levels of SYT1 and NPTX decreased over time in subjects with early symptomatic AD, while higher baseline levels of other synaptic proteins were associated with future disease progression. This dissociation may reflect complex synaptic changes in early disease stages and may have added value in a prognostic model for AD.
Self‐reported sleep quality interacts with Alzheimer’s disease biomarkers on brain structure and metabolism in cognitively unimpaired adults
Authors: Stankeviciute Laura , Falcon Carles , Operto Grégory , Garcia Marina , Shekari Mahnaz , Niñerola‐Baizán Aida , Perissinotti Andrés , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Cacciaglia Raffaele , Gispert Juan Domingo , Grau‐Rivera Oriol
Published: December 2022

Background

Poor sleep quality has been associated with a greater burden of AD pathology and altered brain structure in cognitively unimpaired (CU) individuals. However, there is a lack of studies analysing associations between sleep quality and brain structure and function, while taking into account AD pathology. We aimed to test associations of self‐reported sleep quality with grey matter volume (GMv) and brain glucose metabolism in middle‐aged CU and sought interactions with biomarkers of AD pathology.

Method

This study included 340 CU adults from the ALFA+ cohort (Table 1). Sleep quality was assessed using the Pittsburgh sleep quality index (PSQI) questionnaire. We used Statistical Parametric Mapping software to process T1‐weighted MRI and [18F]fluorodeoxyglucose (FDG) PET scans, and analyse voxel‐wise associations with sleep quality. We created separate general linear models with GMv and FDG metabolism as dependent variables, and PSQI total score, age, sex, APOE‐ε4 status, education level and sleep medication as predictors. GMv analyses were additionally corrected for total intracranial volume. In additional models, CSF Aβ42/40 and phosphorylated tau (p‐tau181) ‐ were entered as covariates. We also tested the interaction between PSQI and AD biomarker status, (A+: Aβ42/40<0.071, T+: p‐tau181>24 pg/mL). Statistical significance was set at p<0.005 uncorrected for multiple comparisons, with a cluster‐level threshold of 50 voxels.

Result

Higher PSQI scores, indicating poorer sleep quality, were significantly associated with lower GMv in the left occipital fusiform gyrus and right middle orbitofrontal gyrus, and with lower brain glucose metabolism in the right temporal pole and parahippocampal gyrus (Figure 1.). Interaction analyses showed poorer sleep quality is associated with higher GMv in bilateral supramarginal gyrus in A+T‐ vs A‐T‐, and with higher glucose metabolism in bilateral thalamus in A+T+ vs A‐T‐ individuals (Figure 2).

Conclusion

Poorer sleep quality is associated with lower GMv and glucose metabolism in CU individuals, involving AD‐vulnerable regions. Sleep quality interacted with altered AD biomarkers to determine GMv and glucose metabolism in brain areas in which they are commonly found to be increased in preclinical AD stages. Altogether, our findings support sleep quality as a relevant factor early in the AD continuum.
Development and validation of a blood‐based protein predictor of 20‐year dementia risk from middle age
Authors: Paterson Clare , Zhang Amy , Ostroff Rachel , Hagar Yolanda , Loupy Kelsey , Williams Stephen
Published: December 2022

Background

In the US the number of individuals affected by dementia is expected to double by 2040. Thus, tools enabling identification of at‐risk individuals earlier in disease progression, or before disease onset, are vital. Proteomics‐driven risk stratification for dementia may enable the initiation of life‐planning and/or elicit changes in modifiable lifestyle‐related risk factors. Moreover, test results may facilitate enrichment of clinical trial enrollment, and ultimately as an aid in precision prescribing of preventative therapeutics. Therefore, we sought to develop and validate a blood‐based protein‐only predictor of 20‐year dementia risk from middle age.

Method

Using modified‐aptamer proteomics technology, SomaScan® assay v4.0, we scanned ∼5,000 proteins in 11,277 EDTA plasma samples from individuals aged 49‐73 without known dementia at visit 3 blood draw of the Atherosclerosis Risk in Communities (ARIC) study, totaling ∼56million protein measurements. A total 1,305 incident dementia diagnoses occurred within 20 years of blood‐draw. Time to dementia diagnosis events were modeled with protein measurements using machine learning methods in 70% of ARIC V3 as a training dataset. A model was selected based on performance in a 15% holdout sample subset and validated in the remaining 15% samples. In a subset of 3,852 individuals with known ApoE status, the performance of the proteomic model was compared to that of the predictive performance of risk genotype.

Result

A 25‐feature protein‐only accelerated‐failure‐time Weibull model was successfully developed to predict the probability of a dementia diagnosis within 20 years of blood draw. Model performance was measured using AUC, which was equal to 0.73, 0.73, and 0.70, in the training, model selection, and validation datasets, respectively. Based on predicted probabilities from the model, individuals were stratified into low, medium‐low, medium‐high, and high risk bins, with a 20‐year event rate of 3.79% vs 35.58% in low vs high risk bins. Model performance was significantly superior to that of ApoE genotype.

Conclusion

We successfully developed a well calibrated protein‐only model with a 10‐fold dynamic range that predicts 20‐y risk of a dementia diagnosis. Performance of the protein model out‐performs leading genetic risk factors for dementia and given the exclusion of immutable factors it has the potential to monitor changing risk.