bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of transthyretin gene therapy in the 5XFAD mouse model of Alzheimer’s disease
Authors: Batista Ana Rita , Rodriguez Paola , Otero Monique , King Robert M. , Gounis Matthew J. , Sena‐Esteves Miguel
Published: December 2020

Background

Epidemiological studies and work in transgenic animals suggest that transthyretin (TTR) levels in plasma and/or CSF may modulate Alzheimer’s disease (AD) presentation and/or progression. AD patients exhibit lower levels of TTR in CSF compared to age‐matched healthy individuals. Similarly, genetic reduction of TTR in mouse models of AD is associated with earlier onset and more severe phenotypes. The current study was designed to determine the potential of somatic AAV mediated TTR expression to modulate disease presentation in AD.

Method

We designed an AAV9 vector to express TTR specifically in liver and choroid plexus using a TTR promoter to drive transgene expression. Two months old male and female 5XFAD mice were injected systemically with 2E12 gc AAV9‐TTRp‐TTRT119M (n=3M+6F), or PBS as controls (n=3M+6F). At nine months of age animals were subjected to neurobehavioral tests to assess cognitive function, and 3D isotropic T2‐weighted MRI to evaluate differences in brain volume.

Result

Cognitive function was assessed through measure of working and spatial memory using forced and spontaneous alternation tasks in the Y‐maze, and novel object recognition tests. All treated animals showed increased recognition index of novel objects, increased % of alternation, and % time in novel arm, compared to controls. General locomotion and anxiety were evaluated using the open field test, where AAV treated females presented higher locomotor activity and decreased anxiety levels. Interestingly, MRI revealed increased CSF volume in all treated animals compared to controls, with females showing larger differences.

Conclusion

Our initial results show that systemic delivery of an AAV9 vector that expresses TTR in appropriate tissues improves overall cognitive function, locomotor activity and anxiety symptoms in 5XFAD mice; Interestingly more noticeably in females. The unexpected increase in CSF volume may be related to increased TTR production by the choroid plexus of AAV treated animals, and additional experiments are ongoing to determine the cause of this outcome. Biochemical and histological studies of the brain are currently ongoing to assess the disease status in all experimental groups. This new AAV vector is an outstanding platform for therapeutic development and addresses biologically relevant questions about the role of TTR in AD.
Sleep‐dependent association between atrophy and functional connectivity in mild cognitive impairment
Authors: Wennberg Alexandra MV , Pini Lorenzo , Mitolo Micaela , Meneghello Francesca , Burgio Francesca , Semenza Carlo , Venneri Annalena , Mantini Dante , Vallesi Antonino
Published: December 2020

Background

Sleep quality might influence the risk of developing Alzheimer’s disease (AD) in mild cognitive impairment (MCI) patients, driving alterations in brain morphology and functional connectivity. However, the relationship between sleep, gray matter atrophy, and functional connectivity is poorly understood. The present study aims to compare levels of these brain alterations associated with sleep habits in MCI patients.

Method

Structural magnetic resonance imaging (MRI) and resting‐state functional MRI (rs‐fMRI) data from 38 MCI and 38 age‐matched controls were analyzed to investigate atrophy and connectivity, respectively. MCI were stratified into “good” (n=20) and “poor” (n=18) sleepers, stratified at the 50th percentile of the Sleep Continuity in Alzheimer’s Disease Scale, a self‐report questionnaire assessing sleeping quality. Independent component analysis was used to identify the default mode (DMN) and frontoparietal (FPN) networks. For each patient and modality (i.e., structural and rs‐fMRI), z‐score maps were computed based on the control sample. Moreover, for each subject and network, a composite z‐score map across modalities was computed with the following formula: z‐score atrophy – z‐score connectivity. Voxelwise between‐modality comparisons were performed with nonparametric inference using FSL randomise (n=5000 permutations). Multiple comparisons were corrected at a threshold‐free‐cluster enhancement level of p < 0.025 FWE‐corrected.

Result

Connectivity DMN values within the precuneus significantly exceed atrophy in both MCI groups. By contrast, only MCI good sleepers showed connectivity FPN values exceeding atrophy, widespread in frontal, temporal, and parietal regions. Finally, comparing MCI groups using composite z‐score maps, we reported significant FPN connectivity values exceeding atrophy within the right inferior frontal gyrus in MCI good sleeper.

Conclusion

These findings suggest that, among MCI patients, sleep quality may influence the relationship between brain morphology and functional connectivity, resulting in FPN connectivity exceeding atrophy. Our findings might suggest different sleep‐induced slopes in brain atrophy and connectivity within the FPN network. These results might offer novel targets and surrogate outcomes for interventions aimed at restoring sleep disorders in MCI.
Waiting for results of RECage clinical trial: A preliminary context analysis
Authors: Fascendini Sara , Barocco Federica , Mara Zanni , Cosetta Sangiovanni , De Fanti Carlo Alberto , Avesani Mirko , Stucchi Carlo Maria , Matarazzo Carmine , Elena Mariani , Cristina Cilia Maria , Ciccone Alfonso , Casanova Georgia
Published: December 2020

Background

The RECage Project, funded by the European Commission, in the framework of the H2020 RIA projects, has a threefold objective: a) to validate a clinical intervention (the Special Care Unit for Behavioural and Psychological Symptoms of Dementia: acronym SCU‐B); b) to adapt it and produce a consensus document on a model SCU‐B c) to promote the implementation and scaling up of the intervention.

The first objective is pursued through a clinical trial comparing two cohorts of persons with dementia of any etiology and important BPSD, the first one followed by clinical centres endowed with a SCU‐B and the second by centres lacking this facility. The study involves 520 patients and the follow‐up will last three years. Presently the recruitment phase has just ended and the results are foreseen in 2023. The clinical centres are located in six countries: Italy, France, Germany, Greece, Switzerland and Norway.

Method

In order to provide useful data for the second and third phase of the Recage project the Consortium decided to conduct a qualitative analysis in two Italian centres, the one with SCU‐B (Gazzaniga) and the other without SCU‐B (Mantova).

The aims of this qualitative study were: to provide context and needs analysis for each case, underlying strengths, weaknesses, opportunities and threats (SWOT analysis); to identify the (social) innovations promoted by SCU‐B experiences; to identify the replicability characteristics of the SCU‐Bs, to support its implementation in different context. Seven expert interviews and four focus groups have been conducted, with 40 experts and stakeholders involved by specific invitation. The focus groups have been carried out both with the professionals (physicians, physiotherapists, psychologists, occupational therapists, nursing assistants, nurses, educational workers) and with the local stakeholders (local institutions, social services, volunteers, GPs, informal caregivers).

Result

The qualitative analysis shows that: the SCU‐B promotes social innovation; there are opportunities to promote SI and to build a SCU‐B in context in which it is lacking; currently, the complete system seems less replicable than some specific part of it.

Conclusion

We hope that these preliminary results can be confirmed by future analysis and help the development of new SCU‐B.
Early dysregulation of neuronal activities in models of Alzheimer’s disease
Authors: Busche Marc A.
Published: December 2020

Background

Alzheimer’s disease (AD) is a fatal brain disease with a massive societal impact. Identifying effective treatments for AD has proven extremely challenging and has instigated a recent shift in AD research focus towards the earliest disease‐initiating cellular and circuit processes.

Method

We employ in vivo multiphoton calcium imaging alone and in combination with electrophysiological recordings to determine how the abnormal accumulation of proteins (ie, amyloid‐beta and tau) in AD mouse models affects the activity of brain circuits and their components.

Result

We find that soluble amyloid‐beta causes hyperexcitability of neurons in vivo. In striking contrast, tau, even before tangles form, suppresses neuronal activity. Remarkably, the combination of amyloid‐beta and tau leads to suppressed activity as well, as the tau phenotype seems to dominate.

Conclusion

We have identified an unexpected functional effect of tau leading to the suppression of brain circuit activity, blocking the pro‐excitatory effects of Abeta. These data help to understand possible reasons for the recent failures of anti‐amyloid therapies for the treatment of AD.
Neuronal network hyperactivity in computational models of AD
Authors: de Haan Willem , van Nifterick Anne M. , Gouw Alida A. , Stam Cornelis J. , Scheltens Philip
Published: December 2020

Background

Neuronal excitation/inhibition imbalance is a core feature of early Alzheimer’s disease (AD). Although non‐invasive clinical diagnostic methods have not yet reported reliable detection of this phenomenon, MEG studies do report transient increases in oscillatory power and functional network connectivity. However, the relation between these phenomena at different scales is unclear. Computational modeling can be employed to simulate multiscale brain dynamics, relating abnormal neuronal behaviour to brain network impairment. This way, a macroscopic EEG ‘signature’ of underlying neuronal hyperactivity can be predicted.

Method

Our dynamic brain network model consists of 78 neural mass models (representing AAL‐atlas brain regions) coupled according to human DTI‐based structural network topology. By altering neural mass parameters, the level of excitability of inhibitory and/or excitatory neurons can be tuned, in order to assess their influence on overall oscillatory network behavior (absolute and relative power, peak frequency and spike density). The model produces EEG‐like neurophysiological data that can be analyzed the same way as patient data. We compared model outcomes with clinical data of amyloid‐positive (CSF) MCI patients.

Result

Recent computational brain network modeling experiments show a strong effect of inhibition on oscillatory activity as compared to excitation, in line with existing literature. The scenario most compatible with MCI patient data is ‘global decreased inhibition’, producing a decrease in peak frequency and lower relative alpha power, and higher total and relative theta power. This scenario also resulted in the highest spike density levels.

Conclusion

This preliminary study illustrates how computational brain network modeling can aid to construct a coherent framework for the neuropathophysiological findings in AD at different scales of investigation. Although further systematic exploration is needed, computational brain network modeling in AD can become a powerful tool for both research and clinical purposes.
Presynaptic membrane cholesterol homeostasis: A multifactorial contender in Alzheimer’s disease pathogenesis
Authors: Zhang Qi , Stawikowski Maciej
Published: December 2020

Background

Cholesterol (Chol) is highly enriched in the axonal plasma membrane and crucial for exo‐/endocytosis of synaptic vesicles (SVs). At axon terminals, the neuronal activity causes massive SV turnover and in turn perturbs Chol homeostasis between the surface and intracellular membranes. Amyloid precursor protein (APP), enriched at axon terminals, exhibits an intricate association with Cholesterol in multiple aspects. First, it directly binds to Chol via a Chol‐binding motif (CBM) that overlaps with the Abeta sequence. Second, its cleavage by secretases is heavily influenced by Chol. Third, its cleavage products, namely AICD, regulates neurons’ Chol uptake. Our recent work revealed an even more intriguing relationship between APP and neuronal membrane Chol, an inverse correlation between the two in the synaptic membrane.

Method

Here, we developed a novel fluorescent reporter for acute surface‐intracellular exchange of Chol at active synapses.

Result

Surprisingly, we observed a significantly delayed Chol recycling upon stimulation, which intriguingly coordinates with APP turnover at axon terminals. Moreover, point mutations disrupting APP‐Chol binding disengaged the APP and Chol coordination, and disrupted Chol recycling as well as surface Chol distribution. Such disruption led to disruption in SV regeneration, presynaptic sustainability, and axon membrane integrity after extended stimulation or moderate reduction of membrane Chol. Moreover, familial Alzheimer’s Disease (AD) mutations outside of APP’s Chol‐binding motif but increasing APP surface distribution also altered Chol recycling and distressed axon functionality as well as integrity. Last but not the least, we found AD‐related pathological phenotypes like hyperphosphorylated Tau and gliosis as well as higher death rate in aging APP knockout mice.

Conclusion

Taking together, we postulate that APP and its proteolytic processing a part of the regulatory mechanism for the homeostasis of neuronal membrane cholesterol. More importantly, presynaptic Chol dysregulation is a multifactorial contender in AD pathogenesis.
Altered resting state activity associated with anosognosia in Alzheimer's clinical syndrome: Findings from the DELCODE study
Authors: Incesoy Enise I. , Metzger Coraline D. , Yakupov Renat , Spottke Annika , Schneider Anja , Fließbach Klaus , Wiltfang Jens , Boecker Henning , Bürger Katharina , Perneczky Robert , Teipel Stefan J. , Laske Christoph , Priller Josef , Jessen Frank , Wagner Michael , Düzel Emrah , Peters Oliver
Published: December 2020

Background

Anosognosia, or lack of awareness of cognitive impairments, is a common phenomenon in Alzheimer’s clinical syndrome (ACS). Not just patients with dementia(AD) but also patients with mild cognitive impairment(MCI) may have diminished awareness of their deficits. Previous studies have shown that anosognosia is associated with dysfunction and reduced connectivity in the default mode network of the brain and insula. However, less is known about the level of awareness and its neural correlations in individuals with subjective cognitive decline(SCD). This study investigated the underlying neural mechanisms of anosognosia at different stages of ACS.

Method

504 participants (59 AD, 88 MCI, 176 SCD and 181 healthy controls[HCs]) from the DELCODE, a longitudinal multicenter observational study, were included. Cognitive awareness was assessed with a discrepancy score between participants’ report about their own cognitive abilities and report provided by informants. Resting‐state fMRI data of all subjects were analyzed and the fractional amplitude of low frequency fluctuations(fALFF) were calculated as an index of regional spontaneous neural activity. Voxel‐ and clusterwise correlations were conducted using SPM12, controlling for multiple comparisons(GRF). Age, gender and site (9 sites total) were controlled for in each statistical model.

Result

Compared to HCs, subjects with SCD showed heightened awareness for cognitive changes and on the contrary, MCI and AD subjects had higher anosognosia scores. Within‐group comparisons revealed that MCI subjects with anosognosia had reduced neural activity in the left anterior insula compared to MCI subjects without anosognosia (GRF corrected, p<0.005). Moreover, SCD subjects with heightened awareness showed reduced right amygdala activity(GRF corrected, p<0.005), whereas higher activity was observed in the dorsomedial prefrontal cortex (dmPFC) compared to SCD subjects without heightened awareness(GRF corrected, p<0.001).

Conclusion

This is the first study evaluating the association between cognitive awareness at different stages of ACS and regional neural activity using fALFF. Consistent with prior findings, MCI subjects with anosognosia showed reduced neural activity in the anterior insula. Heightened awareness in SCD was associated with higher activity in the dmPFC. Future work should examine the interplay between amyloid pathology and fALFF measures for cognitive awareness, in order to specify neural correlates of cognitive awareness in the Alzheimer’s continuum.
The identification of mild cognitive impairment in Parkinson’s disease using EEG and machine learning
Authors: Sweeney Aoife , Devereux Barry , Ong Charlie , McKinley John , Kearney Seamus , Doherty Karen , Foy Julia , Murphy Brian , McGuinness Bernadette , Passmore Anthony Peter
Published: December 2020

Background

Electroencephalography (EEG) is an inexpensive, non‐invasive and faster method to assess cognition in aging clinical groups. In this study, we are investigating the feasibility of using a ‘dry‐EEG’ mobile headset to assess cognitive impairment in Parkinson’s disease (PD) over a 12‐month period. Cognitive impairment is prevalent in PD with approximately 75% of patients developing dementia within 10 years (Aarsland and Kurz, 2010). The presence of mild cognitive impairment (PD‐MCI) has been associated with increased dementia risk (Pederson et al. 2013). Very little is known about the EEG correlates of PD‐MCI, however EEG has previously been used to predict outcomes in MCI associated with Alzheimer’s disease.

Method

50 Parkinson’s disease patients and 50 age and sex‐matched controls have completed a battery of baseline neuropsychological and EEG tasks. These tasks measured attention, language, memory, visuospatial and executive function domains. Resting state EEG was also recorded. Event‐related potential components and spectral analyses on the delta, theta and alpha oscillatory bands were computed. Differences between groups were assessed using randomisation tests with FDR‐corrected pairwise comparisons. Random forest, k‐nearest neighbours, support‐vector machine and logistic regression machine learning algorithms were also applied to these data. An identical 12‐month follow‐up assessment will be conducted.

Result

Findings from the baseline assessments are presented. 52% of the Parkinson’s disease cohort fulfilled the criteria for MCI. There was no difference in age, education or pre‐morbid IQ between groups. Machine learning classifiers derived from EEG and neuropsychological test metrics discriminated between PD‐MCI, PD normal cognition (PD‐NC) and healthy controls with over 80% accuracy.

Conclusion

Cognitive impairment is prevalent in PD. Our findings show that it is feasible to use dry‐EEG to profile cognition in PD and can differentially discriminate between cognitively normal and cognitively impaired PD patients at an early stage. The features selected are in agreement with the dual syndrome hypothesis of cognition (Kehagia et al., 2013) and those identified in a 10 year follow‐up study (Williams‐Grey et al., 2013). The stability of these features and their ability to predict cognitive status at 12 months will be investigated at a follow‐up assessment.
Differential effects of APOE2 and APOE4 alleles on PET‐measured amyloid‐β and tau deposition in older individuals without dementia
Authors: Grothe Michel J. , Salvadó Gemma , Groot Colin , Moscoso Alexis , Gispert Juan Domingo , Schöll Michael , Ossenkoppele Rik
Published: December 2020

Background

The APOE4 allele is the best‐established genetic risk factor for sporadic Alzheimer’s disease (AD), whereas the APOE2 allele has been linked to decreased AD risk. Although the most prominent neurobiological effect of the APOE polymorphism appears to relate to altered amyloid‐β (Aβ) deposition, recent PET imaging evidence has also pointed to Aβ‐independent APOE4 effects on increased medial temporal tau deposition. Here, we investigated whether APOE2 has a reversed (i.e. protective) association with PET‐measured tau deposition.

Method

From the ADNI cohort we identified 467 APOE‐genotyped individuals without dementia (31% with mild cognitive impairment (MCI); 53% female) who underwent tau ([18F]flortaucipir) and Aβ ([18F]florbetapir or ([18F]florbetaben) PET as well as a structural MRI scan. 257 were APOE3/3 homozygotes, 45 had an APOE2/3 genotype, 160 were APOE3/4 or APOE4/4. Five individuals with a APOE2/4 genotype were excluded from the analysis. Linear models, controlled for age, sex, education, and diagnosis, were used to compare genotype groups on multimodal imaging biomarkers, including entorhinal cortex (ERC) flortaucipir standard uptake value ratio (SUVR, inferior cerebellum reference), cortical Aβ load expressed as centiloid values, and hippocampal volume on MRI. On the basis of an emerging literature highlighting female‐specific risks for developing AD, we also studied sex*APOE interactions on biomarker outcomes.

Result

Compared to APOE3/3, APOE2/3 carriers had significantly reduced Aβ burden (14.2 vs 25.5 centiloids, p=0.021), but did not differ in ERC tau (1.166 vs 1.148 SUVR, p=0.52) or hippocampal volume (p=0.82)(Fig‐1). These effects did not differ between males and females, and similar results were obtained when using alternative medial/inferior temporal tau regions‐of‐interest. By contrast, APOE4 carriers showed both significantly increased Aβ (48.3 centiloids, p<0.001) and ERC tau burden (1.249 SUVR, p<0.001), but no difference in hippocampal volume (p=0.33). In combined regression models, Aβ load fully mediated the APOE4 effect on ERC tau in males (APOE4: t(188)=0.6/p=0.52; Aβ: t(188)=5.3/p<0.001), whereas in females APOE4 retained a minor direct effect (t(217)=2.2/p=0.03) in addition to the prominent effect of Aβ (t(217)=10.6/p<0.001).

Conclusion

We demonstrate a relatively minor Aβ‐independent effect of APOE4 on medial temporal tau deposition, which was observed in females only. Our data do not support a corresponding protective effect of APOE2.
A single ascending dose study in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of O‐GlcNAcase (OGA) enzyme
Authors: Kielbasa William , Phipps Krista M , Tseng James , Natanegara Fanni , Cheng Eden , Monk Scott A. , Bundgaard Christoffer , Kevin Donnelly B. , Nuthall Hugh Norman , McDonald Nicholas , Lindsay‐Scott Peter , Dreyfus Nicolas , Hawk Mai Khanh , Warner Susan , Biglan Kevin , Gilmore Julie A. , Zhang Xiaoyu , Mergott Dustin J. , Lowe Stephen L.
Published: December 2020

Background

LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein we report the first clinical study that assessed safety and pharmacokinetics (PK) of LY3372689 after single oral doses in healthy volunteers (HV).

Method

The phase 1 clinical trial (NCT03819270) was a single ascending dose, randomized, crossover, placebo controlled, investigator‐ and subject‐blind study. Each HV received up to 3 escalating single doses of LY3372689 or placebo over 3 study periods with an approximately 7‐day follow‐up period after each dose, such that a total of 6 LY3372689 dose levels were evaluated. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma PK was assessed up to 48 hours after LY3372689 administration.

Result

A total of 23 HV (15 males, 8 females; 22 – 63 years) participated in the study, of which 18 completed and 5 did not complete due to loss to follow up procedures or did not meet randomization criteria. LY3372689 was generally well tolerated up to the maximum dose administered. There were no serious AE reported and no subjects discontinued the study because of an AE. A total of 13 treatment‐emergent AE reported by 5 subjects considered as possibly related to study treatment were mostly mild in severity, and included pain of skin, headache, limb discomfort, pain in extremity, chest discomfort, muscle fatigue, nausea, and rash macular. The PK of LY3372689 supported daily dosing and was generally dose proportional based on AUC and Cmax.

Conclusion

LY3372689 demonstrated an acceptable safety and PK profile following single oral doses of LY3372689 in HV, which supports further investigation of LY3372689 as a potential treatment for tauopathies.
Discrepancies in the detection of early impairment in elderly individuals: Implications for the clinic and research
Authors: Ritter Aaron , Kaylegian Jaeson , Calvin Kirsten , Ivey Brooke , Cummings Jeffrey L. , Shan Guogen , Caldwell Jessica Z.K.
Published: December 2020

Background

Women’s lifelong advantages in verbal memory persist well into the early stages of Alzheimer’s disease (AD) and may delay AD diagnosis. This has important implications for clinical trials, which frequently use verbal memory tests for eligibility. We examined whether discrepancies between neuropsychological testing and a semi‐structured clinical interview provides enhanced ability to detect early AD, particularly in women. We also examined whether these discrepancies provide meaningful information about disease progression and/or underlying AD biomarkers.

Method

Data was retrospectively analyzed from the Center for Neurodegeneration and Translational Neuroscience (CNTN), a longitudinal, natural history study of elderly individuals. Participants were cognitively normal (CN—with and without subjective cognitive impairment), or diagnosed with mild cognitive impairment (MCI) or mild dementia. We looked for discrepancies between memory tests (Rey Auditory Verbal Learning Test, Brief Visuospatial Memory Test‐Revised) and the Clinical Dementia Rating (CDR) using baseline data from 163 consecutive individuals. Discrepancies were defined as: (1) Neuropsychologically worse (NP worse): CDR=0 and impairments in ≥2 memory scores; or a CDR=0.5 and impairments in ≥5 memory scores. (2) Clinically worse (CDR worse): CDR=0.5 and 0 memory impairments; or CDR=1 and 0 memory impairments.

Result

The overall discrepancy rate was 36% (22% NP worse; 13% CDR worse). In both directions, discrepancies were more common when the participant was male. NP worse individuals were also more often amyloid positive (66%) than CDR worse (43%). When examined longitudinally, participants with discrepancies more often progressed diagnostically (e.g., CN to MCI or MCI to mild dementia) than those without discrepancies. NP worse individuals were almost twice as likely to progress than CDR worse. We found no effects of study partner characteristics (time spent together, gender, education or rate) on discrepancy rates.

Conclusion

In our sample, we found a high rate of discrepancy between CDR and memory scores. Memory impairment more often anticipated cognitive decline and better identified those with underlying AD biomarkers than the CDR. Discrepancies were more common in men than women. Further research is needed to account for sex differences in early AD and should be incorporated in clinical trial design.
Early adult to midlife trajectory of inflammation and midlife cognition
Authors: Yaffe Kristine , Gross Myron , Levine Deborah A , Jacobs David R , Bahorik Amber L
Published: December 2020

Background

Late‐life inflammation, often measured by peripheral biomarkers, has been linked to risk of developing dementia and preclinical cognitive decline. Little is known about early adulthood inflammation and if this could influence cognition earlier in life. Furthermore, few studies have investigated repeated measures of inflammation.

Method

We studied 1920 adults (mean age 33.3 ±3.5, 53% female, 62% white) who were enrolled in the Coronary Artery Risk Development in Young Adults study. We used latent class analysis to identify inflammation trajectories using repeated C‐reactive protein (CRP) measurements (≥3 CRP assessments) over almost two decades. At midlife (mean age 55.4 ±3.5), we assessed cognition using the Digit Symbol Substitution Test (DSST), Stroop Test, Rey Auditory Verbal Learning Test, Montreal Cognitive Assessment, and fluency tests. Logistic regression was used to evaluate the association between inflammation trajectories and poor cognitive performance, defined as a score ≥1 standard deviation below the cohort mean for each test.

Result

Three early to mid‐adult inflammation trajectories were identified: consistently low (34% [n=676]), moderate/increasing (15.0% [n=150]), and consistently high (51% [n=1094]). Those participants in the moderate/increasing or high trajectories had about a two‐fold greater risk (adjusting for age, race, sex, and education) of poor cognitive performance on processing speed and executive function tasks compared to those in the consistently low trajectory. Further adjustment for physical activity, smoking, alcohol, hypertension and diabetes led to similar results (DSST: moderate/increasing OR=2.11 95%CI 1.22‐3.65, high OR=1.52 95%CI 1.07‐2.15; Stroop: high OR=1.68 95%CI 1.16‐2.44). There were no differences by trajectory in odds of poor cognitive performance on memory or global cognition domains.

Conclusion

High or moderate/increasing early to mid‐adult inflammation trajectory was associated with an almost 2‐fold higher odds of worse executive function and processing speed in midlife. These findings suggest that inflammation is an important association for cognitive aging and may begin much earlier in life than previously known.
Intergenerational interactions between people with dementia and children up to the age of five in care homes—what are the outcomes and how are they measured?: A systematic review
Authors: Sakure Jelena , Livingston Gill , Beeke Suzanne
Published: December 2020

Background

Intergenerational projects in care homes are often run for people with dementia and children of pre‐school and Reception age. These projects are thought to be beneficial for people with dementia and the children involved. We systematically review existing research on the different models of such projects and the effect of these on communication.

Method

We searched six electronic databases (Medline, PsychINFO, CINAHL, Scopus, Web of Science, CENTRAL (Cochrane Library)). We searched from inception to present and did not limit the language. Two researchers decided independently on whether references fitted inclusion criteria. We included qualitative and quantitative studies of intergenerational programmes for children not older than 5 years and people with dementia in care homes. Our search terms were adapted for each source and included subject headings and keywords for dementia, children/intergenerational activities and long‐term care settings. We involved a steering group of stakeholders in the discussion of included studies and the synthesis of extracted data.

Results

We report on the impact of intergenerational activities on people with dementia and children, highlighting the domains of verbal and non‐verbal communication. We document the links of these outcomes with the settings, programme types and facilitation contexts in which they occur. We also discuss reported methods for measuring outcomes of intergenerational activities.

Conclusion

We present the existing evidence and give a new interaction and communication‐focused perspective on long term care‐based intergenerational programmes for people with dementia and children up to the age of five. We make recommendations about further research.
β‐amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline
Authors: Hammond Tyler C , Xing Xin , Ma David W , Nho Kwangsik , Crane Paul K , Elahi Fanny M , Ziegler David , Liang Gongbo , Cheng Qiang , Jacobs Nathan , Lin Ai‐Ling ,   Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: December 2020

Background

Over the past several decades, treatment development for Alzheimer’s disease (AD) has been largely focused on modifying amyloid‐beta (Aβ), but no drugs that modify the pathophysiological processes underlying the disease have been FDA approved; it is therefore possible that Aβ may not be the optimal target for treating AD. The NIA‐AA consortium has proposed the use of amyloid, tau, and neurodegenerative (A/T/N) biomarkers in diagnosis and treatment of AD. However, it remains unclear whether each arm of the A/T/N framework has an equally weighted contribution to the progression of AD or rather a stage‐dependent importance to AD development.

Methods

Here we use random forest, a machine learning algorithm, in participants from the ADNI dataset (Table 1) to predict AD cognitive decline using integrated biomarkers from the A/T/N framework: Aβ‐PET, CSF‐pTau, and FDG‐PET and MRI‐Structural, respectively (Table 2). We chose random forest for its high prediction accuracy and interpretability. We also analyzed the relationship between A/T/N biomarkers and memory composite and executive functioning composite scores.

Results

We show that the A/T/N biomarkers have stage‐dependent importance to AD development, with Aβ and phosphorylated‐tau (pTau) better predicting early dementia status (i.e. mild cognitive impairment) and neurodegeneration, especially low glucose uptake, better predicting later dementia status (i.e. clinical AD) (Table 3). We show a similar pattern when correlating markers to performance on memory and executive functioning tests.

Conclusions

Our results provide evidence that AD treatments may need to be stage‐oriented to match the natural disease progression. (Figure 1) Aβ and tau may be appropriate targets early in the disease course, but brain metabolic restoration should be explored as a treatment target later on in the disease process.
Association of cerebrovascular risk burden with mild cognitive impairment, dementia and brain vascular pathologies
Authors: Song Ruixue , Xu Hui , Pan Kuan‐Yu , Qi Xiuying , Buchman Aron S , Bennett David A , Xu Weili
Published: December 2020

Background

To examine the association of cardiovascular risk burden assessed by Framingham General Cardiovascular Risk Score (FGCRS) with incidence of mild cognitive impairment (MCI) and dementia, and brain vascular pathologies.

Methods

Within the Rush Memory and Aging Project, 1203 cognitively intact participants were identified at baseline and followed up to 21 years to detect incident MCI and dementia. FGCRS was assessed at baseline and categorized into tertiles (the lowest, middle, and the highest). MCI and dementia were diagnosed following standard criteria. During the follow‐up, 423 participants died and underwent autopsies for neuropathological assessments. Data were analyzed using Cox regression model, linear regression and logistic regression.

Results

During the follow‐up, 457 participants developed MCI and 192 developed dementia. FGCRS, as continuous variable, was dose‐dependently related to the incidence of MCI and dementia. Compared to the participants with the lowest tertile of FGCRS, those with the highest tertile had the multi‐adjusted hazard ratio (HR) of 1.34 (95% CI 1.04‐1.73) for MCI and 1.49 (95% CI 1.01‐2.21) for dementia. Further, FGCRS was dose‐dependently associated with gross chronic cerebral infarctions (odds ratio [OR] 1.08, 95% CI 1.01‐1.15) and cerebral atherosclerosis (OR 1.09, 95% CI 1.00‐1.18), but not with other brain pathologies.

Conclusion

Higher cardiovascular risk burden is associated with an increased risk of MCI and dementia. Cerebral infarctions and atherosclerosis might underlie this association.
Translating genetic risk variants in disease‐associated enhancers into novel mouse models of Alzheimer’s disease
Authors: Preuss Christoph , Chen Xi , Chen Kathleen , Theesfeld Chandra , Cofer Evan , Uyar Asli , Cary Gregory A. , Pandey Ravi S. , Garceau Dylan , Kotredes Kevin P. , Logsdon Ben , Mangravite Lara M. , Howell Gareth , Sasner Michael , Troyanskaya Olga , Carter Gregory W.
Published: December 2020

Background

The enrichment of late‐onset Alzheimer’s disease (LOAD) GWAS variants in noncoding regions of the genome reveals new potential for modeling disease risk. Yet, identifying noncoding causal variants and the cell types in which they are functional remains challenging. Translating noncoding variants into novel mouse models can elucidate phenotypic effects of those variants through specific perturbations of gene enhancers associated with LOAD risk.

Method

We developed a multi‐tier approach to translate noncoding GWAS risk variants into novel mouse models of LOAD. First, we used publicly available GWAS summary statistics and eQTL data from the AMP‐AD consortium (ROS/MAP, Mayo Clinic) across two brain regions (DLPFC, TCX) to prioritize LOAD risk variants. Then, a deep learning approach (DeepSEA) was implemented to identify regulatory variants in conserved enhancers that are likely to disrupt expression of nearby candidate genes in both human and mouse. Further, ATAC‐seq data from human and mouse was integrated to predict cell‐type specific effects of the prioritized regulatory elements. Finally, the top‐predicted disease‐associated variants were used to develop novel mouse models as part of the MODEL‐AD initiative.

Result

Our integrative approach for prioritizing disease‐associated variants revealed a set of conserved risk variants that mediate the expression of nearby LOAD candidate genes in a cell type‐specific manner. These included several well‐known LOAD risk loci (BIN1, PT2KB, SCIMP, CD2AP). In addition, we identified a genome‐wide significant risk variant (rs4575098, p = 2.05 × 10(‐11), Jansen et al. 2019), which decreased expression of the novel candidate FCER1G in the brain of LOAD patients (ROS/MAP eQTL p = 1.81 × 10(‐05), beta = ‐0.27). This highly conserved variant resides in a microglia specific enhancer and overlaps with a binding site of the transcriptional regulator PU.1 (SPI1). We created a 2kb enhancer deletion mouse model for the FCER1G associated variant and knock‐in models for variants linked to increased expression in three well‐known GWAS loci (BIN1, SCIMP, PT2KB). We provide initial functional characterization for our novel models based on RNA‐seq data.

Conclusion

Our findings expand the list of LOAD candidate genes likely to be impacted by noncoding variants and provide a novel set of mouse models to study their effects in vivo.
Human glia‐specific functional dysregulations affected by APOE ε4 risk of Alzheimer's disease
Authors: T.C.W. Julia , Qian Lu , Liang Shuang A. , Pipalia Nina H. , Chao Michael J. , Shi Yang , Bertelsen Sarah , Kapoor Manav , Marcora Edoardo , Sikora Elizabeth , Holtzman David M. , Maxfield Frederick R. , Zhang Bin , Wang Minghui , Poon Wayne W. , Goate Alison M
Published: December 2020

Background

Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset Alzheimer's disease (AD). APOE ɛ4/ɛ4 homozygosity increases AD risk by >15‐fold. Although its association with AD is well‐established, the mechanisms underlying this genetic risk on particular brain cell types remains elusive. We hypothesized that the APOE ε4/ε4 genotype contributes to disease risk through cell autonomous mechanisms in glia.

Method

We used three models: human induced pluripotent stem cells (hiPSCs), post‐mortem brains and human APOE‐targeted replacement (TR) mice. We have differentiated microglia, astrocytes, cortical neurons and brain microvascular endothelial cells from hiPSC derived from non‐isogenic and isogenic cohort of cells selected based on APOE genotype. We also deconvoluted AD vs control whole brain transcriptome by cell types to confirm the findings from iPSCs in human brain tissue. Primary mouse microglia and astrocytes were purified from APOE‐TR mice. Global transcriptomic analyses were performed to identify APOE ɛ4 impact on particular cell type and to compare species differences. We validated predicted functional pathways in vitro using isogenic hiPSC lines using gas chromatograph‐mass spectrometry, fluorescently tagged cholesterol efflux assay, protein biochemistry and Luminex multiplex immunoassay.

Result

Gene set enrichment and pathway analyses of whole transcriptome profiles showed that APOE ε4 is associated with dysregulation of cholesterol homeostasis in human glia but not mouse astrocytes and microglia. Elevated matrisome signaling associated with chemotaxis, glial activation and lipid biosynthesis in APOE ε4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell‐type deconvoluted transcriptomic data from APOE ε4 glia and AD post‐mortem brains. Experimental validation of the transcriptomic findings showed that isogenic APOE ε4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE ε4 glia also secrete higher levels of proinflammatory chemokines, cytokines and growth factors, indicative of glial activation.

Conclusion

Thus, CNS cell type based models allowed us to elucidate APOE ε4‐driven cell autonomous effects; APOE ε4 induces human glia‐specific dysregulation in reactivity of the cells and associated lipid metabolism that may initiate AD risk.
Lifespan neuroimaging of the 5xFAD mouse model of Alzheimer’s disease: Evolution of metabolic and vascular perturbations
Authors: Szu Jenny , Jullienne Amandine , Obenaus Andre , Territo Paul R , Consortium MODEL‐AD
Published: December 2020

Background

The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) consortium seeks to develop the next generation of Alzheimer’s disease models guided by human data. As new mice models become available, they are extensively phenotyped and compared to existing models, such as the 5xFAD. The 5xFAD models familial AD onset, which results in amyloid β (Aβ) deposition and cognitive decrements early in life; however, no studies have comprehensively phenotyped the vascular and metabolic aspects of this mouse over its lifespan (∼15mo). Here we report lifespan perturbations in male and female 5xFAD mice compared to healthy aging C57BL/6J (WT) mice using multi‐modal neuroimaging with assessment of vascular networks.

Method

Age (4, 8, 12mo) and sex‐matched 5xFAD and healthy aging WT (C57BL/6J) mice underwent ex vivo MRI and in vivo PET evaluation for regional brain volumes (T2‐weighted imaging), Aβ load (susceptibility weighted imaging and 18F‐AV45 PET) and brain metabolism (18F‐FDG PET). After neuroimaging, selected mice underwent novel vessel painting (VP) to label whole brain vascular networks. Histology and immunohistochemical analyses verified neuroimaging findings.

Result

Whole brain volumes were significantly decreased (∼6%) in 8mo female 5xFAD compared to WT, as were hippocampal volumes in both sexes. SWI and AV45‐PET were able to detect elevated Aβ plaques with age in 8‐12mo old 5xFAD mice when compared to WT. 18F‐FDG showed a reduction in glycolysis with age when compared to WT. Whole brain vascular networks in 8mo 5xFAD mice had vessel numbers and complexity compared to 4mo 5xFAD, with males having larger reductions than females. The middle cerebral artery vessel density in 5xFAD was also decreased. Immunohistochemistry confirmed Aβ deposition and microglia activation with genotype and age.

Conclusion

This is the first report of vascular and metabolic disturbances during the lifespan in the 5xFAD model of AD. Our findings suggest that vascular and metabolic ageing are correlated to temporal cumulative Aβ deposition. Early decrements in vascularity in the 5xFAD may precede the development of pathology. Further, the 5XFAD mice exhibit age and region‐specific neuroimaging alterations coincident with metabolic disturbances.
Brain target occupancy of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme: Translation from rat to human
Authors: Shcherbinin Sergey , Kielbasa William , Dubois Susan , Lowe Stephen L , Phipps Krista M , Tseng James , Kevin Donnelly B , Natanegara Fanni , Warner Susan , Dreyfus Nicolas , Lindsay‐Scott Peter , Hawk Mai Khanh , McDonald Nicholas , Zhang Xiaoyu , Gilmore Julie A , Biglan Kevin , Mergott Dustin J , Russell David , Gunn Roger N , Constantinescu Cristian , Nuthall Hugh Norman , Collins Emily C
Published: December 2020

Background

LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein, we report on nonclinical and clinical studies that assessed the effect of LY3372689 on brain OGA enzyme occupancy (EO).

Method

Brain OGA EO of LY3372689 was measured in the frontal cortex of rats using tracer LSN3291920, a non‐fluorinated analog of a positron emission tomography (PET) radioligand 18F‐ LY3316612. A single oral dose study in healthy volunteers (HV) utilizing18F‐LY3316612 is ongoing to assess brain OGA EO of LY3372689 (NCT03944031). The study consists of up to 5 Cohorts (N = 3 – 6 subjects per Cohort). Upon completion, each subject will have participated in one cohort and have received a baseline PET scan and up to two post‐dose PET scans. In the initial cohorts, the post‐dose PET scans were conducted at approximately 2 and 24 hours after LY3372689 administration. The study design is adaptive to allow adjustment of the LY3372689 dose, timing of PET scans and pharmacokinetic samples, and number of subjects, pending results of prior cohorts.

Result

In rat studies, LY3372689 demonstrated a dose‐dependent change in OGA EO following a single oral dose with a maximum EO of greater than 90%. In the human PET study, a total of 12 healthy volunteers across 3 dose cohorts (N = 4 HV per cohort) have been enrolled to date. A plasma concentration‐dependent increase in brain OGA EO was observed with EO exceeding 90% at 24 hours following the highest dose of LY3372689 administered.

Conclusion

Non‐clinical and clinical EO studies demonstrated that occupancy of the OGA enzyme effectively translated from rats to humans after single doses of LY3372689. The human PET data can be used to support LY3372869 dose selection for efficacy trials in tauopathies.