bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploration of the endo‐lysosomal pathway genes in frontotemporal dementia: The use of protein‐protein interaction networks to prioritize rare‐variant association analysis results
Authors: Kocoglu Cemile , Manzoni Claudia , Ferrari Raffaele , Van Broeckhoven Christine , van der Zee Julie
Published: December 2020

Background

Genetic studies in frontotemporal dementia (FTD) have identified multiple genes linked to the disease, yet explain only 30% of the patients. Identification of genetic causes in the remaining inherited cases is needed to elucidate the molecular biology of disease development, and thereby to pinpoint novel targets for therapeutic applications. Multiple lines of evidence have demonstrated disruption of the endo‐lysosomal pathway (ELP) in dementia. Here, we aimed to search for novel FTD genes in the ELP through rare variant association analysis.

Method

We applied weighted protein‐protein interaction (PPI) network mapping using 66 dementia‐associated genes (FTD, Alzheimer disease and Lewy‐body dementia) as seed genes. From this ‘Dementia interactome’, we extracted brain expressed ELP associated genes consulting Gene Ontology, Reactome, GTEx and Braineac. Exome‐wide rare variant association was tested using SKAT‐O, CMC and Madsen‐Browning tests.

Result

We generated whole exome sequencing data on 238 Belgian FTD patients and extracted exonic variants from whole genome sequencing data of 176 Belgian controls, obtained through collaboration with Project MinE (van der Spek et al., 2019). No genes passed exome‐wide significance level in the rare‐variant burden tests. Mapping ELP‐associated genes on the PPI network resulted in a list of 2.486 genes to be prioritized in our gene burden test results. As a result of this prioritization, 31 genes reached nominal significance. We are presently investigating those genes by incorporating their weight in the network (i.e. distance to known gene products and network topology), as genes with a higher weight are more likely contributors to disease development. Preliminary results suggest a role for vesicle‐mediated transport (GO:0016192) genes in FTD risk.

Conclusion

Applying a tailored PPI network approach, we prioritized ELP‐associated genes as potential disease (risk/protective) genes for FTD. ELP candidate genes pointed towards a role for vesicle‐mediated transport in FTD pathogenesis. This prioritization approach increases the power needed for rare variant disease association. Furthermore, we present an accessible disease pathway‐based analysis pipeline that is applicable to different types of genetic studies (rare high‐penetrant vs common‐risk) and disease phenotypes and pathways of interest.
Preclinical development of PR006, a gene therapy for the treatment of frontotemporal dementia with progranulin mutations
Authors: Heckman Laura D. , Burstein Suzanne R. , Brandes Alissa , Wong Li Chin , Yang Zhaohui , Lin Hsuan‐Ni , Fenn Tim , Nelson Stuart , Aziz Zarah , Kamalakaran Sid , Garimalla Swetha , Haller Jorge , Daily Jenn , Politi Jason , Dai Yong , Hefti Franz , Abeliovich Asa
Published: December 2020

Background

Frontotemporal dementia (FTD) caused by GRN haploinsufficiency (FTD‐GRN) represents 5‐10% of all FTD cases. GRN encodes progranulin, a glycoprotein that is essential for normal lysosomal function and neuronal survival. FTD‐GRN patients exhibit approximately 50‐70% reduction in progranulin levels. We are developing PR006, an AAV vector designed to deliver the GRN gene, for FTD‐GRN patients with a goal of slowing or stopping disease progression. We aimed to evaluate the efficacy of PR006 in preclinical models of FTD‐GRN.

Method

We evaluated the efficacy of PR006 in vitro using neurons differentiated from human induced pluripotent stem cells (iPSCs). iPSC‐derived neurons from individuals carrying GRN mutations exhibit reduced progranulin levels and decreased activation of the lysosomal enzyme cathepsin D. Additionally, we assessed the therapeutic effects of PR006 in vivo using a Grn knockout (KO) mouse model of FTD‐GRN. Grn KO mice exhibit progressive brain‐wide lipofuscinosis, ubiquitin accumulation, microgliosis, and neuroinflammation. PR006 was administered by intracerebroventricular (ICV) injection to Grn KO mice, and vector biodistribution, progranulin levels, lysosomal alterations, and neuroinflammation were assessed. Nonhuman primates (NHPs) were used to assess the safety and tolerability of PR006.

Result

PR006 transduction in iPSC‐derived FTD‐GRN mutation carrier neurons resulted in robust, dose‐dependent secretion of progranulin and restored cathepsin D maturation. In the Grn KO mouse model, ICV PR006 treatment was well‐tolerated and resulted in broad vector biodistribution and increased progranulin expression in biofluids and tissues. PR006 treatment in the Grn KO mouse model decreased lipofuscinosis, ubiquitin accumulation, and expression of neuroinflammatory markers in the brains of these animals. PR006 treatment in NHPs was well‐tolerated and resulted in broad vector biodistribution and progranulin expression in the central nervous system and the periphery.

Conclusion

These in vitro and in vivo preclinical studies demonstrated that PR006 effectively increased expression of progranulin and reduced pathological features of FTD‐GRN, supporting clinical development of PR006 for patients with this disease.
A qualitative review of areas of conflict within post‐diagnostic healthcare in dementia triads
Authors: Tuijt Remco , Rees Jessica , Frost Rachael , Wilcock Jane , Manthorpe Jill , Rait Greta , Walters Kate
Published: December 2020

Background

The functioning of a dementia healthcare triad, namely a person living with dementia, their (family) carer and their healthcare professional, is a recent focus of improving the understanding of relationships that are important in person‐centred care. Evidence was reviewed to synthesise qualitative research that included members of the triad to explore where triad members hold dissenting or discordant views on their dementia care.

Methods

English‐language Medline, PsycINFO, Embase and CINAHL were systematically searched up to January 2020 for qualitative research on healthcare experiences including all members of dementia healthcare triads: people living with dementia, carers and healthcare professionals. Data were coded and thematically synthesised. Relationships between members of the triad were explored by coding the views held by one or two members of the triad, where these were presented by the authors as unique or opposing the views of another.

Results

The synthesis included 28 papers from 26 studies, including 243 people living with dementia, 433 carers, and 475 healthcare professionals. We identified areas where triad members held discordant or conflicting views. Professionals found it difficult to engage when people living with dementia did not accept their diagnosis, or when carers did not see a need for formal care. In addition to this, triad members commonly held different priorities for care, for example people living with dementia prioritised stability, whereas carers focused more on safety. People living with dementia were unlikely to initiate decision‐making discussions, which removed them from discussions carers and professionals were having. This also led to carers and professionals making decisions without input from the person living with dementia despite people living with dementia voicing their concern about being excluded. In order to re‐establish a working triad, conflict resolution was expected from the professionals.

Conclusion

By exploring the differing viewpoints of members of a triad, we may increase understanding of how triads function and pre‐empt potential factions developing. Further research will examine how coalitions form that hinder or help wellbeing, as well as exploring further opportunities to work within dementia care triads that hold dissenting views.
The impact of patient and partner personality traits on learning success for a cognitive rehabilitation intervention for patients with MCI
Authors: Locke Dona E , Devick Katrina , Khayoun Renata , Cuc Andrea , Shandera‐Ochsner Anne , Francone Andrea , Smith Glenn E , Chandler Melanie
Published: December 2020

Background

One nonpharmacological intervention for persons with amnestic Mild Cognitive Impairment (MCI) is development of a compensatory memory notebook/planner system. De Wit et al. (2019) showed that global cognitive status is the primary predictor of learning success with training on a memory notebook system and that learning success predicts ongoing adherence to the tool. The purpose of our work is to validate their analysis in a new sample and evaluate whether or not patient or partner personality traits predict learning success over and above that explained by cognitive status.

Method

Training in the Memory Support System (MSS) is one component of the multi‐disciplinary behavioral intervention program called Healthy Action to Benefit Independence and Thinking (HABIT) offered at Mayo Clinic. 183 patient and partner dyads completed the HABIT program and enrolled in our IRB approved ongoing research registry to allow use of their clinical data for research purposes. Personality traits were measured with the self‐report Ten Item Personality Inventory (TIPI) based on the five‐factor model of personality (Agreeableness, Conscientiousness, Emotional Stability, Openness, and Extraversion) completed by both the patient and the partner. For our analyses, we fit logistic regression models to predict full MSS mastery at the end of the two‐week program and dichotomized TIPI into “high” or “low” for each trait based on its median (low was the reference group).

Result

Consistent with De Wit et al. (2019), global cognitive status again was the only significant predictor of MSS learning mastery when considering age, education, baseline depression score and baseline global cognitive status (Table 2). When adding patient personality traits, only openness significantly added to the model with higher openness predicting learning success (Table 3). Adding both patient and partner personality traits resulted in a significant interaction between patient and partner openness (Table 4). The direction of this interaction indicates that learning success is highest when either the partner or patient is high in openness (but not both).

Conclusion

High openness to experience in the patient with MCI or their partner (but not both) significantly improves learning success for a cognitive rehabilitation memory support tool in patients with MCI.
Association of brain amyloid accumulation and glucose hypometabolism with memory loss
Authors: Wang Ying , Huang Qi , Ren Shuhua , Huang Lin , Jiang Donglang , Li Junpeng , Guan Yihui , Guo Qihao , Xie Fang
Published: December 2020

Background

Memory loss is the main syndrome of Alzheimer’s disease (AD). Extracellular accumulation of amyloid‐β (Aβ) neuritic plaques and neurodegeneration such as glucose hypometabolismwere the main pathology of AD. In this study, we try to figure out the association of Aβ accumulation and glucose hypometabolism with memory loss.

Methods

91 normal cognition (NC) healthy volunteers, 37 subjective cognitive decline (SCD), 32 mild cognition impairment (MCI) and 34 AD patients were enrolled in this study from Chinese preclinical Alzheimer’s disease (C‐PAS), which is initiated by Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and Huashan Hospital. 6 types of neuropsychological tests from 3 cognitive core, including Auditory verbal learning test (AVLT) 30‐minute delayed free recall and AVLT recognition for memory, MMSE, Moca B were performed. FDG and amyloid PET (18F‐Flortabetapir) were conducted in these participants. 18F‐FDG and 18F‐Flortabetapir PET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space. The associations of FDG and Aβ with impairment of language were explored by performing multiple regression between the 18F‐FDG and neuropsychological scores, as well as 18F‐Flortabetapir PET images and neuropsychological scores with age, gender, educationalyears as covariates. The statistical level was set at p<0.05 with FDR correction and a minimum cluster extent Ke>20 voxels.

Results

No relationship was found between memory loss and amyloid accumulation. Glucose metabolism in precuneus, middle frontal cortex, cuneus, posterior cingulate gyrus has association with AVLT 30‐minute delayed free recall. Association was observed between glucose metabolism in inferior frontal cortex, insula and AVLT recognition.

Conclusion

Associations were observed between memory loss and glucose hypometabolism, but no association was found between amyloid and memory loss.
Neuropsychiatric symptoms and cognitive decline: Trait or state effects?
Authors: Vik‐Mo Audun Osland , Melvær Giil Lasse , Ballard Clive , Aarsland Dag
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are associated with more rapid cognitive decline but the effects of specific NPS remain unknown. NPS could have distinct association with the symptomatic state (within‐person effects, WP), but also as a symptom‐trait over time irrespective of current symptoms (between‐person effects, BP). The aim of study was to disentangle these effects.

Method

Patients with mild Alzheimer’s disease (AD, n = 111) and Lewy‐body dementia (LBD, n = 85) were assessed annually from diagnosis until death with a mean follow‐up of 5.4 years (range 1‐12). Total, within‐person and between‐person associations between specific NPS (assessed with the Neuropsychiatric Inventory (NPI)) and cognition (measured by annual Mini‐Mental State Examinations (MMSE)) were analysed using a Tobit mixed‐effects model. NPI items were classified using ≥ 1 and 4 cut‐offs, and the models were adjusted for age, gender, diagnosis and survival.

Result

Hallucinations, agitation, anxiety, apathy and appetite were associated MMSE decline in the overall analysis. Hallucinations, agitation and apathy had both WP and BP associations with more rapid MMSE decline, with BP associations being stronger. Delusions and motor disturbances had strong BP association with MMSE decline. NPI symptom severity did not impact the results.

Conclusion

Different NPS had distinct state and trait associations with cognition that also differed from the total association. Treatment of NPS might improve cognition and should be tailored for different NPS based on history and current symptoms. Importantly, the effect of mild symptoms is similar to that of severe symptoms. These findings underline the importance of treatment as well as prevention of NPS. The high degree of instability of NPS has relevance for the design of clinical trials.
Associations of peak width of skeletonized mean diffusivity with cardiovascular disease risk and cognitive decline in clinically normal older adults
Authors: Scott Matthew R. , Schultz Aaron P. , Buckley Rachel F. , Chou Hsiang‐Chin Lori , Hampton Olivia L , Hanseeuw Bernard J , Jacobs Heidi I.L. , Properzi Michael J. , Rabin Jennifer S. , Johnson Keith A. , Sperling Reisa A. , Chhatwal Jasmeer P.
Published: December 2020

Background

Cardiovascular disease (CVD) is associated with cognitive decline, both alone and synergistically with Aβ burden, and can have a stronger relationship with cognitive trajectories than many standard imaging biomarkers. However, the effects of CVD and Aβ on cognitive decline have not been examined alongside diffusion markers of small vessel disease (SVD). With data from the Harvard Aging Brain Study (HABS), we examined the influence of CVD risk and peak width of skeletonized mean diffusivity (PSMD; a DTI measure of SVD) on cognitive trajectories in clinically normal participants, while accounting for Aβ burden.

Method

264 clinically normal participants from HABS (mean [SD]: age=73.2[7.1] years; follow‐up range=6.3[1.8] years) underwent at least four longitudinal assessments of the Preclinical Alzheimer’s Cognitive Composite (PACC96), as well as PiB‐PET imaging and DTI at baseline. PSMD was calculated from skeletonized mean diffusivity maps using FSL. CVD risk was quantified using the Framingham Heart Study‐CVD risk score. We used linear mixed‐effect models to examine the influence of baseline PSMD and CVD on longitudinal PACC, while controlling for, or interacting with, PiB DVR, correcting for baseline age, years of education, and biological sex.

Result

PSMD and CVD were significantly correlated (r=0.38, p<1.0x10‐9), though this weakened when correcting for age (r=0.15, p=0.01), while PSMD and PiB showed no association (r=0.09, p=0.13). Higher PSMD was associated with faster cognitive decline (t(1808)=‐2.40, p=0.02) and this effect remained (t(1806)=‐2.26, p=0.02) after correcting for PiB. The effect of PSMD was marginally significant (t(1804)=‐1.93, p=0.05) when correcting for both CVD (t(1804)=‐4.44, p<1.0x10‐5) and PiB (t(1804)=‐7.79, p<1.0x10‐13). No significant interactive effect of PSMD and PiB on cognitive decline was observed.

Conclusion

CVD risk and PSMD were significantly correlated, though this was largely driven by age, while PiB and PSMD were not. PSMD was significantly associated with faster cognitive decline. After adjusting for both CVD and PiB however, the effect of PSMD on cognitive decline was attenuated. It is possible that CVD risk may capture variance related to cognitive decline beyond that of PSMD. However, future research is needed to understand which domains of the CVD risk score are driving these findings.
Quantification of amyloid accumulation and glucose metabolism in Chinese Alzheimer’s disease population
Authors: Li Junpeng , Jiang Donglang , Huang Qi , Ren Shuhua , Guo Qihao , Guan Yihui , Xie Fang
Published: December 2020

Background

Extracellular amyloid‐β (Aβ) neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neurodegeneration, such as glucose hypometabolsim were the main biomarkers of Alzheimer’s disease (AD). The uptakeof Aβ radiotracers, such as Flortabetapir, and uptake of FDG for glucose metabolism in subjective cognitive decline (SCD), mild cognition impairment (MCI) and Alzheimer’s disease (AD) is very important for diagnosis and management. Currently, no study was found to investigate the uptake of Flortabetapir and FDG in these cohorts. In this study, we try to figure out the standard uptake value ratio (SUVr) of different brain regions in Chinese SCD, MCI, AD.

Methods

93 normal cognition (NC) healthy volunteers, 37 SCD, 34 MCI and 36 AD patients were enrolled in this study. 3 cognitive domains (2 neuropsychological tests of each domain) and MMSE, Moca B were performed in these participants. FDG and 18F‐Flortabetapir were conducted in these participants. 18F‐FDG and 18F‐FlortabetapirPET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space. SUVr values were calculated with cerebellum as referencefor Flortabetapir and whole brain for FDG.

Results

In Chinese NC, SCD, MCI and AD, SUVr of flortabetapir in precuneus were 0.87 ± 0.25, 0.84 ± 0.18, 0.83 ± 0.32, 1.08 ± 0.46, respectively. 1.09 ± 0.24, 1.02 ± 0.15, 1.05 ± 0.28, 1.24 ±0.38 in posterior cingulate. SUVr of flortabetapir in AD is significant higher (p < 0.05) than other groups. SUVr of FDG in precuneus were 1.17 ± 0.08, 1.19 ± 0.07, 1.13 ± 0.12, 1.07 ± 0.10, 1.05 ± 0.10, respectively. 1.08 ± 0.10, 1.03 ± 0.12, 0.90 ± 0.18 in posterior cingulate. SUVr of FDG in AD is significant lower (p < 0.05) than other groups.

Conclusion

The uptakes of Flortabetapir were signifigant higher and uptakes of FDG were lower in Chinese AD than in NC, SCD, MCI in precuneus and posterior cingulate.
Cross‐sectional relations of subclinical cardiovascular disease to AD blood biomarkers in cognitively intact older adults
Authors: Wright Regina Sims
Published: December 2020

Background

Subclinical cardiovascular disease (CVD) is a key, early step in the development of frank CVD. Generally characterized by an age‐related increase in atherosclerosis and arterial stiffness, and/or reduced endothelial function, emerging evidence suggests subclinical CVD confers risk for Alzheimer’s disease and related dementias (ADRD) well before the onset of frank CVD. However, despite increasing recognition of the utility of blood biomarkers for understanding the pathophysiological events and progression of AD, little research has examined the association between markers of subclinical CVD and AD blood biomarkers. Thus, we sought to examine these associations in a sample of cognitively intact older adults enrolled in the Healthy Heart & Mind Study.

Method

Participants were 34% male and 41.7% African American with a mean age of 68.43y. Participants completed a health and medication screening, a battery of cognitive tests, a psychosocial assessment, a fasting blood draw, vascular testing (including assessment of carotid intimal‐media thickening (IMT), pulse wave velocity (PWV), and brachial artery flow‐mediated dilation (FMD), and structural brain MRI. Serum Ab1‐40 and Ab1‐42 (and ratio) were available for 99 participants at the time of this analysis.

Result

Bivariate correlation results showed a significant, positive association between % FMD change and Ab1‐40 only (p<.05). Ordinary least squares regression was run to further examine this association adjusting for the following potential confounding variables: age, gender, education, depression, and mean arterial BP. Results showed the significant, positive association between % FMD change and Ab1‐40 persisted after adjustment (p<.05).

Conclusion

Findings showed that worse endothelial function may be associated with lower Ab1‐40 in healthy older adults. While some research illustrates Ab1‐40 is reduced in AD, other research suggests increased levels are associated with vascular conditions such as hypertension, ischemic heart disease, and white matter lesions. Thus, our findings suggest a need to further examine the association between endothelial function and AD blood biomarkers to confirm the directionality of the relationship. Longitudinal research is also needed to examine the association over time.
Validating digital cognitive biomarkers for Alzheimer’s disease
Authors: Bock Jason R , Lee Michael D , Hara Junko , Fortier Dennis , Mangrola Tushar , Shankle William R
Published: December 2020

Background

This study sought to validate a pragmatic method to predict impending cognitive decline in Alzheimer’s disease (AD) patients, prior to the development of hallmark symptoms. The method, a Hierarchical Bayesian Cognitive Process (HBCP) model, uses item responses to a wordlist memory (WLM) test to generate digital cognitive biomarkers (Table 1). We replicated our earlier study, performed on AVLT item response data from Mayo Clinic, by applying the HBCP model to distinguish non‐decliner and decliner groups of normal subjects at baseline from a novel dataset, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), with a distinct WLM test, ADAS‐Cog.

Method

From the ADNI dataset, we classified non‐decliner subjects (n = 442) as those whose diagnosis remained normal for 3 or more years after normal baseline assessment and decliner subjects (n = 61) as those who developed amnestic MCI or AD within 3 years of normal baseline assessment. Three analytic approaches were compared: 1) Traditional summary scores per ADAS‐Cog task were assessed for group differences with a commonly‐used statistical approach, logistic regression; 2) summary scores were assessed with a Bayesian modeling approach; and 3) item response data were assessed with our HBCP model, generating digital cognitive biomarkers.

Result

Logistic regression of summary scores generated β coefficients (Table 2) that did not significantly discriminate between groups. Bayes Factor assessment of fitted Gaussian distributions to the per‐task group recall by summary score measurement provided moderate evidence that the groups were measurably the same (BF
sd = 3.4, 3.1, 2.9, and 1.4, respectively). The HBCP model produced posterior distributions of group differences. Bayes Factor assessment identified three with notable group differences: Immediate Retrieval from Durable Storage, L1 (BF
ds = 11.8, strong evidence), One‐shot Learning, r (BF
ds = 4.5, moderate), and Partial Learning, a (BF
ds = 2.9, weak; Figure).

Conclusion

The obtained strong evidence for L1 group differences represents successful replication of previous work with our HBCP model on this novel dataset. The ability to identify differences in subjects diagnosed cognitively normal at time of assessment demonstrates the HBCP model’s advantage over summary score assessment and its applicability for detection of impending cognitive decline in asymptomatic AD patients.
The accumulation rate of tau aggregates is higher in females and younger individuals
Authors: Smith Ruben , Strandberg Olof , Mattsson Niklas , Leuzy Antoine , Palmqvist Sebastian , Pontecorvo Michael J. , Devous Michael D. , Ossenkoppele Rik , Hansson Oskar
Published: December 2020

Background

Tau pathology is a key hallmark of Alzheimer’s disease (AD), but factors modifying the rate of tau accumulation are still largely unknown. Tau‐PET allows tau pathology to be visualized in vivo in AD. Our aim was to study factors associated with the accumulation rate of tau pathology, using [18F]flortaucipir PET.

Method

419 participants from four longitudinal cohorts in the United States (AVID05, n=157; Expedition 3, n=82; and ADNI, n=123) and Sweden (n=57) were scanned between June 2014 and May 2019. Study participants were cognitively unimpaired (CU, n=153), or patients with mild cognitive impairment (MCI, n=139) or AD with dementia (AD, n=127).Participants underwent two to four [18F]‐flortaucipir PET scans with a mean of 538 (±163[SD]) days between the first and last scan. Amyloid‐β(Aβ) status was determined using PET. [18F]‐flortaucipir was quantified in a temporal meta‐region of interest (ROI) and a neocortical ROI. Subject‐specific slopes (reflecting annual change) of [18F]‐flortaucipir SUVR were derived from linear regression models for each ROI. Generalized linear models were used to predict the subject‐specific slopes using the following variables: diagnostic group, age, sex, baseline tau‐PET SUVR, baseline Aβ‐status, APOE‐ε4 status and study cohort.

Result

Accelerated increase in [18F]‐flortaucipir retention was observed in Aβ+ MCI and AD dementia, respectively, when compared to either Aβ‐ CU and Aβ‐ MCI (Figure 1). We found associations between change in [18F]‐flortaucipir over time and female sex (temporal meta‐ROI: t=2.93, p=0.004; neocortical ROI: t=2.96, p=0.003), younger age (temporal‐meta ROI: t=‐2.42, p=0.02), and baseline [18F]‐flortaucipir retention (temporal‐meta ROI: t=3.60, p<0.001; neocortical ROI: t=4.88, p<0.001) (Figure 2). There was a significant interaction between age and Aβ‐status on change in [18F]‐flortaucipir SUVR (temporal‐meta ROI: t=‐2.50, p=0.013). There was no effect of study cohort or APOE‐ε4 genotype. In a similar analysis on longitudinal Aβ‐PET (in ADNI subjects only, n=639) we found significant associations between the rate of Aβ‐accumulation and APOE‐ε4 positivity, older age and baseline Aβ‐positivity, but no effect of sex.

Conclusion

These findings indicate that the tau accumulation rate is increased in females and Aβ‐positive younger individuals, in contrast to Aβ‐accumulation which is increased in APOE‐ε4 carriers and older individuals.
Protocol of a cluster randomised controlled trial to assess the effectiveness of a care management programme for caregivers of people with dementia (GAP study)
Authors: Klein Olga A , Kilimann Ingo , Thyrian Jochen René , Teipel Stefan J , Keller Armin , Boekholt Melanie , Michalowsky Bernhard , Zwingmann Ina , Dreier‐Wolfgramm Adina , Hoffmann Wolfgang
Published: December 2020

Background

About 75% of dementia care is provided by family caregivers who often experience adverse health outcomes. The identification of unmet healthcare needs of family caregivers is crucial to provide appropriate support thereby relieving the economic burden of dementia. As the first point of contact, general practitioners (GPs) have a key role in identifying burden and care needs of family caregivers. However, in routine care, this opportunity is hampered by time constraints and even if caregiver needs are being recognised, GPs often lack detailed information on regionally available support and healthcare services. Aim: To assess the clinical and cost‐effectiveness of a GP‐ and computer‐based care management programme to reduce unmet care needs of family caregivers of people with dementia (PwD).

Method

This is a multi‐site, cluster randomised, controlled trial comparing a digital care management programme (intervention) with usual care (control). Five hundred family caregivers will be randomised at GP offices, specialist practices, and memory clinics, with about n=250 participants per arm. A computer‐based assessment will identify needs of family caregivers of PwD and will automatically generate an individual management plan. The treating GP will carry out the management plan generated in close collaboration with specifically qualified nurses, so‐called dementia care managers, who support and monitor the implementation of the care plan via four monthly telephone follow‐ups. All participants will receive a final follow‐up assessment at six months after randomisation. Participants in the control group will receive usual care at first and the individual management plan at the six months follow‐up. Primary outcomes are the Camberwell Assessment of Need for the Elderly and the EQ‐5D. Secondary outcomes include the Zarit Burden Interview, the Social Lubben Network Scale, and use of medical and non‐medical services. This trial is funded by the German Federal Joint Committee (G‐BA) and registered in the clinical trials database under NCT04037501.

Result

We expect to obtain significant differences in primary and secondary outcomes between groups in favour of the intervention group.

Conclusion

The findings of this trial will be useful in informing and improving current healthcare system structures to support family dementia caregivers within routine care practice.
The impact of protocol design on MMSE changes in the screening period
Authors: Kott Alan , Miller David S.
Published: December 2020

Background

Anecdotally, we have observed subgroups of subjects who in the screening period of clinical trials in early Alzheimer’s disease exhibit unexpectedly large changes in MMSE scores. Such changes could be explained by a number of reasons, such as learning effects, regression to the mean, measurement error, or intentional score manipulation. If the latter was the case, differences in MMSE changes between screening and baseline should be observed between protocols where MMSE inclusion criteria are required to be met at screening only and protocols requiring the criteria be met at screening and baseline. We hypothesized that MMSE changes would be larger in protocols with criteria required only at screening.

Method

Data were pooled from multi‐national dementia clinical trials in early AD where MMSE was collected at screening and baseline. Subjects were categorized into 2 groups depending on whether the inclusion criteria were applied to screening alone or to both the screen and baseline visits. T‐test was used to compare the change between screening and baseline between the two groups of subjects. Additionally we compared the distribution of subjects changing by a) 3 and b) 5 MMSE points in either direction between screening and baseline between the two protocol groups using a chi‐square test.

Result

Data were collected from 1,409 subjects. The MMSE change in subjects with criteria required at screening only was ‐1.2 points compared to ‐.05 points in subjects with criteria required at screening and baseline (t(1,407) = 5.99, p < 0.001). MMSE changes of 3 or 5 points were seen significantly more often in studies where the requirement was applied at screen alone (chi2(1)=18.2, p < 0.001 and chi2(1)=13.1, p < 0.001, respectively).

Conclusion

Our analyses indicate that protocol design has a significant impact on the MMSE change observed in the screening period. Given the only difference between the two groups was the absence of inclusion criteria at baseline, we hypothesize that the MMSE score change observed differences can most likely be explained by score manipulation happening at either screening only or screening and baseline, depending on protocol type. We plan to replicate these results in larger datasets.
Chronic phospholipase D1 inhibition via small molecule inhibitors ameliorate dendritic spine dystrophy in ADRD mouse models via phosphocofilin mediated changes
Authors: Natarajan Chandramouli , Bourne Krystyn Z. , Medina Perez Carlos X. , Krishnan Balaji
Published: December 2020

Background

Phosphatidyl choline phospholipase D (PC‐PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms ‐ a constitutively expressed PLD2 and an inducible PLD1 isoform ‐ are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.

Method

Synaptosomal Western blot analysis on 3xTg‐AD mice hippocampi were used to investigate neuronal PLD1 expression and function. Long term potentiation of PLD1 dependent changes using pharmacological approaches in ex vivo slice preparations from wildtype and transgenic mouse models were used to assess synaptic perturbations that were first studied using the novel object recognition memory (NOR) and fear conditioning (FC) paradigms. Chronic PLD1 small molecule inhibitor treatment was assessed in different age groups to ascertain the efficacy of treatment at different stages of Aβ and tau‐driven AD‐like memory deficit progression in transgenic animal models. Lastly, brain tissues from these animals were subjected to Western Blot analyses, Golgi analysis, immunohistochemical analysis to ascertain the potential signaling mechanism(s) that is/are perturbed/altered by overexpression of PLD1 in such diseased states.

Result

Chronic PLD1 inhibition ameliorates the synaptic dysfunction and underlying memory deficits in the 3xTg‐AD mouse model by specific action on preserving mushroom spine dendritic spine integrity. Further analysis using Western Blots revealed an underlying mechanism that increases the levels of phosphocofilin in the crude synaptosomal fractions.

Conclusion

Using chronic administration of a well‐tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory. Furthermore, we also observed that the mechanism involves actin cytoskeletal dynamics that are modulated via phosphocofilin.
In vivo testing of the role of Alzheimer’s disease coding variants
Authors: Sasner Michael , Oblak Adrian L. , Garceau Dylan , Kotredes Kevin P. , Preuss Christoph , Pandey Ravi S. , Uyar Asli , Lamb Bruce T. , Carter Gregory W. , Howell Gareth ,   MODEL‐AD Center
Published: December 2020

Background

Numerous AD risk loci and variants have been identified by large‐scale genetic studies, but few have been functionally verified and models to study their mechanism of action are lacking. The Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center was created to develop, characterize, and distribute more precise preclinical models for late‐onset AD (LOAD) by engineering these disease‐associated variants into mouse models, and characterizing the resulting phenotypes using clinically relevant assays.

Method

Diverse criteria including replication in multiple studies, predicted pathogenicity of variant, sequence conservation between human and mouse, and expression in relevant cell types were used to prioritize risk variants, which were then engineered into a mouse model that expresses the AD risk variants APOE4 and Trem2*R47H. Primary screening was done by transcriptomic analysis using the nanoString Mouse AD Panel at 4, 8, and 12 months.

Result

Bioinformatics studies enabled us to prioritize coding variants in the Abca7, Clasp2, Mthfr, Mtmr4, Plcg2, Shc2, Slc6a17, Snx1, and Sorl1 loci. Knockouts of Abca7, Ceacam1, Il1rap, and Plcg2 have also been created to model human loss of function variants. Transcriptomic analysis demonstrated that the Abca7*A1527G and Mthfr*C677T models exhibited some age‐dependent similarities to transcriptomic changes seen in post‐mortem samples from the AMP‐AD cohort. These will move on to deep phenotyping out to 24 months of age. Analysis of other models are still in progress and will be presented. Humanized APP and Tau (MAPT) models are also in progress.

Conclusion

We have prioritized Abca7*A1527G and Mthfr*C677T models to be comprehensively characterized up to 24 months of age in the MODEL‐AD program. We will discuss our approach to prioritize genetic variants, develop novel models relevant to LOAD, and use clinically relevant measures to determine which models are most useful for translational studies. All models are made available for both academic and for‐profit use from The Jackson Laboratory, and all validation data will be shared via the AMP‐AD knowledge portal. For more information see www.model‐ad.org.
Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms
Authors: Novikova Gloriia , Marcora Edoardo , Kapoor Manav , TCW Julia , Renton Alan E. , Efthymiou Anastasia M. , Abud Edsel M. , Bendl Jaroslav M. , Cheng Haoxiang M. , Fullard John F. , Roussos Panos , Poon Wayne W. , Hao Ke , Goate Alison M.
Published: December 2020

Background

Genome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis.

Method

We used an integrative genomic approach to determine the epigenomic annotations enriched for AD risk variants and applied a summary‐data based Mendelian Randomization to link myeloid enhancer activity to target gene expression regulation and AD risk modification.

Result

We show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia, nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the MS4A locus we identified a single candidate functional variant within an CTCF binding site, that is predicted to alter chromatin looping and MS4A gene expression. We used human induced pluripotent stem cells (hiPSC)‐derived microglia to provide experimental validation of this putative causal variant.

Conclusion

Combined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD.
Does suppressing one’s emotions increase the risk of all‐cause dementia among older adults?
Authors: Lisko Inna , Hall Anette , Håkansson Krister , Neuvonen Elisa , Kulmala Jenni , Ngandu Tiia , Solomon Alina , Kivipelto Miia
Published: December 2020

Background

An increasing body of evidence is showing that psychological risk factors are associated with Alzheimer’s disease (AD) and other dementias. However, limited data exists on the effects of suppressing one’s emotions on dementia/AD risk. The aim of the study is to explore if suppressing one’s emotions is associated with a risk of all‐cause dementia in a population‐based sample of older adults.

Method

The study uses data from a Finnish population‐based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. In 1998, altogether 1137 individuals aged 65 to 79 years (mean 70.9 years) without dementia/AD responded to an inventory on ways of coping, where it was asked to describe how they usually respond to adverse events in life. For the statement “I suppressed my emotions from others”, the response options ranged from 4 (fully agree) to 1 (fully disagree). Data on all‐cause dementia incidence were derived from clinical diagnoses during follow‐up in 2005–2008 and from a national register till the end of year 2009. Cox proportional hazards model was used in the analyses which were adjusted for age, gender, APOE ε4 allele, smoking, obesity and education.

Result

Individuals who reported to fully agree on suppressing their emotions had nearly five times higher risk of developing dementia/AD as compared to those who fully disagreed on suppressing their emotions (Hazard ratio [HR] 4.93, 95% Confidence Interval [CI] 1.11–21.93). For those who fairly well agreed (HR 2.05, 95% CI 0.48–8.84) and quite strongly disagreed (HR 1.51, 95% CI 0.33–6.88) on suppressing their emotions the results were statistically non‐significant.

Conclusion

When facing adverse events in life, suppressing one’s emotions appears to be associated with an increased risk of developing dementia/AD. Further studies are needed to explore the mechanisms behind the found association.
Autistic spectrum behaviors in late‐life dementia are associated with an increased burden of neurofibrillary tangles in the frontal lobe
Authors: Rhodus Elizabeth K. , Barber Justin M. , Bardach Shoshana H. , Nelson Peter T. , Jicha Gregory A.
Published: December 2020

Background

Previous clinical studies have described autism spectrum‐like behaviors in approximately 16% of late‐onset dementia cases. The neuropathologic substrate for such behaviors is currently unknown, but may shed light on shared neuroanatomic and molecular pathways involved in these otherwise distinct forms of brain dysfunction. This study investigates the hypothesis that subjects with late onset dementia associated with autism‐like behaviors will exhibit increased pathologic features in both the frontal and parietal association cortices.

Method

An age, education, and gender‐matched case‐control design was used. Subjects were recruited from the University of Kentucky Alzheimer Disease Center longitudinal autopsy cohort. Subjects had a diagnosis of MCI or dementia at the time of completion of the Gilliam Autism Rating Scale‐2 (GARS‐2) in addition to standard clinical, genetic, and cognitive assessments (n = 148). Those who have come to autopsy demonstrating either no evidence of (n = 24) or a high level of (n = 19) autism‐like behaviors on the GARS‐2 were included. Comprehensive neuropathologic evaluation included assessment of all common late‐life dementia pathologies using both semiquantitative rating scales and digital quantitative measures of global and regional pathological features.

Result

Between group analyses demonstrated no significant differences in age, education, gender, clinical diagnosis, or apoE4 status. High‐autism vs. no‐autism cases scored significantly higher on the Clinical Dementia Rating scale (p < 0.05). Approximately 80% of cases had a primary pathologic diagnosis of Alzheimer’s disease, with the remaining 20% of individuals demonstrating pathologic features consistent with LATE (16%), cerebrovascular (2%), or Lewy body disease (2%). No cases had frontotemporal lobar degeneration (FTLD) as a primary or comorbid pathology. Quantitative measures of neurofibrillary tangles and tau burden were higher in the frontal lobes of high‐autism subjects compared to the matched no‐autism controls (p < 0.02).

Conclusion

These data are the first to link autism‐like behaviors to increased levels of tau and neurofibrillary pathology in the frontal lobes at autopsy in subjects with late‐life dementia. Yet, the present data demonstrate that FTLD pathology is not a major contributor to such behaviors in a community‐based cohort of late‐life dementia. Further work understanding potential links between tau‐mediated neurodegeneration and autism‐like behavior is warranted.
The Alzheimer's Prevention Registry: Accelerating recruitment and enrollment into Alzheimer's‐focused studies
Authors: High Nellie M , Kettenhoven Cassandra L , Graf Hayley , Reiman Eric M , Tariot Pierre N , Langbaum Jessica B
Published: December 2020

Background

The Alzheimer’s Prevention Initiative (API) is a collaborative program conducting preclinical Alzheimer’s disease (AD) trials in people who are at elevated risk of developing AD symptoms. To support these and other trials, we developed the web‐based Alzheimer’s Prevention Registry (“APR”) program to provide resources to the AD scientific community, aiming to accelerate recruitment and enrollment into studies and complement local efforts.

Method

Adults age 18+ are eligible to join APR at www.endALZnow.org. At enrollment, individuals provide their name, email address, zip/postal code and year of birth; after enrollment they provide additional demographic information at their convenience with the option to select “prefer not to answer.” The APR team works with researchers to promote AD‐focused studies to members via its website and email. APR members receive email communication for engagement purposes and are notified when new study opportunities are available. Members interested in a study fill out an online contact form with their name, email address and phone number, review and acknowledge the study’s eligibility criteria and authorization for APR to share their contact information with the enrolling study team. The APR team provides enrolling studies with a secure dashboard for tracking referrals.

Result

The APR launched in May 2012; as of January 2020, >347,000 have joined. APR members have a mean age of 63.3 years (SD 11.7), are predominately female (75%), self‐report being cognitively unimpaired (94%), and 50% report a family history of AD/dementia. To date, the APR has promoted 82 AD‐focused studies, results from which will be presented. Only anecdotal enrollment metrics are available prior to the launch of the online contact form, however web‐traffic metrics that are available from our promotions of online studies (e.g., TRC‐PAD, Brain Health Registry) suggest >16,000 APR members expressed interest in joining these studies. The 6‐month pilot phase of the online contact form included 7 studies and referred 320 APR members.

Conclusion

Enrollment into the APR continues to increase, as does the number of studies the APR promotes to its members. We are exploring novel approaches for increasing enrollment and engagement of members, and collaborating with researchers and sponsors to help promote studies in their communities.