bluuebunny/crossref_metadata_2025 huggingface dataset:
The rat as a model for ketogenic drug formulation development
Authors: Henderson Samuel T , Walker Judith Anne , Morimoto Bruce , Ambarkhane Ameet
Published: December 2020

Background

Ketogenic compounds such as ketone esters and medium chain triglycerides have been tested as treatments for mild‐to‐moderate Alzheimer’s disease (AD) in several studies. Ketogenic compounds are given at high doses in an attempt to compensate for regional cerebral glucose hypometabolism characteristic of AD. Upon ingestion, ketogenic compounds lead to the induction of ketosis. Previous studies have shown the formulation of the ketogenic compounds can influence kinetics of digestion of the drug and transformation into active moieties which induces ketosis, hence any changes in formulation may influence clinical outcomes. In order to rapidly screen new formulations, we have investigated the rat as pharmacokinetic (PK) model of ketogenic potential of formulations in human. PK studies are performed using different formulations to define dose, dosing frequency, route of dosing and onset of action.

Method

We have previously tested several formulations in human PK studies and found several differences in Cmax, Tmax and AUC related to the release from the excipients. In the present study we evaluated the PK profiles of these same formulations in rat to determine if rats qualitatively replicated the human results. Healthy young adult male Sprague Dawley (SD) rats were used as a test system for this PK study. Five animals per group were used, animals were between 9 to 12 weeks old and the weight variation of animals did not exceed ± 20% of the mean weight. Animals were dosed by oral gavage and concentrations of acetoacetate and β‐hydroxybutyrate in rat serum were determined by LC/MS. Ketone body concentrations (µM) were calculated as a sum of acetoacetate (µM) and β‐hydroxybutyrate (µM) concentrations. Ketone body data was analyzed using WinNonlin.

Result

Rats qualitatively mirrored results from human studies. Formulations that exhibited slow release and thereby lower ketogenic in humans similarly were found to be slow releasing and less ketogenic in SD rats. Formulations that exhibited fast release and more ketogenic in humans were found to be fast releasing and more ketogenic in SD rats.

Conclusion

From these preliminary studies rat represents a model to evaluate future ketogenic drug formulations for ketogenic potential in human.
Heterogeneous air pollutant exposure effects on episodic memory decline: Evidence from WHIMS‐ECHO study
Authors: Younan Diana , Wang Xinhui , Petkus Andrew J , Beavers Daniel P , Espeland Mark A , Chui Helena C , Resnick Susan M , Gatz Margaret , Kaufman Joel D , Wellenius Gregory , Whitsel Eric A , Manson JoAnn E , Chen Jiu‐Chiuan
Published: December 2020

Background

Episodic memory (EM) declines vary by age and underlying neuropathology. Whether exposure to ambient air pollutants contributes to the observed heterogeneity of EM decline in older people is unclear.

Method

We examined the associations between exposures and EM trajectories in the US‐based Women’s Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes (WHIMS‐ECHO) cohort (N=2042, aged 74‐92 in 2008). EM was assessed annually (2008‐18) using the immediate recall total correct (3 trials) in the telephone‐based California Verbal Learning Test. Recent 3‐year average exposures to regional PM2.5 (particulate matter with aerodynamic diameter < 2.5μm) and NO2 (a proxy of traffic‐related air pollutants) and the corresponding remote 3‐year averages approximately at 10 years prior to inception were derived from yearly exposures estimated by regionalized national universal kriging. Latent‐class mixed models were used to classify EM trajectories and examine the exposure effect in each identified latent class. All models adjusted for social‐demographic factors, lifestyle, cardiovascular risk and other clinical covariates.

Result

There were two latent EM trajectories that differed by WHIMS‐ECHO baseline age (≤80 vs. oldest‐old 80+; Figure 1) and exposure characteristics (Table 1). In women aged ≤80 (N=836), greater EM decline was associated with higher PM2.5 in the subgroup with slow‐decline (76%; −0.18/year), but not in those with fast‐decline (24%; −1.75/year). The observed association, equivalent to 1‐2 years of aging, was stronger for recent 3‐year exposure (−0.151/year, per inter‐quartile‐range [IQR]=2.86µg/m3, p=0.02), as compared with remote exposure (−0.096/year, per IQR=3.28µg/m3, p=0.09). In the oldest‐old (aged>80; N=1206), EM decline (70% steady decline by −1.37/year; 30% no apparent decline) was not associated with recent or remote PM2.5 exposures. In both age groups, no appreciable NO2 effects on EM decline were observed, and neither PM2.5 nor NO2 exposures during recent or remote years affected the levels of EM trajectories. Adjusted models further accounting for propensity scores of exposures revealed very similar results.

Conclusion

The accelerated EM declines associated with late‐life exposures to ambient air pollutants vary by age‐related cognitive trajectories, exposure time‐windows and pollution sources. The observed association was most consistent with PM2.5 exposure during recent years in older women aged ≤80 with slow EM decline.
Using cerebrospinal fluid amyloid‐beta(1‐42) in the memory clinic: Concordance with PET and use of biomarker ratios across immunoassays
Authors: Willemse Eline A.J. , Tijms Betty M. , Van Berckel Bart N.M. , Gannon Sara , Le Bastard Nathalie , Latham Jessica , Radwan Rachel R. , van Der Flier Wiesje , Scheltens Philip , Teunissen Charlotte E.
Published: December 2020

Background

Shifting to automated cerebrospinal fluid biomarker platforms urges re‐evaluation of biomarker interpretation in the memory clinic setting. We aimed to evaluate whether different ratios of biomarkers, pTau:Aβ1– 42 and Aβ1– 42:Aβ1– 40, improved the discrimination of amyloid PET positivity in a retrospective cohort and whether this was dependent on the platform used.

Method

Cerebrospinal fluid samples of individuals in the biobank of the Amsterdam Dementia Cohort were selected based on availability of visual amyloid PET reads (n=288; n=133 florbetaben, n=86 Pittsburgh compound‐B, n=64 flutemetamol, n=5 florbetapir; 179 (62%) amyloid PET positive; age 63±7 years; 131(45%) female; MMSE 24±4; diagnoses subjective cognitive decline (n=58), mild cognitive impairment (n=42), Alzheimer’s disease (AD; n=145), or other dementias (n=43)). Aβ1– 42, Aβ1– 40 (Lumipulse only), pTau and tTau were measured using both Elecsys and Lumipulse automated platforms. Sensitivity and specificity percentages were determined based on optimal Youden’s index in receiver operating curve analyses with amyloid PET result as gold standard.

Result

Both pTau:Aβ1– 42 and Aβ1– 42:Aβ1– 40 ratios showed higher concordance with amyloid PET compared to Aβ1– 42 alone. Sensitivity and specificity percentages for Elecsys were 96% and 89% for pTau:Aβ1– 42 (cut‐point 0.020), 96% and 80% for Aβ1– 42:Aβ1– 40 (cut‐point 0.091), and 91% and 75% for Aβ1– 42 (cut‐point 1089 pg/ml). For Lumipulse, sensitivity and specificity percentages were 97% and 91% for pTau:Aβ1– 42 (cut‐point 0.072), 99% and 83% for Aβ1– 42:Aβ1– 40 (cut‐point 0.071), 91% and 73% for Aβ1– 42 (cut‐point 714 pg/ml). Areas under the curves were higher for pTau:Aβ1– 42 than Aβ1– 42:Aβ1– 40 using Elecsys (0.949 and 0.924, respectively, p‐value = 0.014) but comparable for both ratios using Lumipulse (0.956 and 0.942, respectively, p‐value = 0.20).

Conclusion

We recommend the pTau:Aβ1– 42 ratio as optimal biomarker for use in memory clinic setting using the Elecsys platform, since it showed the strongest concordance with PET amyloid. For Lumipulse assays, pTau:Aβ1– 42 and Aβ1– 42:Aβ1– 40 perform equally well.
Synergistic effects of an innovative combination therapy on treating Alzheimer's disease involving modulation of gut dysbiosis
Authors: Shie Feng‐Shiun , Hsu Chia‐Yu , Chao Po‐Kuan , Hsueh Jung‐Tsung , Hsu John Tsu‐An , Su Ih‐Jen
Published: December 2020

Background

Chronic neuro‐inflammation leading to excessive neuronal damages predates the presence of clinical manifestations of Alzheimer’s disease (AD) by many years. Due to the complex pathogenesis of AD, a multi‐target regimen using a combination therapy is proposed to be essential to the effectiveness of AD therapy.

Method

An innovative combination therapy using a newly developed multi‐functional Aβ antibody (NP106) and a novel curcumin derivative (TML‐6) was applied to treat APP/PS1 mice. To investigate whether synergistic effects of combination therapy on reducing AD‐like pathology in APP/PS1 mice alter fecal microbiome, high‐throughput 16S rRNA sequencing was performed.

Result

Here, we demonstrate that monotherapy with either weekly intraperitoneal injection of low‐dose NP106 or TML‐6‐supplemented diet for four months showed beneficial effects on counteracting AD‐like pathology in APP/PS1 mice, while combination therapy using these two drugs outperformed monotherapy and exerted synergistic effects on improving behavioral abnormality and reducing cerebral Aβ accumulation. Data from microbiome indicate that the gut bacterial community structure of APP/PS1 mice was different from those of wt littermates. Intriguingly, relative abundant genera of APP/PS1 mice can be restored by either monotherapy or combination therapy to levels similar to wt littermates, indicating that these treatments possessed prebiotic effects against gut dysbiosis. Importantly, analyses of samples diversity further reveal that combination therapy might lead to better normalization of microbiota.

Conclusion

Combination therapy exerted synergistic effects on attenuating AD‐like pathological features and behavioral deficits in APP/PS1 mice. Furthermore, the synergistic effects of combination therapy were concurrent with the normalization of gut microbiota.
Serum neurofilament light in memory clinic practice
Authors: Willemse Eline A.J. , Teunissen Charlotte E. , Scheltens Philip , Vijverberg Everard
Published: December 2020

Background

Neurofilament Light (NfL) is an accurate blood biomarker for axonal damage across the spectrum of neurology. Although serum NfL (sNfL) levels are increased in dementia, the diagnostic value of sNfL and appropriate use criteria need to be defined before implementation. The aim of this study is to evaluate the clinical use of sNfL in a tertiary memory clinic cohort.

Method

This single‐center implementation study included 111 patients that visited the Alzheimer Center Amsterdam between May–Oct 2019. In addition to routine neurological examination and cerebrospinal fluid (CSF) biomarker analysis, sNfL levels were analysed on Simoa (NfL‐Light kit, Quanterix) and reported together with normal values in relation to age. Six neurologists filled out a questionnaire regarding the added value of sNfL after discussing the results with the patient (n=5–43 questionnaires per neurologist). The clinical usefulness of sNfL was evaluated with regard to age (62±9 years) and diagnosis (subjective cognitive decline:n=31; Alzheimer’s disease:n=28; psychiatry:n=9; other diagnoses:n=43), whether diagnosis was uncertain (n=19), and whether CSF biomarker results were available (n=76). These results were translated into recommendations for use of sNfL in clinical practice.

Result

SNfL was evaluated as useful diagnostic tool in 54% of the cases. SNfL was more often useful in patients below the age of 61 (60%,n=42); patients with a diagnosis of subjective cognitive decline (61%) or psychiatry (78%), in cases for which there was uncertainty regarding the diagnosis (68%) and less in Alzheimer’s disease (39%). Whether sNfL was regarded as useful, strongly depended on which neurologist filled out the questionnaire (ranging from 0–73% of useful cases per neurologist). Availability of CSF biomarker results at time of result discussion had no influence.

Conclusion

In more than half of the evaluated cases, sNfL was perceived as useful diagnostic tool for memory clinic practice. SNfL analysis is mostly recommended as biomarker tool to exclude neurodegeneration in patients below 61 years old or in patients with suspected subjective cognitive decline, psychiatric disorders, or uncertainty regarding the diagnosis. The appreciation of sNfL as useful diagnostic tool was different across neurologists, probably due to differences in level of experience with biomarker sNfL.
Popular MRI de‐facing software does not sufficiently protect participants from re‐identification via face recognition
Authors: Schwarz Christopher G. , Kremers Walter K. , Therneau Terry M. , Sharp Richard R. , Gunter Jeffrey L. , Vemuri Prashanthi , Arani Arvin , Spychalla Anthony J. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R.
Published: December 2020

Background

Data shared for research use must be de‐identified to protect participant confidentiality. A recent study has shown that face imagery from brain imaging studies could be used to re‐identify anonymous participants via automatic face recognition, linking them with all study‐collected protected health information. Here we measure how well existing software for removing MRI face imagery protects against this privacy threat.

Method

We recruited 153 participants with existing 3D FLAIR MRI and photographed their face from 5 varying angles. We used surf_ice to reconstruct each participant’s face from their MRI and tested whether free, publicly‐available face recognition software (Microsoft Azure) could match their photos to their correct MRI. We tested two existing programs for removing face voxels in MRI: mri_deface (FreeSurfer) and pydeface (python package), and one in‐house implementation. We observed that existing methods often left participants’ eyes intact while removing most of their nose/mouth/chin. This prevented Azure from detecting the reconstructions as faces, therefore preventing its attempt of face recognition. We hypothesized that the retained eye imagery alone could be sufficient for face recognition, if a face were detected. Therefore, we also reconstructed each de‐faced MRI after applying novel pre‐processing that replaced any removed/missing face voxels with those from our population‐average template, e.g. replacing missing noses/mouths/chins with population‐average noses/mouths/chins, before testing face recognition.

Results

Without any MRI de‐facing, Microsoft Azure correctly matched 78% of participants’ photos to their MRI. After mri_deface and pydeface, 8% and 6% were still identified, respectively. After preprocessing the de‐faced MRI to replace missing areas with those from a population‐average template prior to face reconstruction, the face imagery remaining in the de‐faced images was enough to allow re‐identification of 23% and 20% of participants, respectively. With an in‐house face removal implementation that removes the whole face from every image, 0% of faces were re‐identified from the standard reconstructions, and 5% were identified from the “missing‐parts‐replacement” reconstructions.

Conclusions

Even after applying popular MRI de‐facing software, Microsoft Azure face recognition automatically re‐identified up to 23% of participants. Better de‐facing software is needed to remove more of the face more reliably, without affecting brain measurements from de‐faced images.
Hallmarks of late‐onset Alzheimer’s disease in a humanized mouse model
Authors: Kotredes Kevin P. , Preuss Christoph , Pandey Ravi S. , Territo Paul R. , Oblak Adrian L. , Kaddurah‐Daouk Rima F. , Arnold Matthias , Seyfried Nicholas T. , Duong Duc , Williams Harriet M. , Lamb Bruce T. , Rizzo Stacey J. Sukoff , Carter Gregory W. , Sasner Michael , Howell Gareth
Published: December 2020

Background

If progress is to be made in the pursuit to cure Alzheimer’s Disease (AD), researchers and clinicians require better resources to understand this heterogenous pathology. Thus, the Model Organism Development and Evaluation for Late‐onset AD consortium (MODEL‐AD) is charged with creating, defining, and distributing novel mouse models of late‐onset AD (LOAD) carrying human‐relevant risk factors. Characterization of these variants in aging mice will reveal more appropriate disease pathways useful in the treatment of LOAD.

Method

APOEe4 and Trem2*R47H variants, two primary risk factors of LOAD, were incorporated into the genome of C57BL/6J (B6J) mice. Cohorts of B6J.APOE4/Trem2*R47H mice were established on multiple sites and aged to 4, 8, 12, and 24 months. Behavior and wellness assays measured vigor, activity, coordination, cognition, and biometrics. In vivo MRI and PET cerebral imaging, to measure perfusion and metabolism, were also completed, as were post‐mortem analyses of blood chemistry, neuropathology, transcriptomics, metabolomics, and proteomics.

Result

As expected, mice expressing the humanized APOEe4 allele showed decreased plasma lipoprotein levels across all time points. Further, a novel splicing event was observed in mice expressing the Trem2*R47H variant, leading to a reduction of allele expression. In the absence of additional environmental or genetic risk factors, B6J.APOE4/Trem2*R47H mice did not display penetrant behavioral phenotypes, but did exhibit decreased survival probabilities by 24 months. Analysis of 6‐month‐old animals revealed differences in plasma metabolite levels and in brain proteomes compared to controls. Neuropathology analysis in brain tissue is in progress, as are cytokine panels in brain homogenates and plasma.

Conclusion

The MODEL‐AD consortium has established B6J.APOE4/Trem2*R47H model to study the effects of two strong risk factors of LOAD. This strain serves as a platform for the further incorporation of human risk alleles of AD to more closely align phenotypes in the mouse to outcomes observed in the clinic. In accordance, the effect of a high fat diet is being evaluated in B6J.APOE4/Trem2*R47H mice. Ultimately, strains carrying combinations of risk factors that more closely align with human disease will be incorporated into the pre‐clinical testing core of MODEL‐AD to assess the potential of prioritized compounds to treat AD.
Exploring the shared genetic architecture of modifiable risk factors and related endophenotypes of Alzheimer’s disease: A genomic SEM study
Authors: Foote Isabelle F. , Jacobs Benjamin M. , Noyce Alastair J. , Korszun Ania , Bhui Kamaldeep S. , Marshall Charles R.
Published: December 2020

Background

The mechanisms by which modifiable risk factors influence Alzheimer’s disease (AD) remain incompletely understood. Previous work using linkage disequilibrium score regression (LDSC) indicates that many of the modifiable risk factors have high genetic correlation with one another. Modelling this shared genetic architecture between risk factors, associated endophenotypes and AD could yield important insights into shared aetiological pathways.

Method

We used genomic structural equation modelling (SEM) to model the shared genetic architecture between potentially modifiable risk factors (including anxiety, depression, diabetes, education, hearing loss, hypertension, obesity, sleep, smoking) and related endophenotypes (including inflammatory markers and metabolites). Genomic SEM uses summary statistics from genome‐wide association studies (downloaded from leading consortia, the Neale lab group, CTG lab group and UK Biobank) to calculate the genetic covariance between traits using multivariable LDSC. We then used exploratory factor analysis (EFA) to model the patterns of shared genetic architecture into latent constructs.

Result

Multivariable LDSC showed multiple correlations between traits. EFA showed that AD shares genetic covariance with circulating metabolites and cytokines, but not modifiable risk factors. A second factor showed loadings of age‐related hearing loss with cytokines and metabolites distinct from their variance with Alzheimer’s disease. A third factor comprised the majority of other risk factors including depression, insomnia and smoking, but not diabetes or obesity, which did not share significant covariance with any other AD‐related traits.

Conclusion

We found high levels of shared genetic architecture between AD risk factors that were not shared with AD itself. This could suggest that rather than a direct causal effect on AD, risk factors exert their influence via a common intermediary (e.g. pro‐inflammatory states and/or cognitive reserve). Further work is required to establish model fit statistics, identify common SNPs related to these factors and conduct multivariable Mendelian randomisation to measure causal pathways that could lead to AD. This approach could provide important biological insights into the mechanisms underpinning the shared genetic architecture of AD risk factors, and explore how variation at these loci functionally impacts on AD pathophysiology, elucidating aetiological pathways, and ultimately prioritising targets for drug discovery and efforts to prevent AD.
Behavioural symptoms in Alzheimer’s disease are associated with white matter lesions (WML) volume and are independent of atrophy and hypometabolism
Authors: Femminella Grazia Daniela , van der Doef Thalia , Carver Stefan , Holmes Clive , Ritchie Craig W. , Lawrence Robert M , McFarlane Brady , Tadros George , Ridha Basil H , Bannister Carol , Walker Zuzana , Archer Hilary , Coulthard Elizabeth , Underwood Ben , Prasanna Aparna , Koranteng Paul , Karim Salman , Junaid Kehinde , McGuinness Bernadette , Passmore Anthony Peter , Nilforooshan Ramin , Macharouthu Ajayverma , Donaldson Andrew , Thacker Simon , Russell Gregor , Malik Naghma , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Harrison John E. , Ballard Clive , Brooks David J. , Edison Paul
Published: December 2020

Background

Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in Alzheimer’s disease (AD) and associated with adverse outcomes. There is increasing interest in identifying the risk factors for developing BPSD among AD patients. However, the pathophysiological mechanisms underlying BPSD remain poorly understood. Here we evaluated whether BPSD are associated with WMLs volume, brain atrophy and brain metabolism in AD subjects.

Method

130 AD subjects form the Evaluating Liraglutide in Alzheimer's Disease (ELAD) trial (NCT01843075) were enrolled. The presence of BPSD was evaluated with the Neuropsychiatric Inventory Questionnaire (NPI). FLAIR and T1‐weighted imaging were performed on 3T scans. WMLs was determined on FLAIR images using the Lesion Segmentation Tool (LST) in SPM12. Hippocampal and grey matter volumes were estimated using the FreeSurfer analysis on T1 MRI. Glucose metabolism (rCMRGlc) was calculated by parametric images generated using spectral analysis with an arterial plasma input function.

Result

In this AD population, NPI scores were correlated with WMLs volume (Spearman's rho=.197, p=.02), also after correcting for age. NPI scores were not correlated to hippocampal or grey matter volume and to rCMRGlc in frontal, temporal, parietal or occipital lobes. When looking at the NPI sub‐scores, WMLs volume was significantly associated with agitation/aggression (Spearman's rho=.177, p=.05) and with appetite and eating disorders (Spearman's rho=.233, p=.00).

Conclusion

In this study of a clinical AD population, BPSD were associated with WMLs but not with brain atrophy and hypometabolism. This suggests that vascular changes and the prevention of vascular risk factors might play an important role in reducing the impact of BPSD in AD dementia.
Fractional anisotropy and tau‐PET show parallel changes in amnestic AD, MCI, and controls in the medial temporal lobe
Authors: Carlson Mackenzie L , Toueg Tyler , Corso Nicole , Khalighi Mehdi , DiGiacomo Phillip , Zaharchuk Greg , James Michelle L , Greicius Michael D , Mormino Elizabeth C , Zeineh Michael
Published: December 2020

Background

Microstructural tissue alterations in Alzheimer disease (AD) contribute to decreased fractional anisotropy (FA) in white matter (Sexton et al. 2011), which may be secondary to tau‐based neurodegeneration that starts in the medial temporal lobe (MTL). Here, we show that tau accumulation in the entorhinal and perirhinal cortices (ERC/PRC) – the first area of the MTL known to accumulate tau pathology (Braak & Braak, 1991) – correlates with parahippocampal gyral FA, and both are altered in AD and mild cognitive impairment (MCI) compared with control subjects.

Method

21 subjects, 5 amyloid‐positive AD (3 amnestic), 5 amyloid‐positive MCI (4 amnestic), and 11 healthy control, underwent a dynamic 90‐minute tau‐PET scan on a 3T PET‐MR after 5mCi intravenous injection of PI‐2620 (Life Molecular Imaging, Inc.). During the PET acquisition, coronal‐oblique T2‐weighted fast‐spin‐echo (TR 14111ms, TE 102.4ms, FA 111, 0.43x0.43x1.9mm resolution, 3m24s) and DTI (6b=0 s/mm2, 60 b=1000s/mm2 directions, 1.6‐2.0mm isotropic) were acquired. Standardized uptake value ratio (SUVr) maps from 60‐90 were normalized to the inferior cerebellar cortex. DTI and PET were registered to coronal T2 MR image space. Hippocampal subfields (CA1, dentate gyrus and CA2‐4 (DG), subiculum, entorhinal/perirhinal cortex, and parahippocampal gyrus) were segmented using Automated Segmentation of Hippocampal Subfields (Yushkevich et al, 2010) with a tailored atlas (Parivash et al, 2019). Mean subfield SUVr and FA were computed after subfields were 1‐voxel 2D‐eroded in the coronal‐oblique plane. Statistics utilized a linear regression model correcting for age.

Result

SUVr differences were present between amnestic AD/MCI (N=7) and controls (N=11) in the ERC/PRC (p<0.001), more than in other subfields (Figure 1A). Amnestic AD/MCI demonstrated significantly lower FA than controls in the parahippocampal gyrus (p =0.04) (Figure 1B). FA in the parahippocampal gyrus correlates strongly (R=‐0.60) with ERC/PRC tau SUVr in amnestic AD, amnestic MCI, and controls and shows clear clustering by subject group (Figure 2).

Conclusion

The correlation between parahippocampal FA and tau SUVr in the ERC/PRC indicate that simultaneous in vivo PET/MRI measurements of early‐stage tau accumulation and white matter degradation may be useful to interrogate the relationship between tau accumulation and MTL white matter microstructure.
Augmenting cognitive assessment with instruction‐less Eye‐tracking tests: A machine learning approach for detecting abnormal oculomotor biomarkers
Authors: Mengoudi Kyriaki , Ravi Daniele , Yong Keir X.X. , Primativo Silvia , Pavisic Ivanna M. , Brotherhood Emilie V. , Lu Kirsty , Schott Jonathan M , Crutch Sebastian J. , Alexander Daniel C.
Published: December 2020

Background

Eye‐tracking technology is an innovative tool that holds promise for enhanced dementia screening, offering the potential of brief and quantitative assessment of cognitive functions. Critically, instruction‐less eye‐tracking tests may ameliorate some of the issues with complex test instructions and linguistic variations associated with traditional cognitive tests, and capture additional sensitive metrics of task performance. However, the extraction of relevant biomarkers from large, complex eye‐tracking datasets is non‐trivial. In this work, we introduce a novel automated way of extracting abnormal oculomotor biomarkers using machine learning from raw eye‐tracking data acquired during an instruction‐less cognitive test.

Method

A free‐viewing instruction‐less cognitive battery (5 minutes) was administered to healthy controls (N=553) and patients with a range of dementias (N = 30) [Figure 1]. Our method is based on self‐supervised representation learning: a deep neural network is initially trained to solve a pretext task that has well‐defined available labels. Here the pretext task is to identify distinct tasks ‐ scene perception, reading, episodic memory for scenes ‐ in healthy individuals from eye‐tracking patterns. Figure 2 visualises some features of eye‐tracking patterns that correspond to particular tasks. Once trained, this network encodes high‐level semantic information which is useful for solving other problems of interests (e.g. dementia classification) [Figure 3]. The extent to which eye‐tracking features of patients with dementia deviate from healthy behaviour is then explored, followed by a comparison between self‐supervised and handcrafted representations on discriminating between controls and patients.

Result

Based on the results of the handcrafted features, patients with dementia had significantly lower scanpath lengths than controls (z = ‐276.56, SE = 97.09, p =0.00439), consistent with less extensive and efficient scanning of the presented stimuli. The self‐supervised learning features showed higher performance in discriminating dementia patients from controls (F1 score (95% CI: [0.78, 0.82]) vs standard handcrafted features [0.62, 0.67]).

Conclusion

These results suggest that instruction‐less eye‐tracking tests can detect dementia status, even in the absence of explicit task instructions. We reveal novel self‐supervised learning features that are more sensitive than handcrafted features in detecting performance differences between participants with and without dementia across a variety of eye‐tracking‐based cognitive tasks.
Neuroimaging of amyloid pathology in a non‐human primate model of sporadic CAA
Authors: Genovese Thomas S , Ramadane Dina , Kingsley Charles , Nehete Pramod N , Nehete Bharti P , Patel Akash G , Rusinek Henry , Williams Lawrence E , Zaim‐Wadghiri Youssef , Wisniewski Thomas , Scholtzova Henrieta
Published: December 2020

Background

There has been a growing interest in developing MRI technologies to visualize Aβ plaques in animals, using approaches that may eventually be applied to humans. A non‐human primate model, squirrel monkey (SQM), was utilized in the present study due to their unique property of naturally developing age‐dependent cerebral amyloid angiopathy (CAA) identical to that seen in humans. It has been demonstrated that the transverse relaxation rate (R2*) has a linear correlation with iron content, a component of amyloid deposits and microhemorrhages. Here we proposed to evaluate whether the region of interest (ROI)‐based quantitative R2* assessment is able to detect age related differences in SQM neuropathology. An additional focus was to validate the ability of our novel MRI methodology using bi‐functional nanoparticles (USPIO‐PEG‐Aβ) to detect amyloid deposits.

Method

Multi‐gradient echo MR images were acquired in three different SQM age cohorts (ages 5, 16, 21) at various stages of Aβ pathology development. The R2* map of pre‐ and post‐Aβ nanoprobe injection MRI scans were generated (Firevoxel parametric map tool) from each subject to enable (ROI)‐based quantitative R2* analyses. 6E10 immunohistochemistry was used to confirm the presence of CAA and parenchymal plaques to correlate with the R2*.

Result

MGE imaging was effective in differentiating between the MRI brains of a 5 year old SQM with no Aβ deposits and aged SQMs with established Aβ pathology. Absolute quantitation of R2* values, defined by ROI circumventing the cortex, revealed significant differences between the young and old subjects, with the highest R2* counts detected in the 21 year old monkey. Further increase in R2* values was observed 36 hrs post‐contrast injection scans in specific brain regions in our oldest cohort, indicative of plaque labeling with our contrast agent. No toxicity was observed during the scans, demonstrating the safety of our Aβ nanoprobe. The degree of correspondence between amyloid deposits detected by MRI and 6E10 immunohistochemistry was confirmed via matched histological sections.

Conclusion

The present findings validate the utility of our MRI methodologies to monitor age dependent accumulation of Aβ deposits, opening the possibility of longitudinally evaluating novel therapeutic interventions targeting amyloid pathology.
Psychoeducation at our Belgian geriatric day hospital
Authors: Higuet Sandra , Willems Vanessa , Geurts Marie‐Noëlle , Zuinen Tatiana , Institute Global Brain Health
Published: December 2020

Background

With the rising dementia population, more and more programs have been developed to help caregivers. Being a caregiver for people with dementia is associated with psychological stress and physical ill‐health. Benefits in terms of mental health and depression were generally found for caregiver coping strategies involving problem focus, acceptance and social‐emotional support. These programs, call Psychoeducation have been consistently found to be effective in reducing caregiver distress and are suited for delivery in group format. Support groups, multicomponent interventions and joint engagements by both caregivers and people with dementia were generally found to be beneficial.

Method

This is an observational study concerning simultaneous care of dyads (patient with cognitive impairment and caregiver): the family will benefit from Psychoeducation sessions (4 classes of 3 hours during a year) with a psychologist and neuropsychologist in order to learn to modify their interactions with patients via a better understanding of illnesses and thus prevent family exhaustion. At the same time the patient will be supported by an occupational therapist for activities in order to preserve the maintenance at home as long as possible. Measures (Zarit Caregiver Burden Scale, Neuropsychiatric Inventory Questionnaire(NPI‐Q), Beck Depression Inventory (BDI), Scale of Caregiver’s Quality of life (QoL), Scale of Caregivers’ Precariousness, Hospital Anxiety and Depression Scale (HAD) and Lawton Scale) were collected at baseline and post intervention at 12‐months follow‐up.

Results

The results are ongoing; the preliminary results concerning the caregivers (n=10) and the patients aged from 72 to 88 years old (n=5). We observe a trend decreasing in the caregiver’s emotional charge and a psychic well‐being. Patient assessment is more difficult given the actually small sample size and the advanced degree of dementia.

Conclusion

This project made it possible to test the effect of psychoeducation on the helping‐helped dyad allowing on the one hand to make the caregiver expert and on the other hand to try to make the patient as independent as possible in the long term and keeping them in a continuous and transversal link.
Chronic intermittent hypoxia enhances tau seeding and propagation and exacerbates Alzheimer’s‐like memory and synaptic plasticity deficits and molecular signatures
Authors: Kazim Syed Faraz , Sharma Abhijeet , Larson Chloe S. , Ramakrishnan Aarthi , Blitzer Robert , Shen Li , Pena Catherine , Crary John F. , Shimoda Larissa , Nestler Eric , Pereira Ana C.
Published: December 2020

Background

Obstructive sleep apnea (OSA), characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer’s disease (AD) development and progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in elderly with OSA. However, the precise underlying mechanism(s) remain unknown. Tau pathology, a major neuropathological hallmark of the disease, is known to be correlated with cognitive impairment in AD. Further, increase in tau pathology has been linked to CIH suggesting that CIH may mediate AD risk through tau pathology. The present study was undertaken to evaluate the effect of CIH on human tau seeding and propagation, and to further investigate the effects of CIH on cognition, synaptic plasticity, neuronal network excitability, and gene expression profiles in a human mutant tau mouse model of AD and related tauopathies (P301S mice).

Method

We exposed 4‐4.5‐month‐old, male, mutant human tau P301S/WT mice to an 8‐week CIH protocol simulating human OSA (6 m cycle: 21% O2 to 8% O2 to 21% O2, 80 cycles per 8 h during daytime), and assessed its effect on tau seeding and spread and on various AD‐related phenotypic and molecular signatures. Age‐ and gender‐ matched P301S/WT mice were reared in normoxia (21% O2) as experimental controls.

Result

Experimentally induced CIH significantly enhanced human tau seeding and spread across connected neuroanatomical circuitry in the brains of a P301S mutant human tau model of AD; also, it increased phospho‐tau load in P301S mice. CIH also exacerbated memory deficit and synaptic plasticity impairment and increased disinhibition‐like behavior in P301S mice. However, CIH had no effect on seizure susceptibility and network hyperexcitability in these mice. Finally, CIH exacerbated AD‐related pathogenic molecular signaling in P301S mice.

Conclusion

In a comprehensive panel of immunohistochemical, behavioral, biochemical, electrophysiological, and transcriptomic analyses, we found that CIH enhances human tau seeding and spread, and exacerbates tau pathology, cognitive deficit, disinhibition‐like behavior, short‐ and long‐term synaptic plasticity impairment, and AD‐related molecular signaling in P301S mouse model of AD and related tauopathies. These data provide a mechanistic basis of a role for CIH and OSA in AD pathogenesis.
Increased APOE‐e4 expression is associated with reactive A1 astrocytes and may confer the difference in Alzheimer disease risk from different ancestral backgrounds
Authors: Celis Katrina , Griswold Anthony J. , Bussies Parker , Rajabli Farid , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Beecham Gary W. , Dykxhoorn Derek M. , Nuytemans Karen , Wang Liyong , Gardner Olivia K. , Dorfsman Daniel , Bigio Eileen H , Mesulam Marsel , Weintraub Sandra , Geula Changiz , Gearing Marla , Dalgard Clifton , Mcgrath‐Martinez Elisa , Scott William K. , Haines Jonathan L. , Pericak‐Vance Margaret A. , Young Juan , Vance Jeffery M.
Published: December 2020

Background

APOEε4 is the strongest genetic risk factor for Alzheimer Disease (AD) in European populations. African local genomic ancestry (LA) surrounding the APOEε4 allele has been associated with a decreased risk for AD in African‐American (AA) carriers relative to European LA in Non‐Hispanic Whites (NHW) (Rajalbi et al 2018). Identifying the cause of this protective effect in AA could lead to therapeutic intervention lowering AD risk for European carriers of APOEε4.

Method

To identify potential gene expression variations in the LA region contributing to this differential risk Single Nucleus RNA sequencing (snRNA‐seq) was performed on frozen frontal cortex from four APOEε4 homozygote AA AD patients with only African LA and four APOEε4 homozygote NHW AD patients with only European LA. SnRNA‐seq (10X Chromium platform) was analyzed using Seurat for potential differences in expression between the samples.

Result

47,113 total nuclei were sequenced at a median depth of ∼131,000 reads per cell. We detected on average ∼1800 genes per nucleus. European LA carriers had significantly more APOEε4 expressed (p < 1.8E−313) than AA patients in 17 of the 42 snRNA‐seq clusters. Cluster 21 was unique, as it was highly enriched for APOEε4 expression and contained proportionately 12‐fold more NHW nuclei than AA. Examination of the transcriptional signature of cluster 21 revealed a strong enrichment for known astrocyte‐specific markers, with significantly higher levels of GFAP, VIM, LGALS1, FGF2, and HSBP1 compared to other astrocyte clusters.

Conclusion

These findings suggest that the increased risk for AD seen in NHW versus AA carriers of APOEε4 is likely due to increased APOEε4 expression in carriers with the European LA. This increased APOEε4 expression is strongly associated with a large increase in potentially reactive A1 astrocytes, supporting this as a possible mechanism for the increased risk for AD conferred by the APOEε4 allele.
Yoga training impacts physical function 12 months post intervention for care partners of those with mild cognitive impairment
Authors: Chandler Melanie , Locke Dona E , Thomas Colleen S , Crook Julia E , Graff‐Radford Michelle , Lucas Pauline H , Phatak Vaishali S , Smith Glenn E
Published: December 2020

Background

The American Academy of Neurology Practice Guidelines recommends physical exercise to help maintain cognition in people with Mild Cognitive Impairment (pwMCI). We previously demonstrated yoga’s benefit in maintenance of memory related activities of daily living at one year follow‐up in pwMCI (Chandler et al., 2019), and yoga may be beneficial in offsetting a sense of burden in care partners at 12 months (Amofa et al., submitted). In this analysis, we sought to examine the impact of yoga training on physical performance in pwMCI and their care partners.

Method

In this multisite, randomized clinical trial, we enrolled 272 patients meeting National Institute on Aging–Alzheimer’s Association criteria for MCI and a care partner. The intervention program was modeled on the 10 day Mayo Clinic HABIT Healthy Action to Benefit Independence and Thinking® program. Of 5 possible interventions (memory compensation training, computerized cognitive training, yoga, patient and partner support groups, and wellness education), 1 of 5 interventions was randomly selected to be withheld for each intervention group, thus allowing us to examine comparative effectiveness. Participants and their partners had 1‐day booster sessions at 6 and 12 months after intervention. The Short Physical Performance Battery (SPPB), a measure of balance, gait speed, and repeated chair stands was used to assess physical function outcomes.

Result

There was a general pattern of physical decline on the SPPB over the year in pwMCI, regardless of yoga training (d=‐0.04, p=0.78) (Figure 1, Panel A). Among care partners, those randomized to the no yoga group had a worse decline in physical function compared to those receiving yoga (d=‐0.31, p=0.034) (Figure 1, Panel B). While not reaching statistical significance in subgroup comparisons, yoga training tended to have a greater effect on SPPB than computerized cognitive training (d = 0.35, p = .06) or wellness education (d = 0.32, p =.09) (Table 1).

Conclusion

Participation in yoga had a positive impact on physical performance outcomes at one year for care partners, but did not counteract general physical decline in pwMCI.
Microglial activation evaluated using flutriciclamide (11F‐GE180) in subjects with cognitive impairment
Authors: Calsolaro Valeria , Hinz Rainer , Femminella Grazia Daniela , Pasqualetti Giuseppe , Buckley Chris J , Gentleman Steve , Brooks David J , Edison Paul
Published: December 2020

Background

Microglial activation plays a significant role, and could be quantified using PET tracers targeting TSPO. We evaluated the use of Flutriciclamide PET tracer in a cohort of subject diagnosed with Alzheimer’s Disease (AD) or Mild Cognitive Impairment (MCI), using spectral analysis

Method

Twenty‐three subjects with AD, fourteen with MCI and eleven healthy controls (HC) underwent 3T MRI and Flutriciclamide PET with arterial input. Spectral analysis was used to create parametric maps, and IRF at 90 minutes was sampled for region of interest analysis. IRF90 parametric maps were also used for voxel‐wise SPM group analysis.

Result

Mean ages were 70.65±6.2‐ for AD, 70.3±6‐ for MCI and 63.4±1.4‐ for HCs. MCI and AD were age‐matched. Significant difference was found in the MMSE scores between AD and MCI (mean and SD respectively 21.8±3.7‐ and 26.8±3‐, p<0.001) and between AD and HC (mean and SD of HC 28.9±1.4‐, p<0.001). Significant difference was found in the hippocampal volumes between AD and MCI (mean 2711±477 on the left and 2750±455 on the right for AD, and 3942±284 and 4048±394 for MCI, p<0.01) and between AD and HC (mean 3942±284 on the left and 4048±394 on the right for HC, p<0.001).Significant difference was also found between MCI and HC (p=0.01 for left hippocampus, p=0.02 for the right one). When evaluating the IRF90 flutriciclamide uptake, significantly higher uptake was found in the AD group compared to HC in temporal (p<0.01), parietal (p=0.012), occipital (p=0.03) lobes and composite brain (p=0.01). In the AD group, IRF90 was higher in temporal lobe when compared with MCI group (p=0.04). SPM group wise analysis showed significantly higher uptake in part of temporal, parietal and occipital regions in AD compared to HCs, and a smaller cluster including part of temporal and occipital lobes when comparing AD and MCI.

Conclusion

Our study, conducted in a population with a clinical diagnosis of AD or MCI demonstrated higher widespread flutriciclamide uptake in the AD group compared with HC, and more limited difference between AD and MCI, and can be used quantify neuroinflammation.
Gender differences in the association of childhood socioeconomic status and late‐life cognition among African Americans: Findings from the STAR study
Authors: Barnes Lisa L , Peterson Rachel , George Kristen M , Gilsanz Paola , Mungas Dan M , Glymour M Maria , Mayeda Elizabeth Rose , Whitmer Rachel A
Published: December 2020

Background

Low socioeconomic status in childhood has been linked with poor cognitive function in old age. But few studies have focused on African Americans or evaluated gender differences. We examined cross‐sectional associations of childhood socioeconomic factors with late‐life cognition and effect modification by gender.

Methods

Study of Healthy Aging in African Americans (STAR) participants were 722 African Americans (69% women; mean age = 68.4 and education: 60% <High school) community‐residing long‐term members of Kaiser Permanente Northern California. Summary scores in 3 cognitive domains (executive function, semantic memory, verbal memory) and a global cognition composite were based on the Spanish and English Neuropsychological Assessment Scales (SENAS). Participants rated frequency of experiencing hunger as a child (sometimes/often vs. rarely/never), their family’s financial status (average/high vs. poor), and parental education (>= high school vs. < high school), as indicators of childhood SES. Linear regression models adjusted for age were used to examine childhood SES and late‐life cognition, and effect modification by gender.

Results

There were no gender differences in experiencing childhood hunger (p=.08), having poor family finances (p=0.30), or parental education (p=0.17). In the pooled model with women and men, higher frequency of childhood hunger was associated with worse cognition overall (β=‐0.36, 95% CI=‐0.66, ‐0.06) and in all domains (executive: β=‐0.32, 95% CI=‐0.63, ‐0.01; semantic: β=‐0.38, 95% CI=‐0.53, ‐0.23; verbal: β=‐0.42, 95% CI=‐0.73, ‐0.12). Low parental education was only associated with lower global cognition β=‐0.18, 95% CI=‐0.33, ‐0.02 and semantic memory (β=‐0.40, 95% CI=‐0.57, ‐0.23). Childhood family financial status was not associated with late‐life cognition. In gender‐stratified models, women who reported greater frequency of childhood hunger had worse cognition in every domain except semantic memory (overall: β=‐0.53, 95% CI=‐0.94, ‐0.13; executive: β=‐0.61, 95% CI=‐1.01, ‐0.20; semantic: β=‐0.21 95% CI=‐0.64, 0.21; verbal: β=‐0.46, 95% CI=‐0.87, ‐0.06). In contrast, childhood hunger was not associated with cognition in men (overall: β=‐0.14, 95% CI=‐0.59, 0.32; executive: β=0.11, 95% CI=‐0.35, 0.58; semantic: β=‐0.05 95% CI=‐0.57, 0.48; verbal: β=‐0.40, 95% CI=‐0.88, 0.08), but low parental education was associated with semantic memory (β=‐0.43, 95% CI=‐0.73, ‐0.14).

Conclusion

Childhood hunger is associated with worse cognition in old age, particularly among women.