bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid burden assessed by three amyloid PET tracers in the elenbecestat MissionAD Phase 3 program
Authors: Roberts Claire , Kaplow June , Giroux Monique , Krause Stephen , Kanekiyo Michio
Published: December 2020

Background

Eisai’s elenbecestat MissionAD Phase 3 studies in early Alzheimer’s disease (AD) screened a large cohort of nearly 10,000 subjects for eligibility.

Method

Screening was performed in 5 sequential tiers, of which amyloid status was determined at tier 5. Three amyloid PET tracers were used: florbetapir, florbetaben, flutemetamol. PET scans were centrally read by trained raters who determined visually if subjects were amyloid positive (Aß+) or negative (Aß‐). Quantitative analysis calculated a mean composite SUVr using whole cerebellum as a reference region and were converted to centiloid values (CL) to combine data across tracers (Klunk et al., 2015; http://www.gaain.org/centiloid‐project).

Result

3259 subjects had amyloid PET status and SUVr data available; 53% were Aß+, 86% were MCI and 12% mild AD dementia (2% missing), 52% were female, and 45% of were APOE ɛ4 positive. 2452, 542, and 265 subjects were scanned using, florbetaben, flutemetamol, or florbetapir, respectively, of which 50%, 59%, and 65% were determined visually to be Aß+. Centiloid conversion combining the data for the tracers calculated a mean of 1.6 CL for Aß‐ subjects (n=1532) and 83.0 CL for Aß+ (n=1725). No differences were evident between the tracers; mean of 1.2 – 3.1 CL for Aß‐ subjects and 77.3 ‐ 84.1 CL for Aß+ subjects. No impact of gender was evident. 77% of the APOE ɛ4 positive subjects were Aß+, which increased the mean CL value by 9. Mild AD dementia subjects had a higher Aß+ rate compared with MCI (69% vs 52%), which increased the mean CL value by 10.

Conclusion

Aß+ status of subjects was approximately 50%, even when assessed at the end of a screening cascade. Although florbetaben was used in 75% of the subjects, the data was consistent between the tracers when converted to CL. Aß‐ and Aß+ subjects SUVr were normally distributed with an appreciable overlap in the 20‐40 CL range.
Functional network alterations in early‐onset Alzheimer’s disease studied with resting‐state fMRI
Authors: Sala‐Llonch Roser , Contador José , Pérez‐Millan Agnés , Falgàs Neus , Ruiz‐Peris Mariona , Tort‐Merino Adrià , Balasa Mircea , Olives Jaume , Castellví Magdalena , Juncà Jordi , Borrego‐Écija Sergi , Bosch Beatriz , Fernández‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Sanchez‐Valle Raquel , Lladó Albert
Published: December 2020

Background

Changes in functional connectivity (FC) networks have been extensively reported in late onset Alzheimer’s Disease (AD), being the default mode network (DMN) the key system to be affected. However, it remains unclear if FC in early‐onset AD (EOAD) would show a similar pattern than late onset AD.

Method

We studied 48 EOAD patients (mean age=57.40±5.53 years) and 31 healthy controls (CTR, mean age=58.22±3.94 years) who underwent resting state functional magnetic resonance imaging (rs‐fMRI) in a 3T MRI scanner. We used group independent component analysis to identify the main resting state networks (RSNs). We studied group‐differences in the spatial extent of these networks, in the amplitude of their temporal oscillations and in the temporal correlation between pairs of networks, using FSLNETS. We also evaluated the discrimination capability of FC patterns by using a support vector machine (SVM) classifier.

Result

We identified 17 RSNs that were further classified into DMN, visual, motor, executive, salience and cerebellum systems. The network spatial maps' vertex‐wise analysis shows regional increases of some executive networks in EOAD (p<0.05, FWE corrected), suggesting increased aberrant local connectivity surrounding the main RSN nodes. In the temporal domain, we find decreases in amplitude in the posterior DMN and the salience network (p<0.05, corrected), and increases in the anterior DMN and the cerebellum networks. With the study of correlations between networks we describe a pattern of altered inter‐network connectivity that involves both increases and decreases of connectivity. Importantly, the entire pattern of network correlations discriminated AD from CTR subjects with an accuracy of 83.5%.

Conclusion

Our results suggest that EOAD is characterized by a complex pattern of FC alterations involving alterations in the amplitude of the main RSNs and in the way that they interconnect. Increase in connectivity in short‐range connections surrounding the main nodes might be a consequence of the decreases of larger connections between nodes. Alterations in the salience network differ from the late onset AD literature. Overall, the entire FC pattern gives a good classification rate suggesting that it might be a good biomarker for EOAD.
The impact of control conditions on the interpretation of multi‐sensory technology interventions
Authors: Perion Jennifer , Steiner Victoria , McBride Kimberly , Saltzman Barbara , Kinney Jennifer
Published: December 2020

Background

Multi‐sensory interventions utilizing technological elements (e.g. projectors, robotics) create opportunities for increased engagement and well‐being among nursing home residents with dementia. When evaluating multi‐sensory technology, researchers often employ a control condition to measure differences in positive and negative affect. A study’s quality may be compromised when researchers fail to provide sufficient details about control conditions, or when inappropriate control activities are chosen.

Method

University research databases were searched for peer‐reviewed studies that utilized multi‐sensory technology aimed at reducing problem behaviors among nursing home residents with moderate‐to‐severe dementia. Articles were limited to experimental or quasi‐experimental designs published since 2007. A descriptive analysis of the methodologies used in the relevant articles was conducted.

Result

Eleven articles met the selection criteria. A review of the reported design and data collection procedures for the studies revealed three common practices that may impact interpretation of the data. Usual care: Five of the eleven studies (45%) included observation of participants’ routine activities for comparison; however, only two provided more than a sentence to describe the control activities, while the other three simply stated that participants spent an equivalent amount of time engaged in “usual care.” Recall of behaviors: Three studies (27%) relied on nursing staff recall of behaviors reported pre‐ and post‐intervention. Direct observations were not recorded, and the residents’ normal routines were not described. No control: Three studies (27%) introduced novel non‐technological activities such as personalized gardening for comparison to the intervention. No control activity was included in the study design.

Conclusion

A review of eleven studies conducted to evaluate innovative multi‐sensory technology revealed a lack of consistent design and reporting practices. Publications providing scant details regarding normal routines or a definition of “usual care” create difficulties for researchers who may wish to evaluate, replicate, or improve upon the intervention. Additionally, using a novel non‐technological activity for comparison may also affect engagement and the ability to draw accurate conclusions about the intervention’s efficacy. Researchers who wish to determine the effectiveness of multi‐sensory technology interventions with nursing home residents should carefully select and fully justify the choice of control conditions.
Assessment of the integrity of the noradrenergic nucleus locus coeruleus during normal ageing by neuromelanin‐3T MRI
Authors: Galgani Alessandro , Lombardo Francesco , Hana Hlavata , Daniele Della Latta , Ghicopulos Irene , Coi Alessio , Martini Nicola , Marchi Daniele , Keilberg Petra , Tognoni Gloria , Siciliano Gabriele , Ceravolo Roberto , Pavese Nicola , Fornai Francesco , Bonuccelli Ubaldo , Giorgi Filippo Sean
Published: December 2020

Background

The pontine nucleus Locus Coeruleus (LC) provides noradrenergic innervation to the whole brain. It is involved in neuronal homeostasis, sleep/wake cycle and in specific cognitive functions. Several data suggest a degeneration of LC in neurodegenerative disorders. Recent post‐mortem studies showed that LC is not affected by ageing (Theofilas et al., 2017, Alzheimers Dement. 13:236‐46). Using a neuromelanin‐sensitive 3 Tesla MRI protocol, we assessed LC integrity in healthy elderly subjects, exploring also the occurrence of age‐related modifications and evaluating any correlation with cognitive performance.

Method

60 healthy volunteers aged 60‐80y, equally distributed by sex and age, underwent 3‐Tesla brain MRI (Signa‐GEH), including neuromelanin (NM)‐sensitive FSE T1‐weighted sequences for LC study, which were evaluated by two independent operators, using a semi‐automatic software (modified from Garcia‐Lorenzo, 2013, Brain, 136:2120‐9). Results were expressed with the parameter VOX, that is the total amount of MRI‐voxels positive for LC‐signal. Then, subjects were submitted to a full neuropsychological assessment, including evaluation of verbal and visuo‐spatial memory, attention and executive functions. A test‐retest reliability verification was performed, comparing the variability intra and inter‐operator.

Result

We did not observe any significant age or gender‐related variation of the parameter VOX; no correlation was detectable between VOX values and cognitive tasks performances; our protocol showed a good intra‐ and inter‐observer reproducibility.

Conclusion

Our results are in line with recent neuroanatomical post‐mortem data which did not describe any age‐related modification of LC in cognitively healthy subjects; the small variability among subjects we observed for selected cognitive functions did not correlate with significant variations of MRI LC signal. Assessing the LC integrity in healthy elderly subjects is a necessary preliminary step for studies evaluating LC involvement in neurodegenerative disorders, as Alzheimer’s Disease, in which LC degeneration might be a key‐point in the pathogenesis (Kelly et al., 2017,Acta Neuropathol Commun. 5:8). (Funding: Ministero della Salute PE‐2013‐02359574; P.I.:FSG).
Relationship between multimodal neuroimaging biomarkers and white matter hyperintensities across the Alzheimer’s disease spectrum: A region‐of‐interest‐ and voxel‐based study
Authors: Gaubert Malo , Lange Catharina , Garnier‐Crussard Antoine , Bougacha Salma , Gonneaud Julie , De Flores Robin , Tomadesso Clémence , Mézenge Florence , Landeau Brigitte , De la sayette Vincent , Chetelat Gael , Wirth Miranka
Published: December 2020

Background

White matter hyperintensities (WMH) are a frequent marker of cognitive impairment and Alzheimer’s disease (AD). Although WMH have been commonly linked to cerebrovascular disease, recent studies suggest an association between AD pathology and regional WMH distribution. The objective of this study was to investigate the relationship of AD neuroimaging biomarkers of Aß burden, hypometabolism and GM atrophy with regional WMH distribution in older adults across the cognitive continuum at two different levels: regions of interest (ROIs) and voxel.

Method

FLAIR MRI (1), AV45‐PET (2), FDG‐PET (3) and T1 MRI (4), were acquired in 155 participants with normal cognition, subjective cognitive decline, mild cognitive impairment and clinical AD in the IMAP cohort (Caen, France). WMH were segmented using FLAIR MRI with the SPM12‐based lesion‐segmentation‐tool (Schmidt, 2017). Standard pipelines were applied to WMH probability maps and all other images (2‐4) resulting in maps normalized in MNI space. Mean AV45‐SUVR, mean FDG‐SUVR and total GMV were extracted within AD signature templates (Besson et al., 2015). Moreover, regional WMH were computed in multiple ROIs based on previous recommendations (Wardlaw et al., 2013). The associations between AD biomarkers levels and regional WMH distribution were assessed using linear regression models at ROI and voxel levels, adjusting for age, sex, education and blood pressure. Uncorrected p<.05 and p<.005, respectively for ROI‐ and voxel‐wise analyses, were applied.

Result

For the ROI analysis (Table 1), mean AV45‐SUVR was not significantly associated with regional WMH. Mean FDG‐SUVR was negatively related with regional WMH, including periventricular region and corpus callosum (body and splenium). Finally, GMV in the AD signature was found to be significantly associated with WMH in all ROIs (Table 1). For the voxel‐based analyses, the results are comparable (Figure 2B.‐D.). Notably, a positive association was found between the mean AV45 SUVR and the splenium part of the corpus callosum (Figure 2.D).

Conclusion

Our findings confirm that AD neuroimaging biomarkers of Aß burden, hypometabolism and GM atrophy are associated with regional WMH, including periventricular regions and posterior parts of the corpus callosum. These associations might reflect either involvement of vascular damage in AD pathogenesis or contribution of AD pathology to white matter damage.
1H‐MRS signature in Alzheimer disease in Down syndrome
Authors: Barroeta Isabel , Montal Victor , Carmona‐Iragui Maria , Pegueroles Jordi , Vilaplana Eduard , Bejanin Alexandre , González‐Ortiz Sofía , Altuna Miren , Benejam Bessy , Alcolea Daniel , Videla Laura , Valldeneu Sílvia , Fernandez Susana , Videla Sebastián , Blesa Rafael , Clarimon Jordi , Lleó Alberto , Fortea Juan
Published: December 2020

Background

Down syndrome(DS) is a genetically determined form of Alzheimer's Disease(AD). Proton magnetic resonance spectroscopy(1H‐MRS) allows in vivo assessment of brain biochemistry. Few studies have assessed 1H‐MRS metabolites for tracking AD in DS. Our objective was to assess the changes in the myo‐inositol(mI)–a glial marker‐ and N‐acetyl‐aspartate(NAA)‐ a neuronal marker‐ in 1H‐MRS and its correlation with cortical thickness and AD biochemical biomarkers in the AD continuum in DS.

Method

Cross‐sectional study. DS subjects were classified into asymptomatic (aDS) and symptomatic: prodromal AD(pDS) and AD dementia(dDS).Participants underwent a single‐voxel 3TMRS in the posterior cingulate/precuneus and a 3Tstructural MRI. mI, NAA and total creatine (TCr) metabolites levels were quantified using Tarquin. Cortical thickness (CTh) values were computed using Freesurfer. Aβ1‐42, total tau, phosphotau, and NFL levels were determined in plasma using a SIMOA platform and in CSF using Lumipulse. For a subset of subjects, amyloid plaques were spatially mapped using Florbetapir‐PET (PET‐FBP). We performed ANCOVA analyses with Tukey posthoc corrections to assess the mI/TCr and the NAA/TCr between‐groups differences. We computed the vertex‐wise correlation between mI/TCr, NAA/TCr and CTh. We used linear regression to assess relationship between MRS metabolites and PET‐FBT and AD biochemical biomarkers.

Result

We included 83 adults with DS(61aDS, 15pDS and 7dDS) and 25 euploid healthy controls (HC). The three DS subgroups showed significant (p<0.05) increases in mI/TCr when compared to HC. Moreover, we found a gradient of increases of mI/TCr in the DS subgroups (aDS>pDS=dDS). The dDS subgroup showed significant (p<0.05) decrease in NAA/Cr compared to HC and aDS. mI/TCr levels were negatively correlated with CTh in the medial and lateral temporal regions, bilaterally. NAA/TCr levels revealed a similar pattern of positive correlations with Cth but more widespread. mI/TCr levels were positively correlated with PET‐FBP and plasmatic NfL in the DS symptomatic group. NAA/TCr level were negatively correlated with CSF tTau and plasmatic NfL in the DS symptomatic group.

Conclusion

There is a gradient of increases of myo‐inositol in the AD continuum in DS which correlate with atrophy in temporal regions, increased PET‐FBP, and plasma NfL. Our data reveals a 1H‐MRS signature in AD in DS and supports myo‐inositol as a potential glial marker.
Small molecule inhibitors of apolipoprotein E4‐catalyzed amyloid‐β fibrillization as novel therapeutics for Alzheimer’s disease
Authors: Johnson Noah R. , Wang Athena Ching‐Jung , Coughlan Christina M. , Lucero Esteban M. , Viltz Lisa , Allen Cody , Markham Neil , Chial Heidi J. , Potter Huntington
Published: December 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative illness initiated by fibrillization of the amyloid‐beta (Aβ) peptide in the brain. Genetic factors can increase the risk for developing AD, especially in individuals who carry the ε4 allele of the apolipoprotein E (APOE) gene. Having one copy of APOE4 doubles the risk for AD, whereas being homozygous for APOE4 increases the risk by greater than ten‐fold. ApoE4 acts as a catalyst to accelerate the polymerization rate of Aβ into neurotoxic oligomers and filaments; thus, inhibiting this enzymatic process is a promising therapeutic approach to preventing AD. We therefore developed an ApoE4‐Aβ fibrillization assay for high‐throughput drug screening of small molecule compounds.

Method

A design of experiments (DOE) approach was employed to optimize the ApoE4‐Aβ fibrillization assay. A series of fractional factorial and surface response designs were used to determine the concentrations of Aβ, ApoE4, and thioflavin T that yielded the greatest rate and amount of Aβ fibrillization. The optimized assay was then used to screen two small molecule libraries representing more than 3,000 compounds, most of which are drugs or natural compounds that have already been tested in humans for other indications. Hit compounds were next evaluated for cytotoxicity and inhibition of Aβ neuropathology in primary mouse neurons expressing human Aβ and exposed to human ApoE4 over nine days in culture.

Result

A primary screen of two small molecule libraries identified 31 hit compounds that significantly inhibited ApoE4‐catalyzed Aβ fibrillization in a dose‐dependent manner. Primary hit compounds were then tested in primary mouse neurons, where six compounds were validated as non‐cytotoxic and were effective at inhibiting Aβ neuropathology. One of the six lead compounds (epigallocatechin gallate) had been studied previously as a potential therapy for neurodegenerative disease, thus validating the overall screening approach.

Conclusion

Six small molecule compounds were identified as novel inhibitors of ApoE4‐catalyzed Aβ fibrillization in high‐throughput screens. Three are FDA‐approved drugs for indications unrelated to AD. We are currently performing preclinical evaluations of these compounds in AD rodent models to determine their therapeutic potential for the treatment of AD.
Lifespan diffusion MRI reveals regional abnormalities in the 5xFAD model of Alzheimer’s disease
Authors: Jullienne Amandine , Lee Jeong Bin , Yassa Michael A. , Territo Paul R , Obenaus Andre , Consortium MODEL‐AD
Published: December 2020

Background

The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium has been established to develop the next generation of Alzheimer’s disease (AD) models based on human data. We undertook lifespan diffusion magnetic resonance imaging (dMRI) to fully characterize the temporal alterations in brain structure and circuits in 5xFAD.

Method

All 5xFAD mice are compared to age‐matched littermates (C57BL/6J, WT) at 4, 8, and 12mo. Mice underwent high resolution diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) at 9.4T (5 B0, 30 directions b=3000 mm2/sec) to assess regional white and gray matter. Regional tissue features were extracted from fractional anisotropy (FA), radial (RD), axial (AD) and mean (MD) diffusivity parametric maps. Tractography was performed based on the AMBMC mouse atlas. 18F‐AV45 PET was performed to quantitate amyloid β (Aβ) load. Histology and immunohistochemical analyses verified neuroimaging findings.

Result

Our preliminary results focus on CA1 and the subiculum of the hippocampus and show tract differences between WT and 5xFAD females at 8 months of age. DTI metrics in these tracts are also affected by sex and genotype. For example, FA is decreased by ∼30% in 5xFAD females compared to WT females at 8 months. AV45‐PET were able to detect increasing Aβ plaque load with age in 8‐12mo old 5xFAD mice when compared to WT and was verified by immunohistochemistry.

Conclusion

Phenotyping of mouse models using dMRI can identify altered brain connectivity and regional tissue features. The data support that increasing Aβ deposition results in altered dMRI metrics that can be readily translated to the clinic.
Rates of cognitive decline during the preclinical phase and their use in predicting future dementia
Authors: Payton Nicola Maria , Marseglia Anna , Grande Giulia , Fratiglioni Laura , Kivipelto Miia , Bäckman Lars , Laukka Erika J
Published: December 2020

Background

Cognitive deficits can occur years or even decades before a clinical diagnosis of dementia, with a rate of decline which differs from that in normal aging. This study aimed to investigate differences in trajectories of cognitive decline in multiple cognitive domains in the preclinical dementia phase, and whether early rates of decline can be used to predict dementia.

Method

Repeated neuropsychological assessments were conducted for 1652 participants (age ≥60 years) from the Swedish National Study on Aging and Care–Kungsholmen (SNAC‐K). In this sample, 220 developed dementia and 1432 remained dementia free or died without dementia over 12 years. Piecewise linear mixed models were used to compare rates of cognitive decline between people who developed dementia and those who remained dementia free. Individual rates of decline from baseline over six years follow‐up were extrapolated from the mixed models for episodic memory, semantic memory, verbal fluency, and perceptual speed. Fast decliners were identified as those whose rate of decline was >1.5SDs faster than the mean of the no‐dementia group. Multinomial logistic regressions were used to estimate the association between domain‐specific rate of decline and dementia at 9 or 12 year.

Result

Significantly faster decline was observed in all cognitive domains in those who developed dementia vs. those who did not. In piecewise linear mixed‐models, participants in a preclinical dementia phase showed disproportionally accelerated decline as they neared the time of diagnosis in all cognitive domains except episodic memory, where decline was more linear. Being a fast decliner was associated with increased dementia risk and being a fast decliner in at least two cognitive domains further increased the risk of dementia. For the individual domains, however, only rate of decline in verbal fluency added independent variance above that of baseline scores.

Conclusion

The preclinical dementia phase is associated with accelerated cognitive decline, especially in the last 6 years prior to diagnosis. Using early rates of decline (12‐6 years before diagnosis) add some information in the prediction of future dementia and can help identify individuals at increased risk of developing the disease.
Gamma power increased in Alzheimer's disease patients in comparison to healthy controls during recognition of facial expressions
Authors: Güntekin Bahar , Yıldırım Ebru , Kıyı İlayda , Fide Ezgi , Uzunlar Hakan , Calısoglu Pervin , Yirikogullari Harun , Akturk Tuba , Yener Görsev
Published: December 2020

Background

Several researchers have reported the impairment of recognition of facial expressions in Alzheimer’s disease (AD) patients. AD had reduced theta and alpha responses compared to healthy controls during the recognition of facial expressions (Güntekin et al. 2019). Gamma responses also have a crucial role in the recognition of facial expression in healthy young adults (Güntekin and Başar 2014). AD had increased late gamma responses compared to healthy controls during working memory paradigms (Başar et al. 2017). The present study aims to analyze the gamma responses during the recognition of facial expressions in AD and healthy controls. We hypothesized that if the increase of late gamma responses is a general phenomenon in AD patients independent of the stimulation type, we expect to find increase gamma responses in AD patients in comparison to healthy controls.

Method

EEGs of 40 healthy controls (HCs) and 41 AD patients were recorded during their perception of three different facial expressions (angry, happy, neutral). Event‐related power spectrum and phase locking were analyzed for three different gamma bands (30‐35 Hz, 35‐ 40Hz, 40‐48 Hz) in two different time windows (0‐200 ms, 200‐400 ms).

Result

The group difference between AD patients and HCs was not significant for the phase‐locking values. AD patients had higher gamma power responses compared to healthy controls in 200‐400 ms time window for 30‐35 Hz(p=0.016), 35‐40 Hz(p=0.018) and 40‐48 Hz (p=0.039). The only significant group difference for the early time window (0‐200 ms) was found for 35‐40 Hz (p=0.046). The figure shows topographical plots of gamma (35‐40 Hz) power for 200‐400 ms time window in patients (upper part) and healthy controls (lower part) for angry, happy and neutral facial expressions.

Conclusion

The present study showed that the increase of late (200‐400 ms) gamma were independent of stimulus type in AD patients. The increase of gamma power in a 200‐400 ms time window was found in AD patients compared to healthy controls for all three facial expressions. The facial expression recognition in AD patients was differentiated from healthy controls by increased gamma power. Acknowledgments: This work (grant number 218S314) was supported by TUBITAK.
Trends in dementia consultations in two psychiatric hospitals in Mexico City: 2010‐2018
Authors: Astudillo‐Garcia Claudia I , Jaime Beatriz Paulina Vázquez , Ávila Xiasú García , Austria‐Corrales Fernando , Velásquez José Javier Mendoza
Published: December 2020

Background

The analysis of the information about the use of health services is a key input for understanding infrastructure and planning requirements, as well as for contributing to the identification of deficiencies and opportunities aimed at improving the provision of services. Dementia is a condition that is increasing in Mexico; however, the health system lacks long‐term care services, being psychiatric hospitals one of the main centers for providing services to the population affected by this disease. That is why this research aims to identify trends in dementia care for adults over 60 years who were attended in two psychiatric hospitals in Mexico City between 2010–2018.

Method

We used records of the psychiatric hospitals "Fray Bernardino Álvarez" and "Samuel Ramírez Moreno", during the period 2010‐2018. The annual proportion of first and subsequent consultations for dementia (according to ICD‐10, code F00) in both men and women was estimated. The Joinpoint Trend Analysis Software version 4.1.0 was used to explore the change in time trends of care. Trend changes are presented as Annual Percent Change (APC) and was considered statistically significant when p<0.05.

Result

On average, both psychiatric hospitals recorded 9000 dementia consultations per year. Statistically significant increases are observed by sex. Among women, first‐time consultations were recorded with a 16.8% (CI: 5.5‐29.4) and subsequent consultations (APC: 13.4%, CI: 6.2‐21.2). And in men it is only significant in subsequent consultations (APC: 19.5%, CI: 6.6‐34.1).

Conclusion

The number of hospital consultations for dementia has increased significantly; however, the health system in Mexico is limited in resources and infrastructure that could guarantee long‐term care services, so it should restructure services and promote other instances that would allow for quality care to be provided to people affected by the disease, as well as their caregivers.
Discovery of SLC16A9 and SLC22A1 as regulators of acylcarnitines associated with Alzheimer’s disease
Authors: Horgusluoglu‐Moloch Emrin , Arnold Matthias , Kaddurah‐Daouk Rima F. , Zhang Bin
Published: December 2020

Background

Propionylcarnitine (C3) as short‐chain acylcarnitine is highly associated with brain volume changes and cognitive impairment in symptomatic stages of Alzheimer’s Disease (AD), and the lower concentration of C3 level is associated with cerebrospinal fluid amyloid‐beta level in AD (Varma, Vijay et al. 2018). However, the genetic mechanism and key biological pathways underlying changes in propionylcarnitine in AD remain unclear. To better understand the key drivers and biological pathways underlying changes in propionylcarnitine in AD, we performed a genome‐wide association study (GWAS) of propionylcarnitine using Alzheimer’s Disease Neuroimaging Initiative (ADNI) Cohort.

Method

GWAS for propionylcarnitine from Non‐Hispanic Caucasian participants in the ADNI cohort (328 controls, 84 significant memory concern, 712 mild cognitive impairment, and 276 AD) was performed using an additive model with a linear association analysis for quantitative traits in Plink v1.90. Age, gender, education, body mass index (BMI), medication history, cohort, and diagnosis status were used as a covariate. A summary p‐value for each gene (including ± 5kb) was calculated from GWAS results using GATES (Li, Gui et al. 2011). For the pathway analysis of GWAS results, the Molecular Signatures Database was used to identify biological pathways representing the enrichment of association in the GWAS. False discovery rate (FDR) P < 0.05 was considered to identify significant pathways.

Result

We identified nine SNPs resides in SLC16A9 (a carnitine efflux transporter) gene, and four SNPs reside in SLC22A1 (related to acylcarnitine efflux) gene (Table 1; Figure 1). Analysis of the genotyping level of the most significant SNP (rs1171616) shows that the participants carrying at least one copy of the minor allele (N = 560; GT/GG genotype) have less C3 metabolite level in the blood compared to those without minor allele (N = 828; TT genotype) (Figure 2A). Participants with two minor alleles have worse episodic memory scores (Figure 2B and 2C). Enrichment pathway analysis with C3 associated genes (nominal p‐value < 0.05) revealed that the immune system, Alzheimer’s Disease, mitochondrion, neurogenesis, metabolic process, and enzyme binding are among the pathways enriched for the genes from the gene‐based association analysis (Table 2).

Conclusion

SLC16A9 and SLC22A1 are potential regulators of acylcarnitine levels associated with AD.
Effect of Alzheimer’s disease‐related β‐amyloid peptide conformations in transgenic mouse models of β‐amyloidosis
Authors: Célestine Marina , Jacquier‐Sarlin Muriel , Borel Eve , Herard Anne‐Sophie , Buisson Alain , Dhenain Marc
Published: December 2020

Background

Alzheimer’s disease (AD) brain dysfunctions are not exclusively related to amyloid plaques occurence, but are thought to start much earlier, presumably due to soluble pathological forms of b‐amyloid peptide (Aβ). Indeed Aβ oligomers induce synaptic dysfunctions that cause cognitive decline, exacerbate tau pathology[1] and influence neuronal networks[2]. Although mutation‐induced phenotypes are identified in AD patients, the in vivo effects of different Aβ variants are poorly understood. Here we characterized the effects of different Aβ variants in a transgenic mouse model to provide deeper insight of transconformational processes and the subsequent alterations. Deciphering Ab profiles would help in developing new diagnostic and therapeutic approaches.

Method

We developed well‐characterized amyloid variants: Aβ1‐42, Aβ bearing the icelandic mutation (A2T), Aβ bearing the Osaka mutation (E22D[1]) and Aβ bearing the mutation F19S/L34P. First, these variants were overexpressed in cortical neuron cultures. Then, two‐month‐old APP/PS1dE9 mice were inoculated with these variants in the dentate gyrus (n = 5/per group). We assessed Aβ oligomerization profiles, cerebral amyloid load and synaptic health in neuron and mouse (4 months post‐inoculation) models by biochemistry and histology.

Result

The different amyloid forms exhibit distinct aggregation profiles and synaptotoxicity in vitro (Figure 1). They did not have the same effect on mouse survival. Osaka‐Aβ induced the highest mortality. Then, we focused on the local reorganization of amyloid. Osaka‐Aβ led to increased 6‐mer and 12‐mer amyloid forms at inoculation site (Figure 2) but also at distance in the cortex. This suggests that Aβ variants differently modulate Aβ metabolism and aggregation. Amyloid plaque assessment showed an Osaka‐Aβ‐induced increase in amyloid load in the hippocampus (Figure 3) and its connected regions.

Conclusion

A single inoculation of different Aβ variants in APP/PS1dE9 mice expressing wild‐type Aβ is sufficient to differentially modulate Aβ metabolism, amyloid load and mouse mortality. This suggests that Aβ variants differentially interact with the biochemical/biophysical cerebral environments to differentially induce toxic downstream events that are crucial for better AD physiopathology understanding. References: (1) Delacourte et al., Experimental Gerontology, 2002. (2) Bero et al., Journal of Neuroscience, 2012. (3) Tomiyama et al., Ann Neurol, 2008.
IGF‐I modulates sleep patterns through orexinergic neurons: Role in aging
Authors: Zegarra‐Valdivia Jonathan Adrian , Pignatelli Jaime , de Sevilla Maria Estrella Fernández , Munive Victor , Martinez‐Rachadell Laura , Nuñez Angel , Torres‐Alemán Ignacio
Published: December 2020

Background

Aging and dementia are related to sleep and circadian disturbances. These disturbances are attributed to neurodegeneration of brain networks involved in sleep. On the other hand, increasing evidence supports the notion that Alzheimer’s disease (AD), a condition that presents heterogeneous pathological disturbances, including sleep regulation, is also associated with perturbed metabolic function affecting insulin‐like growth factor I (IGF‐I). Moreover, metabolic alterations are commonly associated with sleep disturbances. In this work we took advantage of a very specific group of cells ‐ orexinergic neurons ‐ that are involved in sleep/circadian regulation, to study how IGF‐I may modulate their activity, as well as its role in sleep regulation through aging.

Method

We use electrophysiology, optogenetic, and immunofluorescence techniques. Transgenic mice without IGF‐I Receptor in orexinergic neurons (Firoc mice) and C57 animals (young vs old mice) were used.

Result

We found reduce C‐fos expression in orexin neurons after IGF‐I injection (ip). As well as diminish response to local and systemic IGF‐I in electrophysiology experiments in Firoc mice, determined by the responses of PeF neurons to locus coeruleus (LC) stimulation. We also found perturbations in sleep and lower levels of orexin in Firoc hypothalamus. To confirm the participation of IGF‐I modulation of orexinergic neurons, we optogenetically identify orexin neurons using a mouse expressing channelrhodopsin (ChR) specifically in these cells and inject IGF‐I locally. These results suggest that IGF‐I modulates orexinergic function. Then, we use elderly C57 mice to check if orexinergic neurons respond normally to IGF‐I. We found a reduce orexinergic neurons response to IGF‐I in electrophysiology experiments.

Conclusion

These initial results reinforce recent observations that IGF‐I act as a peripheral circadian marker and modulates sleep through orexin neurons, and suggests that sleep disturbances in the elderly may be related to altered brain IGF‐I input to orexin neurons.
Real‐world site experiences with a recruitment‐related registry: An exploration of Alzheimer’s disease prevention research recruitment
Authors: Bardach Shoshana H , Langbaum Jessica B , Jicha Gregory A
Published: December 2020

Background

Registries have been proposed as a novel way to identify accelerate recruitment for Alzheimer’s disease prevention clinical trials. However, the role of registries in real‐world clinical settings remains largely unknown. Registry enrollment involves a combination of local site promotion of the registry as well as social media and advertising efforts to encourage participation. This manuscript explores one site’s experience with GeneMatch, a novel genetic registry for Alzheimer’s disease research.

Method

Referrals from GeneMatch to the site were tracked to understand the demographics of those referred and ultimate research enrollment decisions. Using the site’s existing recruitment database, referrals were cross‐referenced for prior research contact, to better understand the role of GeneMatch in the context of existing recruitment efforts.

Result

There were a total of 86 GeneMatch referrals to the site, which ultimately resulting in 54 individuals coming into the site to pursue research involvement further. The majority of referrals (52/86, 60.47%) did not have prior contact with the site about recruitment interest, and having such contact did not predict likelihood of ultimately signing a research consent.

Conclusion

GeneMatch helped identify new individuals for participation in AD prevention studies. These results highlight the value of continuing local site‐level efforts while also taking advantage of registries to enhance research recruitment. Ongoing efforts to develop novel strategies for outreach and engagement are still needed.
Synapse disruption by Alzheimer’s Aβ/APP
Authors: Gouras Gunnar K. , Martinsson Isak
Published: December 2020

Background

Synapse loss is known as the best brain correlate of cognitive decline in AD, while numerous lines of evidence support that Aβ/APP are involved in the disease. We previously reported that with AD pathogenesis soluble Aβ42 accumulates in late endosomes near synaptic terminals where it then aggregates and disrupts synapses. Based on these studies our modified amyloid hypothesis views intra‐neuritic Aβ as initiating a cascade that after synaptic degeneration via prion‐like extracellular Aβ propagation perpetuates the pathological process. This scenario illuminates the Aβ‐tau anatomical disconnect, since vulnerable projection neurons with early Aβ accumulation later develop tangles at their cell soma but plaques in their terminal fields. Here we set out to better understand the effects of early Aβ accumulation on synapses using live cell calcium imaging in cultured primary neurons.

Method

Primary cortical/hippocampal neurons are obtained from APP/PS1 mutant transgenic and wild‐type mice. We previously reported that primary AD transgenic neurons show progressive Aβ accumulation and AD‐like synapse alterations. After live cell calcium imaging of neurons with Fluo‐4, neurons are fixed and immuno‐labeled with markers for inhibitory or excitatory cells. In addition, viral constructs harboring fluorescent tags (e.g. TdTomato) and promoters to label excitatory or inhibitory neurons are used to measure calcium oscillations directly in different types of neurons during live imaging.

Result

By live cell imaging primary neurons from AD transgenic compared to wild‐type mice showed hyperactivity consistent with prior in vivo work. Calcium oscillations were increased in both frequency and amplitude in the AD transgenic neurons.

Conclusion

Synapses are increasingly viewed as vulnerable early sites in AD. Here we show evidence for neuronal hyperactivity related to Aβ/APP and aim to dissect the neuron subtype vulnerability of these early Aβ‐induced synaptic alterations.
Longitudinal changes in sedentary behavior, physical activity and aerobic fitness over 5 years in a cohort at risk for Alzheimer’s disease
Authors: Dougherty Ryan J , Mergen Brandon , Lose Sarah , Gaitán Julian M , Okonkwo Ozioma C , Cook Dane B
Published: December 2020

Background

Low levels of physical activity and aerobic fitness are established modifiable risk factors for Alzheimer’s disease and all‐cause mortality. Work from our group and others has demonstrated significant and positive cross‐sectional relationships between physical activity, aerobic fitness and indicators of brain health (e.g. biomarkers of AD, cognition). The aims of the current study were to determine 5‐year changes in sedentary behavior, physical activity and aerobic fitness in adults at risk for Alzheimer’s disease.

Method

This study enrolled fifty‐seven cognitively unimpaired adults from the Wisconsin Registry for Alzheimer’s Prevention. Participants completed 7 days of physical activity monitoring via accelerometry and a maximal exercise test at two time‐points – 5 years apart. Based on current physical activity guidelines, our chosen measures were time spent engaged in sedentary behavior and moderate‐to‐vigorous physical activity. Aerobic fitness was defined as the highest oxygen consumption (VO2peak, mL/kg/min) value recorded during the final stage of the maximal exercise test when standardized criteria were met. A repeated measures model was used to investigate whether sedentary behavior, physical activity, and aerobic fitness changed over a 5‐year period. Cohen’s d effect sizes and bivariate correlations were used to explore the magnitude of these changes and their relationships with age.

Result

At baseline, participants (mean age at baseline 63.81±6.1) spent 77.86±8.11 hours/week sedentary, engaged in 10.34±4.26 hours/week of physical activity and displayed an aerobic fitness level of 28.26 ±0.99 mL/kg/min. At follow‐up (mean age at follow‐up 68.52±6.1), we observed non‐significant increases in sedentary behavior 2.1% (d=.2; p=.09), and significant declines in physical activity 12.3% (d=.3; p=.01) and aerobic fitness 14.2% (d=1.2; p<.001). Age was negatively associated with 5‐year change in physical activity (r=‐.31; p=.02) but not sedentary behavior (p=.19) or aerobic fitness (p=.80).

Conclusion

This study found that physical activity and aerobic fitness significantly declined over a 5‐year period in adults at risk for Alzheimer’s disease, and this decline may accelerate with advancing age. Strategies aimed at promoting physical activity and aerobic fitness (e.g. exercise training) in mid‐late adulthood are warranted. Future studies are needed to test whether changes in sedentary behavior, physical activity, and aerobic fitness are related to brain and cognitive health.
Public policies to support dementia caregivers
Authors: Bangerter Lauren , Kaskie Brian , Dawson Walter D
Published: December 2020

Background

Family caregivers are major providers of long‐term care and support for family members with Alzheimer’s disease and related dementias (ADRD). Caregiving for a person with ADRD is a demanding role that is linked to physical, emotional, relational, and financial burden. Ensuring that ADRD caregivers are adequately supported is rapidly becoming a cornerstone of successful public health policy agendas in the United States.

Method

We conducted a review of publicly available legislation and policy briefs to identify federal policies that support ADRD caregivers, both directly and indirectly.

Result

Federal policies for caregivers have evolved and increased over time, most notably through the National Family Caregiver Support Program, part of the Older Americans Act. The passage of recent legislation (e.g., the RAISE Caregiver Act and the BOLD Infrastructure for Alzheimer’s Act) indicate a pattern of targeted investment in supporting ADRD caregivers.

Conclusion

Gerontology research and public policy can and should intersect in order to optimize the effectiveness of policy efforts to support ADRD caregivers.
Associations of vitamin B12 status with cognitive domain performance in cognitively healthy older adults
Authors: de Jager Celeste A , Nalder Liam , Zheng Bang , Chiandet Giulia , Middleton Lefkos T
Published: December 2020

Background

Increasing longevity worldwide has resulted in an unprecedented high burden of dementia. Several lines of research have implicated factors affecting B‐vitamin status among risk factors for cognitive decline and dementia. We aimed to determine the prevalence of vitamin B12 deficiency among cognitively healthy volunteers from the Cognitive Health in Ageing Register: Investigational, Observational, and Trial Studies in Dementia Research: Prospective Readiness cOhort (CHARIOT:PRO) SubStudy (CPRO‐SS) and also, to explore associations with cognitive performance at screening.

Method

This analysis includes data from cognitively healthy volunteers (n=1946) aged 60‐85 years who underwent, as part of screening, Repeatable Battery for Neuropsychological Status (RBANS), vitamin B12 and folate measures. Levels of B12 biomarkers, homocysteine and methylmalonic acid, were assayed for those with low vitamin B12 (<133 pmol/L); high levels indicating severe B12 deficiency. Gender‐specific linear regression models were computed for associations of B vitamin biomarkers and BMI with RBANS domain indices and individual tests, controlling for confounders. Regression by B12 status group (normal, deficient, severely deficient) for RBANS associations were analysed for all participants.

Result

Vitamin B12 deficiency (<148 pmol/L) was detected in 17.2% of the cohort; folate <10nmol/L in 1%. Low vitamin B12 was associated with subtle deficits in immediate and delayed memory test scores (p<0.03) in men. Elevated folate was associated with poorer Attention index in men (β ‐0.12; p=0.019), and individual subtests in men and women (p<0.03). High BMI was associated with poorer Attention and Visuospatial indices and subtests in men and women (P<0.05), but no interaction with B12 was detected (p>0.05). Regression by B12 status group revealed deficits in Attention (β ‐6.46; p=0.004) for B12 Deficient, and Immediate Memory (β ‐2.99; p=0.019) for Severely Deficient (with elevated homocysteine and/or methylmalonic acid and/or low folate), relative to the Normal group.

Conclusion

This study highlights subtle domain‐specific cognitive deficits that varied between men and women, with evidence of graded cognitive deterioration with increasing severity of vitamin B12 deficiency. High BMI had negative effects on attention and visuospatial skills in this cohort. These results will be discussed in the context of clinical trials for prevention of AD and therapeutic strategies for subgroups.