bluuebunny/crossref_metadata_2025 huggingface dataset:
An examination of white matter integrity and functional network organization in Subjective Cognitive Decline using Diffusional Kurtosis Imaging‐based tractography resting state fMRI
Authors: Nowling Duncan , Bustos Nicholas , Barlis Katie L , Crull Jory , Lawson Andrew , Mintzer Jacobo E , Benitez Andreana , Jensen Jens H. , Joseph Jane E
Published: December 2022

Background

Subjective Cognitive Decline (SCD) may increase the risk of Alzheimer’s Disease and related dementias (ADRD). Brain network changes may occur at both the functional and structural levels in SCD. To better understand these network changes, diffusional kurtosis imaging (DKI) and functional connectome (FC) measures were examined in SCD and healthy controls (HC). We hypothesized that DKI and FC measures in the medial temporal lobe would be sensitive to differences between SCD and healthy controls (HC).

Method

SCD classification was determined by clinician evaluation or Everyday Cognition average item score > 1.6, with objectively healthy cognitive performance (Montreal Cognitive Assessment score > 22). DKI and fMRI images were acquired on a Siemens PRISMA scanner in 33 SCD subjects and 33 age/sex matched HCs (mean age=69.1 yr). DSI Studio’s Automatic fiber tracking extracted the DKI measure mean kurtosis (MK) in 3 bilateral white matter bundles associated with ADRD: inferior longitudinal fasciculus (ILF), cingulum‐parahippocampus (CP), and uncinate fasciculus (UF). FC measure eigenvector centrality (Evc) was calculated in 19 medial temporal nodes using the Brain Connectivity Toolbox. Generalized Linear Models were conducted for each bundle to determine whether EVC in the left ventrolateral amygdala (LAMG) was predicted by MK, Diagnosis or the MK*Diagnosis interaction.

Result

In the left ILF, the effect of MK approached significance (p = .054) as did the MK*Diagnosis interaction (p = .059). Lower MK was associated with higher LAMG EVC in HC (r = ‐.40) but there was no association between MK and EVC for SCD. In the left UF, effect of MK was significant (p = .003), but no effect of Diagnosis and no interaction. Lower MK was associated with higher LAMG EVC (r = ‐.359) in both SCD and HC.

Conclusion

This preliminary study showed that in HC, white matter integrity of the ILF was associated with LAMG functional connectivity, but this association was absent in SCD. While present results should be interpreted with caution due to small sample sizes, these findings indicate that healthy aging structural‐functional associations are disrupted in SCD, but future studies should determine whether this is a reliable marker of brain organization changes.
Postmortem neocortical 3H‐PiB binding and levels of unmodified and pyroglutamate Aβ in Down syndrome and sporadic Alzheimer’s disease
Authors: Pivtoraiko Violetta , Racic Tamara , Abrahamson Eric E , Villemagne Victor L , Handen Benjamin L , Lott Ira T , Head Elizabeth , Ikonomovic Milos D
Published: December 2022

Background

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid‐β (Aβ) overproduction and earlier onset of Aβ deposits compared to sporadic late‐onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound‐B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood.

Method

We performed quantitative in‐vitro 3H‐PiB binding assays and enzyme‐linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N‐terminus truncated and pyroglutamate‐modified AβNpE3‐40 and AβNpE3‐42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43‐63 years and 17 late‐onset AD cases aged 62‐99 years.

Result

Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3‐40, while the two groups did not differ by Aβ42 and AβNpE3‐42 levels, in both the frontal cortex and precuneus. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3‐42/AβNpE3‐40 in the DS group compared to the AD group, in both cortical regions. Correlations of Aβ42/Aβ40 and AβNpE3‐42/AβNpE3‐40 ratios with CAA severity were strong in DS cases, and weak in AD cases. The two diagnostic groups did not differ significantly by 3H‐PiB binding levels in the frontal cortex or in the precuneus.

Conclusion

These results demonstrate that compared to late‐onset AD cases, adult DS individuals with similar burden of cortical Aβ plaques have a preponderance of both pyroglutamate‐modified AβNpE3‐40 and unmodified Aβ40 forms which are associated with greater CAA pathology. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H‐PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. These results underscore the need for development of CAA‐selective PET radiopharmaceuticals in order to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques at the earliest pathology stages in individuals with DS.
Integrity of callosal white matter moderates the relationship between white matter hyperintensities and executive function in older adults
Authors: Marshall Anisa J , Nation Daniel A
Published: December 2022

Background

White matter integrity (WMI) may contribute to brain and cognitive reserve in the face of cerebrovascular disease. We investigated WMI in the genu of the corpus callosum (GCC), an area associated with age‐related WMI and cerebrovascular health, and whether it moderates the relationship between WMH and executive functioning in older adults.

Method

Participants were dementia‐free older adults (N = 175; age range 55‐89 years, M = 72.78; SD = 0.52; 52% male) from the Alzheimer’s Disease Neuroimaging Initiative. Diffusion weighted imaging, T1, and FLAIR scans were used to calculate diffusion tensor imaging (DTI) measures (fractional anisotropy; FA and mean diffusivity; MD) and WMH. Participants were divided into high and low GCC integrity using a median split, stratified by hemisphere and measure (i.e., Right/Left; FA/MD) Neuropsychological tests included Trail Making Test B (TMT B) and Animals. Multiple linear regression determined moderating effects of GCC WMI on WMH and executive function. Education, age, and sex were included as covariates.

Result

In individuals with low GCC WMI, WMH correlated with TMT B (Right FA: p = 0.004, R2= .215; Left FA: p = .014, R2= .222; Right MD: p = .009, R2 = .122 ; Left MD: p = .018, R2= .216) and Animals (Right FA: p = .005; Left FA: p = .022; R2= .131; Right MD: p = .054 (trended); R2= .049). In contrast, WMH did not correlate with TMT B (Right FA: p = .219; Right MD: p = .064; Left MD: p = .095) or Animals (Right FA: p = .411; Left FA: p = .280; Right MD: p = .124; Left MD: p = .274) in older adults with high GCC WMI.

Conclusion

We observed a differential effect of GCC WMI on the relationship between WMH and executive function, such that greater WMH predicted lower executive functioning only in individuals with low GCC WMI. No relationship between WMH and executive function was found in individuals with high GCC WMI. GCC WMI may thus be a source of cerebrovascular‐related brain reserve and contribute to cognitive resilience by mitigating the clinical consequences of WMH in individuals with cerebrovascular disease.
Choroid Plexus Calcification Associations with Brain Morphology and Family History of Alzheimer's Disease
Authors: Gari Iyad Ba , Zhu Alyssa H , Haddad Elizabeth , Dixon Daniel , Islam Tasfiya , Gadewar Shruti , Low Kevin , Nir Talia M , Jahanshad Neda
Published: December 2022

Background

The choroid plexus (CP) is the primary source of cerebrospinal fluid (CSF) production and forms the blood‐CSF barrier which regulates nutrients and hormones to the brain. Changes in CSF production are associated with aging and Alzheimer’s disease (Saade 2019, Hubert 2019). CP calcification (CPcal) has been associated with metabolic disorders, cerebrovascular diseases, and tumors (Wu, 2009). Here, we used MRI‐derived quantitative susceptibility mapping (QSM) from the UK Biobank(Miller, 2016) to investigate whether CPcal is associated with morphological brain alterations and family history of Alzheimer's disease or related dementias (ADRD).

Method

We analyzed susceptibility weighted images (SWI) from 32,426 participants (aged 45‐83 years, F = 54%) from the UK Biobank, and 1716 follow‐up scans (aged 50‐83 years, F = 53%) Table 1. CPcal volumes were extracted from processed QSM maps (Figure 1) within FreeSurfer‐defined brain ventricles: total, lateral (LV), third (3rdV), and fourth ventricle (4thV). 34 regional cortical thickness and surface area measures, and 11 subcortical volumes were extracted using FreeSurfer. Linear regressions were used to assess the relationship between log‐transformed CPcal volumes and cross‐sectional and longitudinal change in FreeSurfer brain metrics (tp2‐tp1/tp1) adjusting for age, sex, LV and intracranial volumes. The false discovery rate (FDR, q=0.05) was applied to adjust for multiple comparisons across brain regions. Linear regression was used to investigate whether CPcal volumes were associated with family history of AD or dementia.

Result

Greater CPcal volumes were associated with regional brain morphometry, cross sectionally, and longitudinally (Figure 2). Total CPcal were associated with family history of AD; specifically maternal history of AD showed a stronger association with total CPcal while paternal history showed no association (Table 2).

Conclusion

Using QSM, we show that CP calcification impacts structural brain measures and is associated with family history of ADRD. This suggests that CPcal may be an important biomarker for tracking age related changes and AD, and may be an important biomarker for imaging genetic studies.
Psychosocial Considerations in Management of Corticobasal Degeneration in Indian American Population
Authors: Singh Neeraj
Published: December 2022

Background

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy primarily affecting the cerebral cortex and basal ganglia, often featuring cognitive decline and parkinsonism. With no proven treatments for this rare condition, the goals of management are to improve patients' quality of life. We evaluate here the unique psychosocial factors that were considered for two women of Asian Indian descent with CBD.

Method

Patient 1 was a 77‐year‐old woman who exhibited short‐term memory loss, and then suffered an acute left anterior cerebral artery territory ischemic stroke with right‐sided hemiparesis and neurogenic pain. MRI Brain confirmed the stroke’s location, but did not account for cognitive decline. Patient 2 was a 75‐year‐old woman who initially experienced dysphagia, and then developed right‐sided hemiparesis, right neck spasms, unstable gait, and short‐term memory loss. MRI Brain and Cervical Spine revealed only showed mild chronic microvascular changes and multilevel cervical spondylosis.

Results

PET‐FDG Brain studies were performed for both patients. Patient 1’s study revealed severe hypometabolism affecting bilateral basal ganglia, bilateral thalami, and left supplementary motor cortex, out of proportion to the known stroke and consistent with CBD. Patient 2’s study revealed mild hypometabolism at the left frontal and parietal lobes, sparing the precuneus and posterior cingulate, also consistent with CBD and helping to explain the right‐sided hemiparesis.

Conclusion

Various psychosocial factors were considered during the evaluation and management for both patients. Both had limited English proficiency, so cognitive testing was performed with the aid of a medical interpreter to ensure accurate results. Symptomatic treatment was tailored for each patient: Patient 1 received carbidopa/levodopa for parkinsonian tremors, and Patient 2 received cyclobenzaprine for intermittent muscle spasms. Both patients had multigenerational households, and results and prognoses were discussed with multiple relatives so they could coordinate responsibilities. Both families initially resisted recommendations to have home health aides, expressing their cultural belief that families should take care of their relatives on their own. As we discussed this belief over time, and explained the expected progression of symptoms over time, both families came to be more accepting of introducing home health aides, seeing them as a supplement, and not a replacement, for the family’s role.
Deep spatial phenotyping of microglial populations and pathological features in Alzheimer’s disease brains using CODEX Multiplexed Imaging
Authors: Sanchez‐Molina Paula , Pratapa Aditya , Singh Jasmine , Chiot Aude , Bogachuk Alina , Nikulina Nadezhda , Woltjer Randy , Braubach Oliver , Ajami Bahareh
Published: December 2022

Background

Recent high‐throughput transcriptomics and proteomics analysis have shown a remarkable heterogeneity of microglia phenotypes across various disease conditions. Differently from neurons, microglia appearance can be characterized as a continuum between ramified and amoeboid morphologies. The transcriptional and proteomic profiles associated to each degree of morphology are potentially multiple and dependent on the healthy/pathological conditions in consideration with sex, anatomical area of the brain and disease stage. While single‐cell RNA sequencing (scRNA‐seq) has been instrumental in revealing microglia sub‐populations, it is lacking in spatial information and phenotypic characterization. The scarcity of fresh human brain tissue imposes a bottleneck for RNA‐seq studies, while paraffin‐embedded tissues are widely available in most brain banks. CODEX multiplexed imaging technology permits a deep characterization of microglial cells preserving their morphology and avoiding cell activation by aggressive sample preparation methods as occurs in tissue homogenates. Moreover, we can discriminate the immune cells in brain blood vessel from those in the parenchyma.

Method

Using this technology, we characterize microglia sub‐population localization in relationship to the distance from neurodegenerative disease pathogenic features in post‐mortem AD brain samples and matching controls. Bioinformatics analysis were performed to achieve microglial segmentation to a single‐cell level and cell clustering by protein expression.

Result

Our results show the existence of different microglial cells populations, which vary between AD and control brains. Expression of blood‐derived macrophages markers was observed in parenchymal ramified cells close to blood vessels and/or Aβ plaques. We were able to deeply characterize this population and measure their distance to the nearest blood vessel and Aβ plaque. Microglial/macrophages activation markers were increased correlating with the distance to the plaques.

Conclusion

This study allowed us to characterize the changes of microglia phenotype in the immediate neighborhood of pathogenic features. Such observation will be instrumental to understanding the role of several Late Onset Alzheimer’s Diseases associated genes and potentially identify novel drug targets.
Centiloid harmonisation across PET cameras without using paired scan
Authors: Li Shenpeng , Bourgeat Pierrick , Lebrat Leo , O'Keefe Graeme , Fripp Jurgen , Villemagne Victor L , Rowe Christopher , Dore Vincent
Published: December 2022

Background

The Centiloid (CL) scale allows quantification of amyloid‐b accumulation across multiple PET tracers for the diagnosis of Alzheimer’s disease. The CL quantification on different PET cameras may result in significant quantification bias when merging cohorts acquired from multiple cameras or in the longitudinal studies when change of camera occurs. In this study, we propose a harmonisation method, based on the non‐negative matrix factorisation (NMF), to reduce the quantification bias between different cameras without using paired scans.

Method

Three hundred and forty‐eight 18F‐NAV4694 scans from Australian Imaging Biomarkers and Lifestyle study acquired on three PET cameras (N=116 each), Siemens Biograph mCT, Philips Allegro and Philips Gemini TF64 were used to train the model. Participants who switched camera between two consecutive timepoints were selected as the validation data. Seventeen participants imaged on the Biograph mCT and Gemini (2.63±0.51 years scan interval), and fifty‐two participants imaged on the Gemini and Allegro (2.73±0.73 years). One hundred participants who have two scans (2.26±0.82 years) on Gemini were used to define a reference rate of change (CL/year). Figure 1 illustrates the harmonisation workflow.

Result

Figure 2 compares the curves of CL change rate against baseline CL for mCT to Gemini compared to the reference. The harmonised fitting is closer to the reference than the one without harmonisation in the low to middle CL range. The fitting in high CL range (CL>80) deviates from the reference probably because of the lack of subjects in this range. Figure 3 compares the results between Phillips Allegro and Gemini TF 64. The harmonised fitting in Figure 3 is nearly parallel to the reference for the entire CL range. In contrast, the fitting on the unharmonized data shows negative rate of change for the very negative subjects and much higher CL change rate for the very positive subjects, which are strongly different compared to the reference.

Conclusion

We propose a practical and economical CL harmonisation for different PET cameras without using paired data. The NMF based method shows promising results for scanner harmonisation, though more validation are needed in future for different PET models.
Artificial Intelligence/Machine Learning Approaches for Gene Discovery and Target Identification in ADSP Data
Authors: Vardarajan Badri N. , Fornage Myriam
Published: December 2022

Background

By 2023, the ADSP will generate and harmonize 68000 whole genome sequences (WGS) from cohorts around the world. Joint analysis of WGS and complex phenotypic data such as imaging, and integration with omics layers at this scale requires non‐traditional statistical and bioinformatics approaches.

Methods

Cognitive systems encompassing Artificial intelligence, machine learning, and deep learning can be leveraged to identify patterns and associations from complex heterogenous datasets for gene and target discovery in Alzheimer’s Disease.

Results

Recently, NIA formed the AI/ML AD consortium to apply cognitive systems approaches to AD genetic and multi‐omics data. The goal of the consortium is to apply machine learning algorithms to existing GWAS, and sequencing data with AD endophenotypes in ethnically diverse cohorts for gene discovery. Insights from these approaches could identify risk and protective factors and pathways perturbed in AD and novel therapeutic approaches to the disease.

Conclusion

We will discuss these technological advances especially in the context of brain imaging and their application to the identification of novel genetic loci for AD.
Alzheimer’s Disease Detection with a 3D Convolutional Neural Network using Gray Matter Maps from T1‐weighted Brain MRI
Authors: Dhinagar Nikhil J , Thomopoulos Sophia I , Owens‐Walton Conor , Stripelis Dimitris , Ambite Jose Luis , Steeg Greg Ver , Thompson Paul M
Published: December 2022

Background

A practical screening tool to detect Alzheimer’s disease (AD) based on brain MRI would be valuable. Here we tested a deep learning method for subject‐wise AD classification; as gray matter (GM) is preferentially affected by AD, we also performed MRI tissue classification on the input data, to test the added value of these input features. We set out to compare different types of imaging data types1 as inputs to a 3D Convolutional Neural Network (CNN) for the AD classification task.

Method

We analyzed T1‐weighted brain MRI scans from 1123 subjects (596M/527F, 55.2 ‐ 95.8 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). After registering the T1‐w MRI scans to a common brain template, GM was segmented as shown in Figure 1. We subdivided the dataset into training (3,302 scans/853 subjects), validation (413 scans/100 subjects) and test (170 scans/170 subjects) data for the CNN2. We also trained the CNN on different proportions (10%, 20%, 50% and 100%) of the overall ADNI training data. We further validated our results independently on 232 scans/232 subjects (78M/154F, 33‐96 years) from the Open Access Series of Imaging Studies (OASIS) dataset.

Result

We summarize our results in Table 1 in terms of the receiver‐operator characteristic curve‐area under the curve (ROC‐AUC). Results were aggregated over two separate runs to demonstrate the model’s stability. The CNN with GM segmented T1‐w MRI as input achieved an Average ROC‐AUC of 0.864, compared to 0.859 with the complete T1‐w MRI. The CNN performs better with gray matter segmented input; this performance boost was more pronounced with smaller training sets, i.e., 10% (330 scans) or 20% (660 scans) as seen in Figure 2. The models trained on gray matter maps from ADNI also yielded better performance on the OASIS test set.

Conclusion

In this work, we found that using GM extracted from T1‐w MRI scans improves deep learning‐based AD diagnosis. Feature selection is improved by regulating the data input into the CNN.

[1] Lu, B., et al., “A Practical Alzheimer’s Disease Classifier… on 85,721 Samples,” bioRxiv Prepr. (2021).

[2] Dhinagar, N. J., et al., “3D CNNs for Classification of Alzheimer’s … with T1‐Weighted Brain MRI,” SIPAIM (2021).
Evaluating Simple Objective Metrics for the Remote Measurement of Physical Activity: Preliminary Results from the RADAR‐AD Study
Authors: Muurling Marijn , Hinds Chris , Wu Yuhao , Conde Pauline , Doherty Aiden , Curcic Jelena , de Boer Casper , Aarsland Dag , Narayan Vaibhav A , Visser Pieter Jelle ,   the RADAR‐AD consortium
Published: December 2022

Background

Higher physical activity is associated with better global cognition and a lower risk of dementia (Rojer et al., 2021). Using questionnaires to assess physical activity is difficult in an Alzheimer’s disease (AD) population, since questionnaires rely on retrospective subjective recall. Wearables measure physical activity objectively and continuously. A variety exists, with some delivering raw high‐frequency research‐grade movement data, others providing summary variables only. The aim of this study is to compare simple activity metrics from two activity trackers monitoring physical activity in AD, and relate these to standard questionnaires.

Method

Participants in the RADAR‐AD study (Remote Assessment of Disease and Relapse – Alzheimer’s Disease) were asked to wear two activity trackers (dominant hand: Axivity AX3, non‐dominant hand: Fitbit Charge 3) for 8 weeks. Features calculated from the Axivity’s raw accelerometer data were: acceleration magnitude, time spent in sedentary, light, moderate‐to‐vigorous activity, and sleeping. Fitbit features included: step count and heart rate. Self‐reported activity levels (Godin Leisure Time Questionnaire), depression (Geriatric Depression Scale), social functioning (Social Functioning Scale), global cognition (Mini‐Mental State Examination), partner‐reported function (ADCS‐ADL) and neuropsychiatric symptoms (Neuropsychiatric Inventory) were assessed and related to activity levels using regression models.

Result

We included amyloid negative controls (n = 36) and amyloid positive preclinical (n = 13), prodromal (n = 15) and mild‐to‐moderate (n = 10) AD participants (Table 1). Expected associations were found between sedentary activity time and age, and between self‐reported activity and both moderate‐to‐vigorous activity time and step count (Table 2, Figure 1). Small group sizes currently make further comparisons of exploratory value only.

Conclusion

Wearable devices have the potential to accurately capture clinically relevant aspects of daily activity and function of interest in AD population. On‐going research in the RADAR‐AD study will focus on developing disease‐specific methods of feature extraction based on raw movement data, and combining features from multiple devices, to explore this further.

This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR-AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
FDG‐PET is a sensitive imaging biomarker of the neurodegenerative changes that accompany early neurofibrillary tangle pathology
Authors: Grothe Michel J. , Silva‐Rodríguez Jesús , Moscoso Alexis , Schöll Michael
Published: December 2022

Background

Neurofibrillary tangle pathology in Alzheimer’s disease (AD) is closely related to neurodegeneration, which can be measured in‐vivo using structural MRI or FDG‐PET. However, previous imaging‐pathologic association studies found that gray matter atrophy on structural MRI is relatively insensitive to early stages of neurofibrillary tangle pathology as assessed by the Braak staging scheme. Here we assessed associations between post‐mortem neuropathological Braak staging and ante‐mortem glucose hypometabolism on FDG‐PET, which may be a more sensitive neuroimaging marker of early neurodegenerative changes preceding macrostructural gray matter atrophy.

Method

The study included 64 individuals from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had Braak staging performed at neuropathological examination and had an FDG‐PET scan acquired before death (FDG‐PET to death interval: 3.4±2.3 years). Distribution of Braak stages was N=1/6/9/3/2/33/10 for 0/I/II/III/IV/V/VI. Associations between Braak stages and regional FDG‐PET standard uptake value ratios (SUVR) were assessed in an exploratory brain‐wide Spearman correlation analysis across 52 cortical and subcortical gray matter regions. For brain regions showing a significant association after multiple comparison correction (p<0.05, FDR‐corrected), we then performed pair‐wise comparisons between grouped Braak stages 0/I (N=7), II‐IV (N=14), and V/VI (N=43). For comparison, we conducted analogous analyses for regional gray matter volume assessed on structural MRIs from the same study visit.

Result

Higher Braak stages were significantly associated with lower FDG‐PET SUVR in several temporo‐parietal cortical regions typically affected by AD (Fig. 1A). When compared to the Braak 0/I reference group, most of these regions showed significant and pronounced (Cohen’s d>0.9) hypometabolism in grouped Braak stages II‐IV, and severity of hypometabolism further increased in Braak stages V/VI. Although gray matter volume on MRI showed a similar regional association with Braak stages (Fig. 1B), effect sizes were considerably lower and differences to the Braak 0/I reference group were only significant for advanced Braak stages V/VI.

Conclusion

Glucose hypometabolism as measured by FDG‐PET is a sensitive neuroimaging marker of the neurodegenerative changes that accompany progressive stages of neurofibrillary tangle pathology. Earliest neurodegenerative changes captured by FDG‐PET hypometabolism may precede macrostructural gray matter atrophy as measured by MRI.
Characterisation of pupillary responses to alternating blue and orange light exposures in a fMRI protocol
Authors: Beckers Elise , Campbell Islay , Paparella Ilenia , Sharifpour Roya , Ekaterina Koshmanova , Berger Alexandre , Sherif Siya , Jacobs Heidi I.L. , Gilles Vandewalle
Published: December 2022

Background

The non‐image forming (NIF) functions of light are diverse and include stimulation of cognition and alertness, sleep regulation and pupil diameter modulation. Previous work indicated that exposure to blue‐enriched light as well as pupil size variations are associated with higher locus coeruleus (LC) activity. Given the central role of LC structure and function in the earliest stages of Alzheimer’s disease neuropathology, light exposure may constitute a promising stimulation technique to delay disease progression. Prior to addressing light impact on the LC, here, we aimed at characterising the pupil responses to light during fMRI protocol, to determine its quality in assessing NIF effects of light.

Method

Pupil diameter was continuously recorded in 11 healthy subjects (20‐30yr, 7 women) with an infrared eyetracker device while they were administered a 15‐min auditory oddball task in a 7T MRI scanner. Participants were concomitantly exposed to pseudo‐randomly alternating 30s blocks of blue‐enriched (4,000K; 200µW/cm2) and orange (589nm; 6x1013photons/cm2/s) lights. Statistics consisted in generalized linear mixed models seeking effects of light condition on pupil response, with subjects as random intercept and controlling for age, sex and BMI.

Result

Blue light condition was associated with a significantly smaller pupil diameter as compared to the orange condition, (main effect of light condition: F(2,270)=571.22;p<.0001; Fig1). Moreover, the impact of the light condition on pupil size did not significantly change over the 15min‐protocol (light condition x block repetition interaction: F(12,240)=1.21 ; p=.28), suggesting that time‐in‐protocol and prior light blocks did not influence pupil constriction.

Conclusion

We report preliminary results confirming that blue‐enriched light triggers a stronger pupil response than longer wavelength light and showing that the protocol induces a stable response in time even when using short alternating light exposures. These findings support the validity of the protocol to assess NIF responses to light in fMRI in healthy participants, including over the LC. Being able to stimulate the LC holds important implications for possibly delaying Alzheimer’s disease progression. We now aim to include more participants, including older individuals, and to extend to other cognitive tasks to assess the generalization of the present findings to other cognitive domains and age‐ranges.
Comparison of Algorithms for Dementia Classification in the Survey of Health, Ageing and Retirement in Europe
Authors: Klee Matthias , Langa Kenneth M , Leist Anja K
Published: December 2022

Background

Low dementia rates, reflecting underdiagnosis in representative cohort studies, limit statistical power of etiological and preventative research. Although several algorithms for automated classification of presence or absence of dementia have been validated in the Health and Retirement Study (HRS), no such algorithm has yet been applied to the Survey of Health, Ageing and Retirement in Europe (SHARE).

Method

The Langa‐Weir classification (LW) was adapted to readily available indicators in SHARE, including immediate and delayed recall. Adapted algorithms additionally included instrumental activities of daily living (IADL) and used cut‐offs defined by either sample‐ or population‐level distributions. Performance was compared to logistic and bayesian‐logistic regression models and a gradient boosting machine (XGBoost) with the same indicators, adjusting for age groups, gender and educational level. The bayesian‐logistic regression used priors for sociodemographic indicators and global dementia incidence. Accuracy, specificity and sensitivity were compared with a train‐test split approach in SHARE wave 7 (2017).

Result

In total, N = 72,329 participants (57% female) above age 50 had no missing data on self‐reported dementia diagnosis, immediate or delayed recall and IADLs. LW based on immediate and delayed recall with a score cutoff based on dementia population‐incidence performed best overall (Accuracy = .92, Balanced Accuracy = .75, Sensitivity = .58, Specificity = .92), and showed greatest similarities to participants with self‐reported dementia diagnosis regarding risk factors and comorbidities (i.e., gripstrength, numerical performance, verbal fluency). Results from XGBoost suggested comparable performance however with risk of overfitting.

Conclusion

LW adaptations outperformed regression models regarding sensitivity. Comparisons of risk factor and comorbidity distributions suggest meaningful differences in comorbidities and risk factors in participants classified with and without dementia. With a lack of proxy assessments in SHARE, a suspected healthy volunteer bias and the absence of standardized cognitive assessments, probable dementia detection in SHARE necessarily comes with less confidence compared to algorithms tested in HRS. Nonetheless, performance of LW adaptations in SHARE is in line with previous validation studies in HRS. Future research should validate the algorithms through more extensive cognitive assessments once available.
Role of astrogliosis in the relationship between cerebrovascular burden and Alzheimer’s disease pathology
Authors: Ottoy Julie , Kang Min Su , Benedet Andréa Lessa , Bezgin Gleb , Lussier Firoza Z , Ruthirakuhan Myuri , McSweeney Melissa , Pascoal Tharick A , Ferrari‐Souza João Pedro , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Gauthier Serge , Black Sandra E. , Rosa‐Neto Pedro , Goubran Maged
Published: December 2022

Background

Cerebrovascular disease represents a common co‐pathology of Alzheimer's disease (AD) contributing to cognitive decline. While both vascular injury and AD pathology were previously linked to reactive astrocytes (astrogliosis), the interrelationship between these biomarkers remains unclear in AD. Here, we investigated potential effects of plasma glial fibrillary acidic protein (GFAP), an assumed marker of astrogliosis, on the relationship between vascular burden and AD pathology.

Method

We enrolled 210 participants across the AD continuum, including 111 cognitively normal amyloid‐negative (CN Aβ‐), 37 CN Aβ+, and 62 MCI/AD Aβ+ (TRIAD). Amyloid‐β pathology was quantified through 18F‐NAV4694‐PET standardized uptake value ratio (SUVR) in the AD‐signature regions, while tau pathology was quantified through 18F‐MK6240‐PET SUVR in regions corresponding to Braak stages. Vascular burden was quantified as the log‐transform of white matter hyperintensity volume by intracranial volume (WMH). GFAP levels were log‐transformed. At baseline, we employed linear regression models to investigate the effects of WMH and GFAP on tau pathology. Longitudinally, we performed linear mixed effect modeling to investigate the effects of baseline WMH and GFAP on tau accumulation over time (613±252 days). All analyses were adjusted for baseline age, sex, APOE‐ε4, and cortical Aβ. Last, we investigated a potential mediating effect of GFAP in the relationship between WMH and tau accumulation over time, using bias‐corrected bootstrapping with 5,000 replications.

Result

At baseline, GFAP (P=0.001), but not WMH, was positively associated with tau in the lower Braak I‐II regions. Conversely, both GFAP and WMH were positively associated with tau in the higher Braak regions (P<0.001), as was their interaction (WMH*GFAP; Braak III‐IV β=0.14±0.06, P=0.014; Braak V‐VI β=0.19±0.06, P=0.001). Longitudinally, baseline Aβ but not WMH or GFAP predicted tau accumulation (P<0.001). Serial mediation analysis revealed a significant indirect effect of WMH→GFAP→cortical Aβ→Tau increases [95%CI 0.03,0.29].

Conclusion

We observed an interaction effect between higher WMH volumes and plasma GFAP levels on tau pathology across the AD continuum. Furthermore, we observed an indirect effect of WMH volumes on tau accumulation over time through amyloidosis and plasma GFAP. These results may indicate that reactive astrogliosis, potentially secondary to vascular injury, may be a factor contributing to AD progression.
Engaging cognitive domains of people with dementia during tablet game play
Authors: Sachdev Sukriti , Acenas Maria , Dove Erica , Astell Arlene J.
Published: December 2022

Background

Keeping cognitively active is important for people living with dementia or MCI but finding engaging activities can be challenging. Playing digital games has been shown to engage cognitive processes such as visual attention, working memory, and visuomotor skills, in children and adults. This study explored whether these cognitive domains are engaged when people living with dementia or MCI play digital games.

Method

Participants (n = 32) with dementia or MCI, mean MoCA 13.9, were recruited from adult day programs to play four mainstream games on touchscreen tablets. Each session was recorded and a video coding scheme was developed using behavioral analysis software to map observable behaviors, including eye gaze, hand movements, and game strategy, to five DSM cognitive domains : complex attention, executive function, learning and memory, language, and perceptual motor (DSM‐V, 2013). Five minutes from each initial gameplay session were analyzed to explore the engagement of cognitive domains.

Results

All five cognitive domains were engaged but varied across the games. For example, a word search games engaged language much more than a jigsaw puzzle game which was higher on perceptual‐motor skills. The most engaged cognitive domain was ‘complex attention’ and the least engaged cognitive domain was ‘language’. All participants demonstrated cognitive engagement whilst playing the games.

Conclusion

Playing digital games can provide cognitive engagement for people living with dementia or MCI. Using mainstream games increases accessibility of opportunities for cognitive engagement, in a way which is also immersing and rewarding. Future research incorporating eye tracking will increase understanding of how people living with dementia learn to play digital games and respond to prompts. This study presents huge potential for low cost cognitive activity for people with dementia or MCI.
Psychosocial and Physical Functioning Predictors of Everyday Functioning in The Kaiser Healthy Aging and Diverse Life Experience (KHANDLE) Study
Authors: Chan Michelle L , Zhou Kevin , Eng Chloe W. , Farias Sarah , Gilsanz Paola , Whitmer Rachel A.
Published: December 2022

Background

While Alzheimer’s disease and associated cognitive impairments are major contributors to functional decline, other variables including physical functioning and psychosocial variables may also impact functional status. Our study examined how psychosocial factors (depression, loneliness, and emotional support) and physical functioning (gait speed and grip strength) may independently contribute to instrumental activities of daily living (IADL) functioning among a diverse ethnoracial cohort.

Method

The Kaiser Healthy Aging and Diverse Life Experience (KHANDLE) study is a diverse cohort of long‐term members of an integrated healthcare delivery system ages ≥65, without a dementia diagnosis at time of recruitment. At enrollment, participants completed self‐report IADL measure, neuropsychological testing, physical functioning assessment (grip strength and walk speed), and self‐report psychosocial inventories assessing depression, loneliness, and perceived emotional support through the NIH Toolbox. Analytic sample included 1,243 participants (395 Caucasian (32%), 331 African American (27%), 292 Asian (23%), and 225 Latino (18%)). Cumulative logit models adjusting for cognition and demographics were used to determine significant predictors of IADL functioning, both in separate and combined models. Possible effect modification by race/ethnicity were assessed through interaction terms.

Result

Average baseline age was 75.5 and 59% were female. In separate models, gait speed, grip strength, loneliness, and emotional support were significant predictors of IADL functioning after controlling for cognition and demographics. Depression was not a significant predictor. When adding all significant variables into a single model as independent predictors, slower gait and greater loneliness were associated with more IADL difficulty, while stronger grip strength and more emotional support was associated with less IADL difficulty. Emotional support was no longer a significant predictor of IADL functioning. Interaction terms between independent variables and race were not significant.

Conclusion

Very few studies have simultaneously examined psychosocial factors and physical functioning as predictors of everyday functioning, particularly among a diverse ethnoracial sample. Our results indicate that independent of cognition, slower gait and greater loneliness were independently associated with worse IADL functioning, while stronger grip strength was associated with better IADL functioning. Such findings have important implications for identifying older adults at risk for disability and for treatments that could prevent excess disability.
Using Oligodendrocytes for studies in Alzheimer disease
Authors: Ramirez Aura M , Shepherd Jihanne J , Simon Shaina A , Oron Oded , Vasquez Marina Lipkin , Moura Ana Sofia , Muniz Maria , Rajabli Farid , Wang Liyong , Liu Xiaoxiao , Jin Fulai , Kunkle Brian W. , Nuytemans Karen , Griswold Anthony J. , Young Juan J , Vance Jeffery M. , Dykxhoorn Derek M. ,   Hussman Institute for Human Genomics
Published: December 2022

Background

Genomic regulatory architecture (GRA) has been primarily studied in European ancestry. As part of the functional Consortium of the Alzheimer Disease Sequencing Project, we are determining the GRA in African and Amerindian ancestries. Oligodendrocytes (OLs) are the largest glial population in the adult central nervous system. While their main role is to support neuronal metabolism and connectivity, few studies have examined their importance in Alzheimer’s disease (AD), despite reports of low numbers of oligodendrocytes and reduced myelin in the early stages of AD and a demonstrated role of myelinating oligodendrocytes in learning and memory. Several studies have reported the derivation of OLs from pluripotent cells, such as induced pluripotent stem cells (iPSC) to be challenging. Here, we optimized a protocol to derive oligodendrocytes from iPSC for studies in AD patients with different ancestries and how ancestry‐specific genomic differences drive the onset and pathogenesis of AD.

Method

iPSC lines derived from AD patients were cultured and differentiated into oligodendrocytes using different induction media, as well as different seeding densities. The cells in each treatment were compared at multiple time points using immunocytochemistry (ICC) and qRT‐PCR for oligodendroglia lineage markers with the goal of identifying the culture conditions that increase the yield of O4+ cells and myelinating oligodendrocytes.

Result

Our results showed that increasing the initial seeding density positively correlates with the number of Olig2+ cells that subsequently transitioned into mature O4+ cells capable of producing myelin. Additionally, we showed that the addition of N2 supplement to the induction media was necessary to maintain the cell viability during the initial stage of differentiation.

Conclusion

We have optimized a protocol to derive OLs from human iPSC lines. We determined that both the seeding density and the media supplements used during the initial stage of differentiation directly influence viability and, consequently the amount Olig2+ cells that could be obtained to be terminally differentiated into O4+ and myelinating cells. Our optimized protocol will be used to evaluate the GRA and functionality of potential GWAS driving loci in cultured oligodendrocytes from individuals of African and Amerindian ancestries.
Lower CSF ApoE glycosylation associates with measures of Alzheimer's disease biomarkers
Authors: Nedelkov Dobrin , Meuret Cristiana , Martinez Ashley , Hu Yueming , Smadi Sabrina , Yassine Hussein N.
Published: December 2022

Background

The mechanisms of how APOE4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated but its contribution to AD pathology is not known. The objective of this study was to determine the impact of APOE genotype and cognitive status on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma.

Method

Total glycosylation and ApoE isoform‐specific glycosylation were analyzed in plasma and CSF from a group of older individuals (n = 106) from the USC ADRC cohort, grouped into cognitively normal, with mild cognitive impairment, and with AD dementia. We used a new mass spectrometric immunoassay that simultaneously detects the apoE isoforms and glycoforms (O‐linked GalNAc(‐Sia)‐Gal‐Sia, and various combinations thereof).

Result

In heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O‐linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In CSF, ApoE4 was 35% and 25% less glycosylated (P<0.001) than ApoE2 and ApoE3 carriers respectively. The % of secondary glycosylation was positively correlated with CSF Aβ42 levels (R=0.55, p<0.001) and negatively correlated with CSF total Tau (R=‐0.38, p=0.001). Patients with AD dementia had lower % glycosylation than individuals with MCI (p=0.008).

Conclusion

CSF glycosylation is lower in CSF apoE4 isoform and in those with dementia, and correlate with markers of AD pathology. Ongoing experiments are delineating the effects of ApoE glycosylation on its functions. ApoE4 glycosylation may represent a newer target of treatment in AD.
Parental SES buffers the effect of plasma pTau181 on memory among non‐Latinx White, Latinx, and non‐Latinx Black middle‐aged adults
Authors: Manly Jennifer J , Starks Tiara M. , Simoes Sabrina , Turney Indira C , Lao Patrick J. , Banjoko Michael B. , Brickman Adam M.
Published: December 2022

Background

Inclusive ADRD research should consider social and structural forces as potential sources of cognitive reserve and resilience. Characterization of neuropathology is critical for cognitive reserve research, but few cohorts have AD biomarker data in concert with sufficient sample size, population representativeness, and multi‐level, lifecourse measurement of determinants that is necessary to contribute substantial or novel evidence for when and where to intervene. We partnered with participants in a population‐representative intergenerational study in NYC to determine whether parental socioeconomic status (PSES) buffers the association of plasma pTau181 concentrations with memory among middle aged adults, and whether moderation of neuropathology is similar across racialized and ethnic groups.

Method

Offspring participants were 1038 adult children (56±11‐years‐old range: 28‐88, 68% women, 12.6±4 years education, 48% Latinx tested in Spanish, 24% Latinx tested in English, 21% non‐Latinx Black, 7% non‐Latinx White) of 694 parents in a longitudinal community‐based study of Northern Manhattan residents age 65+. Blood collected from Offspring determined pTau181 concentration (Quanterix Simoa) and APOE genotype, and memory was tested with the Selective Reminding Test. PSES was measured with years of school collected directly from parents. Regression models examined associations of pTau181 concentration with memory, tested PSES as an effect modifier, and determined whether relationships differed by racial and ethnic group.

Result

In an unadjusted model, higher pTau181 concentrations predicted lower delayed recall (β = ‐0.438, 95% CI:‐0.662,‐0.214,p<0.001), and this was robust to addition of offspring age, sex/gender, years of education, racial and ethnic classification, APOE status, parental age, and PSES into the model (β = ‐0.332, 95% CI:‐0.542,‐0.122,p<0.001). pTau181 concentrations had a weaker relationship to delayed recall among offspring with higher PSES (β = ‐0.291, 95% CI: ‐0.540,‐0.043,p<0.022) than among those with lower PSES (β = ‐0.477, 95% CI:‐0.875,‐0.078,p = 0.019), and this effect modification was similar in all race and ethnicity groups.

Conclusion

Evidence from a multiethnic intergenerational study suggests that early life socioeconomic conditions promote cognitive reserve against AD neuropathology. The buffering effect of parental SES was present in all groups, but because racial and ethnic minoritized groups have disproportionate exposure to low SES in childhood, interventions that reduce childhood poverty could narrow ADRD disparities.