bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimized ACI‐24, an amyloid beta (Abeta) vaccine that safely drives immunity to oligomers and Pyroglutamate Abeta, key pathological species of Alzheimer’s disease (AD)
Authors: Fiorini Emma , Vukicevic Marija , Carpintero Rakel , Rincon Marcela , Lopez‐Deber Pilar , Piot Nicolas , Ayer Maxime , Rentero Inmaculada , Siegert Stefanie , Babolin Chiara , Knittel Delphine , Gollwitzer Eva , Bravo‐Veyrat Sophie , Giriens Valérie , Morici Catherine , Beuzelin Marie‐Gabrielle , Gesbert Anthony , Rivot Sebastien , Chuard Nathalie , Attanasio Vanessa , Delpretti Saskia , Donati Piergiorgio , Streffer Johannes , Pfeifer Andrea , Kosco‐Vilbois Marie
Published: December 2022

Background

Amyloid immunotherapy has received recent clinical validation with monoclonal antibodies. Vaccines, such as optimized ACI‐24, are designed to produce a broader, robust antibody response against multiple pathologic forms of Abeta with the added advantage to reduce treatment frequency. Optimized ACI‐24 builds on the initial safety, immunogenicity and pharmacodynamic data of ACI‐24 that has been studied in AD and Down Syndrome‐related AD. Optimized ACI‐24 is formulated with the additional immune cell help via a non‐Abeta, universal T‐helper cell peptide, aiming to insure sustained antibody production, particularly against pathological Abeta species, such as oligomers and truncated pyroglutamate.

Method

Optimized ACI‐24 was generated using the SupraAntigen® platform. Mice and non‐human primates were immunized and sera/plasma obtained to measure titers against Abeta1‐42, pyroglutamate (Abeta3‐42) and oligomers. Epitope mapping, immunohistochemistry on different human tissues, including AD brains were performed.

Result

Immunization of mice and cynomolgus monkeys with optimized ACI‐24 resulted in potent antigen specific IgG levels. The polyclonal antibody response was observed to mature over time with higher affinity IgGs emerging as well as an increase in titers of IgGs that recognized the highly neurotoxic Abeta species including truncated pyroglutamate and pathological Abeta oligomers. Epitope mapping confirmed the induction of a broader spectrum of antibodies recognizing the N‐terminal containing and the truncated species of pathological Abeta, as compared to the previously clinically tested Abeta vaccines. In addition, target engagement was demonstrated as the immunized monkey sera labeled Abeta plaques in AD patient brain sections while did not show any binding to other human tissues.

Conclusion

These preclinical data illustrate that optimized ACI‐24 generates IgGs with a broader N‐terminal Abeta sequence recognition than offered by clinically tested mAbs or Abeta vaccines. This unique binding profile for the pathogenic forms of Abeta, including truncated pyroglutamate and toxic oligomers, is encouraging as it combines the targets of mAbs, such as Aducanumab and Donanemab, recently linked to clinical benefits, and thus, the potential of enhancing plaque reduction. The presented data support the fast progression of optimized ACI‐24 into clinical development as a disease modifying treatment with potential for prevention in AD and Down Syndrome‐related AD.
How timings of being physically active in adulthood relate to later‐life cognition: over 30 years of follow up in the 1946 British Birth Cohort
Authors: Chiou Yu‐Jie , Schott Jonathan M , Richards Marcus , James Sarah‐Naomi
Published: December 2022

Background

We aim to assess how the timing of being physically active in adulthood is associated with later‐life cognitive function; and estimate to what extent these effects are explained by pathways including earlier life influences, cardiovascular and mental health.

Method

Data from participants (n = 1417, 53% female) in the British 1946 birth cohort were included. Physical activity was assessed across adulthood at ages 36, 43, 53, 60 and 69 by interviews and categorised into: 0)Not active; 1)Moderately active (participated in physical activity 1‐4 times per month); 2) Most active (participated 5+ times per month). Responses were additionally binarized and summed to create a cumulative exposure of adulthood physical activity. Cognition at age 69 was assessed by the Addenbrooke’s Cognitive Examination (ACE‐III)). Regression analyses examined associations between physical activity measures and later‐life cognition, adjusting for childhood cognition; childhood socioeconomic position (SEP); education; cardiovascular health (Framingham risk score at age 69); emotional symptoms (general health questionnaire at age 69); and APOE‐e4 status. A structural equation modelling analysis further tested the life course models of sensitive period and accumulation for describing how physical activity was best related to later‐life cognition.

Result

Compared to those not active, those who were moderately and most physically active, at every age, had higher ACE‐III scores at age 69 (Figure 1). Being physically active across different periods was associated with better cognitive state, in a dose‐response manner (Figure 1). Adjusting for childhood cognition, childhood SEP and education largely attenuated these effects but results mainly remained significant at the 5% level; adjustment for cardiovascular risk, mental health and APOE‐e4 status did not attenuate associations (Figure 1). An accumulation model of physical activity was the best fit (Table 1).

Conclusion

We provide evidence from two complementary analyses that maintaining physical activity across different periods of adulthood is related to better later‐life cognitive state in a dose response manner, even after adjustment for variables that predict physical activity and later‐life cognition, such as childhood cognition, education and SEP. These relationships were independent of cardiovascular and mental health and APOE‐E4 status.
Brain‐Wide Monitoring of Antibody Therapeutics Crossing the Blood‐Brain‐Barrier
Authors: Redd Chase , Guanzon Nathaniel , Gallegos Yessenia , Weiss Jacob , Jensen Camilla Stampe , Vergo Sandra B. , Wheeler Damian G.
Published: December 2022

Background

Recent advances in optical clearing and light sheet imaging have opened an exciting new avenue for brain‐wide, cellular resolution immunostaining at the forefront of a dimensional shift from 2D to 3D histology. Providing access to the intricate anatomy of the whole intact brain, tissue clearing offers neuroscientists unbiased and complete views of brain anatomy and function. One area where these methods have particular utility is in the development of CNS therapeutics where they can be used to examine the regional distribution of the therapeutic in the brain as well as brain‐wide target engagement and phenotypic efficacy.

Method

We have developed an optimized iDISCO‐based clearing method and with our Mesoscale Imaging System for ZEISS Lightsheet microscopes, we can image cellular‐resolution immunoreactivity across entire mouse brains in ∼25 min. Here we examined whether our technology can detect antibody therapeutics crossing the blood‐brain‐barrier. To do this, we took advantage of a bispecific antibody engineered to bind to the Alzheimer’s Disease target, BACE1, as well as the transferrin receptor (TfR1), which helps shuttle the antibody across the brain endothelium and into the brain parenchyma. Twenty‐four hours after dosing we perfusion‐fixed the brains and performed our modified iDISCO‐based clearing and staining protocol using 3 different anti‐human IgG secondary antibodies.

Result

We found anti‐human antibodies revealed high levels of the bi‐specific antibody in the brain vasculature and parenchyma. Importantly, in brains dosed with a monospecific control antibody that does not bind TfR1, immunoreactivity was at background levels, similar to that seen in control mice that were not dosed with antibody. These data are consistent with binding to TfR1 localizing the bispecific antibody in the vasculature and enabling transport into the brain parenchyma. Importantly, the pattern of immunoreactivity in the cleared brain matched the pattern seen with traditional 2D slice immunohistochemistry. But unlike traditional methods, we were able to examine the concentration of the bi‐specific antibody throughout the entire brain and assess whether the pattern matched that of the therapeutic target.

Conclusion

Together, these data provide a clear demonstration of the utility of tissue clearing methods for quantitative brain‐wide monitoring of therapeutic antibody exposure.
Role of neurochemistry in amyloid pathology using 5xFAD transgenic mouse model of AD: A single‐voxel Magnetic Resonance Spectroscopy (MRS) study
Authors: Shahid Syed Salman , Paraiso Hallel C , Yu Ivorine , Wu Yu‐Chien
Published: December 2022

Background

Changes in cerebral metabolic concentrations are markers of aging and are also associated with various neurological disorders. Neurotransmitter and membrane metabolisms are affected in Alzheimer’s disease (AD). These metabolic alterations are suggested to occur in the hippocampus and rhinal cortex during the early stages of AD pathology. Higher levels of glutamine (Gln) in the blood and cerebral spinal fluid are associated with an increased risk of developing AD. Since Gln is capable of crossing the blood‐brain barrier and is involved in the metabolic cycle with glutamate (Glu), elevated levels of Gln in the presence of Aβ pathology may suggest a protective role of Gln in the early stage of the disease. Therefore, alteration in Glu/Gln cycle may serve as an early biomarker in the pathogenesis of AD. Choline‐containing compounds (tCho) are essential for phospholipid synthesis and degradation of cell membranes. Abnormal alterations of tCho levels are indicative of imbalanced cell membrane phospholipid metabolism. At the early stage of Aβ pathology, high levels of tCho in conjunction with elevated levels of Gln may suggest the involvement of compensatory mechanisms to counter declining acetylcholine. Thus, investigating metabolic changes in the hippocampus may improve our understanding of metabolic mechanisms associated with Aβ pathology.

Method

Male 5xFAD mice (N=4) at 6‐months‐old and age‐matched littermates (N=5) were used in this study. Single‐voxel MRS was acquired on a 9.4T Biospec micro‐MRI system equipped with a H1 cryogenic surface coil. STEAM spectra was acquired from a 2mm3 voxel positioned on the left hippocampus region. Glu, Gln, tCho and total Creatine (tCr) levels were estimated with LC Model. A general linear model (GLM) was used to estimate group‐wise differences in Glu/Gln ratio, tCho.Gln and tCr.

Result

Cerebral metabolic concentration levels suggest group‐level differences between wild‐type (WT) and 5xFAD mice. Glu/Gln ratio was significantly higher in WT mice than 5xFAD (pFWE<0.05; d=3.4) and tCho.Gln was significantly lower in WT than 5xFAD (pFWE<0.05; d=2.8).

Conclusion

Single‐voxel MRS in the hippocampus region can identify the neurochemical profile of multiple cerebral metabolites, which may be sensitive to the Aβ burden at the early stages of the pathology.
Cardiorespiratory fitness attenuates the deleterious effects of sleep apnea on cerebral structure, perfusion, and risk of Alzheimer’s disease in the Wisconsin Sleep Cohort study
Authors: Edmunds Kyle J , Driscoll Ira , Hagen Erika W , Barnet Jodi H , Ravelo Laurel A , Plante David T , Gaitán Julian M. , Lose Sarah R , Motovylyak Alice , Okonkwo Ozioma C. , Peppard Paul E
Published: December 2022

Background

Emerging evidence suggests that age‐related changes in cerebral structure and perfusion—hallmark features of preclinical Alzheimer’s disease (AD)—may be sensitive to vascular risk modifiers such as physical exercise and sleep quality. Here, we examine whether cardiorespiratory fitness modifies the effects of obstructive sleep apnea (OSA) on cerebral structure, perfusion, and AD risk.

Method

Using data from a sample of participants (n=134 for analyses of imaging outcomes and n=1,182 for analyses examining AD outcomes) in the Wisconsin Sleep Cohort (WSC) study, we examined cross‐sectional associations between OSA severity, estimated cardiorespiratory fitness (eCRF), and their interaction with MRI‐assessed total and regional gray (GM) and white matter (WM) volumes, WM hyperintensities (WMHs), total lesion volume, and arterial spin labeling cerebral blood flow (CBF), using multiple linear regression models adjusted for age, sex, BMI, hypertension, and education level. We further assessed whether eCRF modifies the associations between OSA and risk of AD using Cox proportional hazard models.

Result

OSA severity was associated with greater total lesion volume, reduced total GM volume, and greater WMHs among less‐fit, but not among more‐fit, subjects. Perfusion models likewise revealed significant regional differences in CBF between fitness groups. OSA severity was likewise associated with greater risk of AD among less‐fit individuals, but there was no significant association among the more‐fit.

Conclusion

This work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging and AD.
Type 2 diabetes and cortical thickness in older Mexican Americans and non‐Hispanic Whites
Authors: Braskie Meredith N , Hazra Nalini , Kothapalli Deydeep , Cho HyungJin , Lester Jacob , Rogers Jessica N , Palmer Raymond F. , Vintimilla Raul , Johnson Leigh , Yaffe Kristine , Toga Arthur W. , O'Bryant Sid E.
Published: December 2022

Background

Type 2 diabetes mellitus (T2DM) at midlife increases dementia risk. Metabolic factors contribute more to Alzheimer’s disease (AD) risk in Mexican Americans (MA) than in non‐Hispanic Whites (NHW). However, most work relating T2DM to brain structure in older adults has been performed in NHWs. We evaluated how T2DM related to regional cortical thickness in cognitively intact older MA or NHW adults. We hypothesized that T2DM would relate more to regional cortical thickness in MA.

Method

We assessed 819 cognitively intact controls (344 MA, mean age=62.2; 475 NHW, mean age =68.8) in the Health and Aging Brain‐Health Disparities (HABS‐HD) cohort who had 1) a T1‐weighted structural brain MRI (3T Siemens Magnatom Skyra) 2) type 2 diabetes diagnostic assessment and 3) successful FreeSurfer (v5.3.0) cortical segmentations (34 cortical regions on the right and left). Regions that failed visual quality checks were imputed using MICE (R studio). We related mean bilateral regional cortical thickness to T2DM diagnosis, covarying for age and sex and controlling for multiple comparisons (Bonferroni correction.) For regions significantly associated with T2DM diagnosis, we evaluated the relationship of HbA1c and fasting blood insulin to cortical thickness, controlling for age and sex.

Result

T2DM was significantly associated with cortical thickness in bilateral gyri: supramarginal, precuneus, superior and middle temporal, banks of the superior temporal sulcus, transverse temporal, temporal pole, lingual, pericalcarine, and left lateral occipital (Table 1). HbA1c levels, but not fasting insulin, were significantly correlated with cortical thickness in all identified regions after Bonferroni correction (p<0.0012). There was a significant effect of ethnicity in most of these regions, after controlling for education and household income (Table 2). Supramarginal gyrus, precuneus, transverse temporal gyrus, and left lateral occipital thickness showed a nominally significant interaction (p<0.05) between ethnicity and T2DM, with stronger T2DM effects in MA. Ethnicity interaction effects were diminished in all regions when HbA1c was added to the model.

Conclusion

T2DM is associated with cortical thickness in temporal, parietal, and occipital regions. Those effects are stronger in MA than NHW, independent of age, sex, and economic status, but may be partly explained by differences in blood glucose level control.
Purpose in life may promote cognitive resilience through default‐mode network connectivity in middle‐aged adults
Authors: Abellaneda‐Pérez Kilian , Cattaneo Gabriele , Cabello‐Toscano María , Sánchez Javier Solana , Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Bargalló Núria , Tormos‐Muñoz Josep Mª , Pascual‐Leone Alvaro , Bartrés‐Faz David
Published: December 2022

Background

Disease‐modifying agents to counteract cognitive impairment in aging remain elusive, and identifying modifiable factors promoting brain reserve is paramount. In AD, education, occupation, and physical activity represent typical reserve proxies (Stern et al. Alzheimers Dement.2020;16(9):1305‐1311), but psychological factors are increasingly being recognized, as their operating biological mechanisms are elucidated (i.e., Arenaza‐Urquijo et al. Neurology 2020;95:e1571). Purpose in life (PiL), one of the pillars of psychological well‐being, was found to reduce the deleterious effects of AD‐related pathological changes on cognition (Boyle et al., Arch Gen Psychiatry. 2012;69(5):499‐505). However, whether PiL operates as a cognitive resilience factor in middle‐aged individuals, as well as its associated neural mechanisms remains unknown.

Method

Data was obtained from 573 middle‐aged adults (mean age 54.28±7.2; 275 women) from the Barcelona Brain Health Initiative cohort (Cattaneo et al. Front Aging Neurosci. 2018;10:321). Individuals with lower (LP; N = 131) and higher (HP; N = 94) PiL rates, according to the division of this variable into quintiles, were compared in terms of cognitive status; a measure reflecting brain burden (MRI‐derived white matter hyperintensities; WMHs); and resting‐state functional connectivity (rs‐FC), examining system segregation (SyS) using 14 brain circuits (Shirer et al. Cereb Cortex. 2012;22(1):158‐165).

Results

Neuropsychological status and WMHs burden did not differ between PiL groups. However, only in the LP group, greater WMHs entailed a negative impact on speed of processing and logical reasoning (Fig.1A‐B). Subjects in the HP group showed lower SyS on the dorsal DMN (dDMN), indicating lesser segregation of this network from other brain circuits (t = 2.423, p = 0.016; Fig.1C). Specifically, HP individuals had greater inter‐network connectivity between dDMN nodes and the rest of the brain. Conversely, subjects in the LP group exhibited more connectivity across DMN‐like regions. Notably, in the HP group, greater functional connectivity was positively correlated with cognitive function previously related to WMHs, while the opposite pattern was observed in the LP group (Fig.1D‐F).

Conclusion

Expanding previous findings on AD‐pathology and advanced age, present results suggest that higher rates of PiL may promote cognitive resilience already in middle age. Possible neurobiological mechanism by which PiL might operate could imply greater integration between the DMN and other brain areas.
Pupil and eye tracking measures as a tool for detection and intervention in neurodegeneration
Authors: O’Callaghan Claire , Hezemans Frank H , Ye Rong , Orlando Isabella , Passamonti Luca , Rowe James B
Published: December 2022

Background

The locus coeruleus–noradrenaline system plays an extensive role in cognition and behaviour. It is among the earliest and most prominent sites of pathology in neurodegenerative diseases of ageing, including Alzheimer’s and Parkinson’s disease. Improving our ability to detect changes in this system in vivo has implications for early diagnosis and for tracking treatment interventions.

Method

My talk will focus on pupil and oculomotor measures as a biomarker to detect changes in the locus coeruleus–noradrenaline system. I will discuss results from a study in Parkinson’s disease patients (N=19) who underwent a pharmacological challenge using the noradrenergic reuptake inhibitor atomoxetine (40mg). In this study, we characterised the locus coeruleus using ultra‐high‐field 7T MRI and tested patients on and off atomoxetine, using a suite of oculomotor eye tracking tasks and a learning task combined with pupillometry.

Result

We show that atomoxetine improves cognitive performance and saccadic reaction times. Crucially, atomoxetine led to larger pupil responses that varied as a function of locus coeruleus integrity.

Conclusion

Together, these results show that pupil and eye tracking measures are an effective biomarker for the locus coeruleus–noradrenaline system, and they are sensitive to pharmacological interventions. I will discuss the implications of these results for early detection and monitoring of subcortical changes in Alzheimer’s disease.
Rural/Urban Disparities in PQIs Among Patients with ADRD – Evidence of Hospital‐based HIT and Enabling Services
Authors: Chen Jie , Wang Nianyang , Buchongo Portia
Published: December 2022

Background

To examine urban and rural disparities in potentially preventable hospitalizations (PPH) among patients with Alzheimer’s Disease and Related Dementias (ADRD) and the use of health information technology (HIT) and enabling services as mediators.

Method

We merged 2017 100% Medicare Fee‐For‐Service (FFS) claims with the Medicare Beneficiary Summary File, American Community Survey, and American Hospital Association Annual Survey to construct a dataset containing patient, hospital, and community‐level data. Logistic regression was applied to examine differences in PPH by HIT and enabling services.

Result

The rates of PPHs related to acute and chronic conditions for rural and micropolitan patients with ADRD were significantly higher compared to the rates among urban patients with ADRD. Having both telehealth post‐discharge and enabling services significantly decreases the odds of PPH due to acute (OR: 0.93, 95% CI: 0.89‐0.98, p‐value <0.01) and chronic conditions (OR: 0.96, 95% CI: 0.92‐1.00, p‐value = 0.07) compared to not having these available. The presence of both telehealth post‐discharge and enabling services significantly decreased the odds of PPH in patients with ADRD in rural (acute PPH OR: 0.56, 95% CI: 0.41‐0.77, p‐value <0.01; chronic PPH OR: 0.73, 95% CI: 0.55‐0.97, p‐value = 0.03) and micropolitan (acute PPH OR: 0.65, 95% CI: 0.57‐0.73, p‐value <0.01; chronic PPH OR: 0.83, 95% CI: 0.74‐0.93, p‐value <0.01) areas compared to urban patients with ADRD.

Conclusion

Results suggest that the combination of HIT telehealth post‐discharge and enabling services are important interventions in helping to reduce preventable hospitalizations among patients with ADRD living in rural and micropolitan areas.
The association between bilingual semantic fluency and episodic memory among bilingual Mexican American older adults.
Authors: Briceno Emily M , Renteria Miguel Arce , Chang Wen , Lewandowski‐Romps Lisa , Heeringa Steven G , Garcia Nelda M , Morgenstern Lewis B
Published: December 2022

Background

Bilingualism is increasingly common in older adults in the US and may impact the expression and course of Alzheimer’s Disease and related dementias (ADRD). Optimal methods for assessing cognition in population‐based studies of bilingual older adults are not established. Given that declines in semantic fluency are associated with declines in episodic memory in ADRD, we examined the degree to which animal naming in English and Spanish is associated with memory performance in a sample of bilingual Mexican American (MA) older adults.

Method

The Brain Attack Surveillance in Corpus Christi‐Cognitive study is a population‐based study of cognition in MA and non‐Hispanic white adults 65+ in south Texas. We included US‐born, bilingual MA participants who completed in‐person neuropsychological assessment in their preferred language (English) with the Harmonized Cognitive Assessment Protocol. We added a Spanish animal naming trial to the standard animal naming trial in English. We used the delayed recall score from a word list as the indicator of memory performance. We performed a series of regression analyses with delayed recall as the dependent variable and the English and Spanish animal naming scores as the independent variables, with age, sex, years of education, and a self‐reported bilingualism index score to account for level of bilingualism (range 0–1; 0 indicates monolingual Spanish; 1 indicates monolingual English) as covariates.

Result

Ninety‐six participants were included (Mage = 73yrs±6; Meducation = 11±4; 60% women; Table 1). In separate regression models including covariates, English animal naming (b = 0.25, p<.0001) and Spanish animal naming (b = 0.20, p <.05) were each associated with delayed recall. When considered together, English animal naming (b = 0.24, p = <.0001) and not Spanish animal naming (b = 0.03, p = .69) was associated with delayed recall, after accounting for age, sex, years of education, and level of bilingualism (Table 2). Results were consistent when the analysis was restricted to balanced bilinguals (Table 3).

Conclusion

Semantic fluency in English and Spanish were each related to episodic memory among bilingual MA older adults assessed in English, although the Spanish trial did not add unique information in its association with episodic memory. Future studies should evaluate how bilingual semantic fluency is associated with longitudinal cognitive decline in ADRD.
LDLR, VLDLR and APOBR in the pathophysiology of sporadic Alzheimer’s disease
Authors: Flores Isabel Sierra , Picard Cynthia , Poirier Judes
Published: December 2022

Background

Alzheimer’s disease (AD) and cholesterol homeostasis have long been linked, most notably by the identification of apolipoprotein E‐ε4 allele as the strongest risk factor. Yet the mechanism by which its pathogenic isoform ε4 impacts AD has remained elusive. Different GWA studies have identified other potential risk factors, many of which are also involved in the maintenance, homeostasis, mobilisation, and distribution of cholesterol. The aim of this study was to analyse three candidate genes involved in cholesterol metabolism, which showed preliminary significance and are strongly related to cholesterol processes and APOE neurobiology.

Method

The three candidates are the receptors LDLR, VLDLR and APOBR which were analysed using neocortical mRNA data from the Religious Orders study/ Memory and Aging Project ROSMAP cohort’s dataset. The receptor mRNA levels were contrasted against several AD pathological markers, such as Braak and CERAD stages. Other apolipoprotein mRNA levels were also analysed for significance. Age, Sex and ApoE4 genotype were also tested for effect.

Result

Preliminary analyses showed significant correlation between mRNA levels of these receptors (most strongly VLDLR) and Braak stages (VLDLR p < 0.008), CERAD stages (VLDLR p < 0.001) as well as several proteins known to be involved in AD pathophysiology. VLDLR expression levels did not correlate with APOE mRNA levels (VLDLR; R2=0.176, p > 0.05) and were only significant in APOε4 negative subjects when split for APOε4 genotype (VLDLR Braak p < 0.003).

Conclusion

The three receptors analysed so far appear to be involved at some level with AD pathophysiology. They will be further studied and investigated in both, symptomatic and pre‐symptomatic AD. The relationship between the receptors and APOE pathophysiology in sporadic AD remains unclear.
Evaluation of an Online Training Program for Savvy Caregiver Program Leaders
Authors: Hepburn Kenneth , Sherman Carey Wexler , Hobday John V , Char Adarsh
Published: December 2022

Background

The Savvy Caregiver® program (SCP) is widely disseminated evidence‐based in‐person psychoeducation program that enhances family caregivers’ knowledge, skills, and mastery for effectively performing the caregiver role. SCP is led by one or two trainers who have been trained in the role by one of the SCP developers, usually in in‐person group sessions. To ensure the fidelity of train‐the‐trainer workshops, facilitate SCP dissemination, and relieve the need for in‐person training, our educational design team, with support from NIH (RO1AG061971), produced a fully online, text and video SCP train‐the‐trainer program. The program contains four modules with sections, the first describing SC purpose, core principles, mechanism of action and role of the trainer; the remaining three cover the content and dynamic of each of the six weekly SCP sessions. Seven assessment exercises, scored by the authors, determined trainees’ ability to move forward in training. Following course revisions based on prototype testing, the training program was offered to agencies in six U.S. states. Additional online events allowed debriefing interaction between learners and course developers. A post‐course evaluation was sent to learners.

Method

The evaluation sought Likert‐type assessments (5 highest; 1 lowest) of the overall course, individual elements within it (e.g., on SCP principles, trainer role, and individual sessions), course materials (videos and slides), and assessments. We sought open‐ended comments throughout. Analysis was based on quantitative and qualitative evaluations.

Result

Forty‐five trainees completed the SCP training course, and 29 completed course evaluations. The course received a score of 4.21 (high/very high) on learners’ assessment of overall preparedness to lead SCP. The average score across all 8 individual segment evaluations was 4.425 and that across evaluation of 4 categories of video materials was 4.54. Comments reflected overall satisfaction with the program and its elements and provided suggestions for improvement (e.g., more illustration of how SCP segments are lead; how to adapt to COVID‐driven online SCP program delivery). The interactive debriefing sessions were deemed helpful for clarifying training questions.

Conclusion

Early results indicate this new online SCP train‐the‐trainer program can successfully prepare individuals to lead SCP programs, affirming the potential of virtual training for intervention practitioners.
User‐led Design of a Self‐administered Smartphone‐based Learning and Memory Assessment
Authors: Edgar Chris J. , Simic Veronika , Stephens David , Murray Erica , Maruff Paul
Published: December 2022

Background

The International Shopping List test (ISLT) is a verbal word list learning assessment set within a realistic shopping list context, supporting ease of cultural adaptation, and addressing content validity and patient relevance. Improvements to and the wide adoption of natural language processing (NLP) software has enabled the possibility for self‐administered tests of verbal learning. A beta version of a self‐administered, smartphone‐application (app) was developed, using the virtual assistant and NLP: the “List Learning and Memory Assessment (LilaTM)”.

Method

To ensure usability of the app, a user led design process was followed. A beta version was created via several rounds of focus group development in older adults. 12 older adults were then recruited for interviews (8 healthy and 4 with Mild Cognitive Impairment). Participants were pseudo‐randomly assigned to participate in interviews during test performance, using either iPhone or Nokia devices. Each participant completed the test and provided concept elicitation feedback. Qualitative analysis of the interview results was performed using thematic coding.

Result

Key positive themes included the ease with which the app could be navigated, and the clarity of visual display and instructions, whilst an important negative theme was the length of time between different components of the test.

Conclusion

Qualitative analysis of concept elicitation interviews has suggested several areas of improvement to the beta‐app, including improvements to performance that shorten processing and wait times between test components. The clarity of the visual display and test instructions were well supported.
Conformation‐specific anti‐tau antibodies distinguish human tauopathies
Authors: Hitt Brian D , Yang Ting , Beaver Joshua D. , Shang Ping , Joachimiak Lukasz A , White Charles , Diamond Marc
Published: December 2022

Background

Neurodegenerative tauopathies are defined by progressive brain accumulation of tau aggregates, and include Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease (PiD). Tau is an intrinsically disordered protein, yet it adopts diverse, highly ordered amyloid assemblies in disease states. These may amplify within cells by acting as “seeds,” or templates for their own replication. Evidence suggests that tau assemblies transfer between cells of the brain, which has inspired the development of immunotherapies that are in clinical trials. Analyses by cryo‐EM of insoluble tau filaments from tauopathies have revealed distinct fibril core structures, but these are not readily distinguished by immunohistochemistry. The tau repeat domain (RD) consists of three or four repeated segments and contains the amino acids comprising each tau filament core. The RD is required for tau assembly and has a different conformation in seed‐competent tau than in inert tau. Antibodies specific for distinct RD conformations have promise as diagnostic and therapeutic agents.

Method

We generated novel anti‐tau monoclonal antibodies against structurally defined synthetic linear peptide epitopes predicted to be exposed in seed‐competent tau. We employed a screening protocol using biosensor cell‐based seeding assays to select antibodies for sensitivity and specificity in binding soluble tau seeds from AD and non‐AD tauopathies.

Result

Two antibodies, MD2.2 and MD3.1, preferentially bind soluble tau seeds versus inert tau monomer, and distinguish seeds in AD and PSP from those of CBD and PiD. They stain tauopathy brain tissue with a pattern distinct from that of AT8.

Conclusion

We have generated novel anti‐tauRD antibodies with specificity for seed‐competent conformations and which distinguish tauopathies. These may be valuable for biochemical and neuropathological investigation of tauopathies and may also improve development of immunotherapy for AD and PSP.
APOE Genotype Moderates the Relationship Between Plasma Phosphorylated‐tau181 and Pattern Separation Performance in Non‐demented Adults
Authors: Diaz Valentina E , Memel Molly B , Gaynor Leslie S , Gontrum Eva Q. , Chan Brandon , Lago Argentina Lario , Yassa Michael A. , Rojas Julio C. , Casaletto Kaitlin B , Kramer Joel H. , Saloner Rowan
Published: December 2022

Background

The apolioprotein e (APOE) e4 allele enhances risk for Alzheimer’s disease (AD), particularly an amnestic AD phenotype with medial temporal lobe tau pathology. Pattern separation, the ability to discern novel yet similar information from previously learned information, is a cognitive marker of hippocampal function. APOE e4 carriers often exhibit pattern separation deficits prior to conversion to AD dementia, however the impact of APOE on tau‐related pattern separation performance is unknown. We examined the relationship between plasma P‐tau181 and pattern separation performance in non‐demented adults, and tested whether this association was dependent on APOE e4 genotype.

Methods

Plasma P‐tau181 levels were measured (Quanterix Simoa) in 171 non‐demented adults (139 cognitively unimpaired, 32 mild cognitive impairment; 29% APOE e4+, 54% female, aged 52‐92) who completed a validated behavioral task of visual pattern separation recognition. The lure discrimination index (LDI), reflecting ability to discriminate similar ‘lure’ items from old items, was modeled as the primary outcome. Linear regression examined LDI scores as a function of plasma P‐tau181, APOE4 genotype, and their interaction, controlling for age, sex, and education.

Result

APOE e4+ had higher plasma P‐tau181 than e4‐ (Cohen’s d=0.64, p<0.001), but APOE4 groups did not differ on LDI scores (Cohen’s d=0.27, p=0.124). In the full sample, higher plasma P‐tau181 significantly related to lower (worse) LDI scores (β=‐0.17, p=0.028). APOE4 status significantly moderated the relationship between plasma P‐tau181 and LDI scores (β=‐0.29, p=0.030) such that higher P‐tau181 related to lower LDI scores in e4+ (β=‐0.38, p=0.004) but not in e4‐ individuals (β=‐0.02, p=0.824).

Conclusions

APOE e4+ individuals had elevated plasma P‐tau181, which in turn related to worse pattern separation performance only within e4+ individuals. These data suggest that APOE4‐related elevations in plasma P‐tau181 may be particularly sensitive to hippocampal functioning outcomes prior to frank dementia, which could reflect underlying hippocampal hyperexcitability due to e4‐mediated GABAergic interneuron loss. Future work incorporating imaging markers of brain structure and function may help elucidate whether P‐tau181‐related alterations in pattern separation among e4+ individuals are mediated by hippocampal‐specific mechanisms.
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.

Conclusions

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.
Positive association of Cerebral Amyloid Angiopathy (CAA) with R2 Relaxation rate: A study of ex‐vivo MRI and pathology
Authors: Yasar Md Tahmid , Tazwar Mahir , Tamhane Ashish A , Evia Arnold M , Bennett David A , Schneider Julie A , Arfanakis Konstantinos
Published: December 2022

Background

Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid‐β in the walls of cortical and leptomeningeal small vessels. CAA is common in older adults and has been associated with cognitive decline and dementia. In this work, the association of CAA with the transverse relaxation rate R2 values in a large community‐based cohort of older adults was investigated.

Method

Cerebral hemispheres from 797 participants of three cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, and the Religious Orders Study (Figure 1) were included in this work. All hemispheres were imaged ex‐vivo at approximately 30 days postmortem using 3T clinical MRI scanners. Each scan included a multi‐echo spin‐echo sequence, and in each voxel, the signals from the different echoes were used to fit a mono‐exponential T2 decay equation (R2 is the reciprocal of T2). The resulting R2 maps were registered to an ex‐vivo brain hemisphere template using ANTS. Following the MRI scan, each hemisphere underwent thorough neuropathologic evaluation (Figure 2). The assessed pathologies were: CAA, Alzheimer’s pathology, LATE‐NC, hippocampal sclerosis (HS), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts.

Voxel‐wise linear regression was conducted to test the association of R2 with CAA, controlling for all other neuropathologies listed above, demographics (age at death, sex, education), and other variables (postmortem interval to immersion in fixative, postmortem interval to ex‐vivo MRI, scanners). Statistical analysis was done using PALM with tail‐accelerated 1000 permutations, threshold‐free cluster enhancement, and family‐wise error rate correction. Statistical significance was set at p<0.05.

Result

The voxel‐wise analysis revealed a spatial pattern of higher R2 values for higher CAA burden (Figure 3). The pattern included subcortical structures such as the caudate, putamen, nucleus accumbens, hippocampus, regions in the insula, anterior cingulate cortex, orbitofrontal cortex, and superior frontal cortex (Figure 3). No voxel showed a negative association between R2 values and CAA burden.

Conclusion

Our work showed that CAA is associated with higher R2 among older adults, independent of other neuropathologies and demographic factors. The spatial pattern for this association derived from the voxel‐wise analysis included subcortical and frontal lobe structures.
Microglial state changes in response to LM11A‐31 promote recovery in a tauopathy mouse model of Alzheimer’s Disease
Authors: Butler Robert R. , Yang Tao , Tran Kevin C , Johnson William A , Liu Harry , Leng Song Albert , Massa Stephen M. , Longo Frank M.
Published: December 2022

Background

Tau pathologies in Alzheimer’s Disease (AD) contribute to neurodegeneration and synaptic degeneration via a variety of mechanisms. Neurotrophic signaling pathways present an avenue to counteract degenerative mechanisms via receptor modulating compounds, such as the p75NTR‐targeted small molecule LM11A‐31 (C31). Treatment with C31 in tauopathy models causes reductions in tau aggregation and microglial activation, restoration of synaptic plasticity, and prevention of synaptic spine loss. Using tauopathy model tauP301S mice (PS19), we examined the impact of long‐term dosing with C31 at the single‐cell transcriptional level to better understand the cell types and cellular mechanisms affected by treatment.

Methods

PS19 and age‐matched (Wt) mice were dosed with either C31 or vehicle for 3 months starting at 6 months of age, when tau pathology was well established. Whole cortex was isolated for nuclear extraction and single‐nucleus RNA‐sequencing. Analysis

Results

Clustering microglia for cell type annotation revealed treatment group‐specific microglial subclusters (Figure 1). Further, microglial gene expression across experimental groups showed a strong inverse correlation (R = ‐0.647; p < 1.01e‐78) between C31 differential expression and PS19 differential expression in genes nominally significant (p < 0.05) for both (Figure 2). In particular, microglial genes that were downregulated in the PS19 tauopathy model and upregulated by C31 were enriched for those falling into GO categories including “synapse organization” and “cell junction organization” (p‐adj: 8.95e‐20, 2.66e‐17). Conversely, expression that was up in PS19 tauopathy and down in C31 showed enrichment for “small GTPase mediated signal transduction”, and “cell junction disassembly” (p‐adj: 8.59e‐05, 0.0431).

Conclusion

These findings demonstrate differences in microglial gene expression between Wt and PS19 mice some of which may be reversed by C31. Loss of homeostatic microglia has been previously associated with AD neurodegeneration, improper dendritic spine formation and inability to maintain synaptic structure. Our findings support the hypothesis that loss of homeostatic microglia exacerbates synaptic dysfunction, and their recovery may be one potential mechanism by which C31 can restore synaptic plasticity.
Identifying Pathways of Physiological Deterioration to Understand Racial Disparities in Cognitive Status: A 4‐way Mediation‐Interaction Decomposition Analysis
Authors: Higgins Cesar , Ware Erin B , Hicken Margaret , Zawistowski Matthew , Kobayashi Lindsay C , Muhkerjee Bhramar , Bakulski Kelly M
Published: December 2022

Background

Exposure to interpersonal and structural racism may increase the risk of adverse cognitive aging in racialized groups. Physiological deterioration may lie on the causal pathway leading racism to cognitive aging, but this potential mediating role has never been investigated. We quantified the extent to which the racial disparity (a proxy measure of exposure to racism) in cognitive status was mediated through physiological biomarkers of inflammation, glucose homeostasis, cholesterol ratios, and renal functioning.

Methods

Data were from the US Health and Retirement Study in 2006 and 2008. We performed cross‐sectional (n = 9,107) and 2‐year follow‐up analyses (n = 6,147) to explore the mediating roles of four physiological biomarkers in racial/ethnic disparities in prevalent and incident dementia. We used self‐reported race/ethnicity as a proxy for exposure to structural and interpersonal forms of racism. Mediators were serum biomarkers of systemic inflammation (hsCRP), glucose homeostasis (HbA1C), cholesterol processing and atherosclerosis risk (TC/HDL‐C ratio), and renal functioning (cystatin C). We performed a 4‐way decomposition analysis that accommodated exposure‐mediator interactions to identify natural direct and indirect effects.

Results

In this sample, the prevalence of dementia was 2.2% among non‐Hispanic White, 8.5% among non‐Hispanic Black, and 6.0% among Hispanic participants. Among non‐Hispanic Black relative to non‐Hispanic White participants, the mediating effect of HbA1C on prevalent dementia was 6% (95% CI: ‐4%, 16%) and the interaction effect with race was 11% (95% CI: ‐11%, 34%) (Table 1). Similarly, we estimated a mediating effect of cystatin C on prevalent dementia of 0% (95% CI: ‐2%,2%) and an interaction effect with race of 10% (95% CI: ‐5%, 25%). For incident dementia, among non‐Hispanic Black relative to non‐Hispanic White participants, the mediating effect of hsCRP on incident dementia was 18% (95% CI: ‐6%, 41%), and the interaction effect with race was 45% (95% CI: ‐20%, 110%) (Table 2). Results were similar for Hispanic relative to non‐Hispanic White participants.

Conclusions

The relationships between race/ethnicity and prevalent and incident dementia were not mediated by or interacted with serum biomarkers of physiological deterioration. Racial disparities in cognitive status in mid‐to‐later life may be attributable to structural factors to racism and the mediating effects of other biomarkers.