bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional correlation analysis between neuronal metabolism and synaptic density using [18F]FDG and [11C]UCB‐J
Authors: DiFilippo Alexandra H , McLachlan Max , Jonaitis Erin M. , Ennis Gilda E. , McVea Andrew K , Bettcher Brecca , Pasquesi Mary‐Elizabeth , Thor Yer , Davenport Nancy J , Grover Ethan , Hudson Sarah , Barnhart Todd E , Betthauser Tobey J , Engle Jonathan W , Johnson Sterling C , Bendlin Barbara B , Christian Bradley T.
Published: December 2023

Background

Neuronal hypometabolism measured with [18F]FDG PET scans can be used to identify neurodegeneration as part of the AT(N) (amyloid, tau, neurodegeneration) framework in AD. PET imaging of synaptic vesicle glycoprotein SV2A using [11C]UCB‐J provides an index of synaptic density, which has been shown to decrease during neurodegeneration. The purpose of this study was to examine the regional relationship between neuronal metabolism and synaptic density in participants across the continuum of AD‐related pathology.

Method

Participants were recruited from the Wisconsin ADRC and the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study. A subset of 13 participants (Table 1) were selected who had completed cognitive testing, structural MR imaging, and PET imaging with the following: [11C]PiB centiloid (CL) for amyloid +/‐ status, [18F]MK‐6240 SUVR for tau +/‐ status, [11C]UCB‐J DVR for regional synaptic density burden, and [18F]FDG SUVR for regional glucose metabolism. UCB‐J and FDG analysis used a whole cerebellum reference region; PiB and MK‐6240 analysis used cerebellar GM reference regions. Inter‐tracer (UCB‐J/FDG) correlations were performed in Freesurfer‐defined bilateral Braak‐associated ROIs (Medial Temporal Lobe [MTL]: entorhinal cortex, hippocampus, and amygdala; Ventral Temporal Lobe [VTL]: fusiform, lingual, and inferior temporal gyri), signature regions of hypometabolism in AD (posterior cingulate, parietal, and frontal cortices) and a region with only marginal hypometabolism in AD (occipital cortex). Associations were determined using Pearson correlations (r).

Result

All ROIs demonstrate a positive association between FDG SUVR and UCB‐J DVR, with r > 0.7 and p < 0.01 (Figure 1). The occipital, frontal, and posterior cingulate cortices demonstrate the strongest correlations (r = 0.84, 0.83, and 0.81, respectively).

Conclusion

In cognitively impaired and unimpaired participants showing varying degrees of β‐amyloid and neurofibrillary tau burden, strong positive correlations are observed in regions associated with AD tau pathology and hypometabolism. Correlations are also observed in regions not typically associated with hypometabolism. This suggests that a relationship may exist between synaptic density and neuronal metabolism in the presence of AD neuropathology.
APOE genotype modifies microglial immunometabolism
Authors: Devanney Nicholas A , Lee Sangderk , Williams Holden C. , Allenger Elizabeth J. , Smith Cathryn T , Segovia Gabriella Morillo , Walsh Adeline E. , Friday Cassi , Golden Lesley R , Morganti Josh M. , Johnson Lance A
Published: December 2023

Background

Metabolic dysfunction and neuroinflammation characterize Alzheimer’s disease (AD), but it is unclear if these two facets of the disease are linked. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset AD and is associated with increased neuroinflammation. Recent data from our lab and others show that E4 is also associated with increased aerobic glycolysis. These two findings may be intrinsically linked through the concept of ‘immunometabolism’ ‐ an emerging paradigm that implicates increased glycolysis as a core requirement during pro‐inflammatory activation, whereas increased oxidative phosphorylation is required for anti‐inflammatory responses.

Method

Primary microglia from mice expressing human APOE isoforms were stimulated with a combination of interferon‐γ and tumor necrosis factor‐α, two pro‐inflammatory cytokines implicated in AD. Metabolic responses were measured using the Agilent Seahorse platform and targeted metabolomics. In addition, we performed single‐cell RNA sequencing on brains from APOE targeted replacement mice at 3‐, 10‐, and 18 months of age. APOE targeted replacement mice were also crossed to the 5x Familial Alzheimer’s Disease model and brains were analyzed by spatial transcriptomics.

Result

Seahorse revealed increased glycolysis and decreased mitochondrial respiration in E4 microglia. Targeted metabolomics revealed increased lactate and succinate in E4 microglia, metabolites known to accumulate in pro‐inflammatory macrophages. Aged E4 brains were found to harbor a metabolically distinct cluster of microglia that expressed a signature similar to the established ‘disease associated microglia’ (DAM) phenotype, even in the absence of neuropathology. SCENIC regulon analysis linked this cluster to the transcription network of HIF1a. Ongoing experiments targeting the HIF1a pathway seek to correct the E4‐associated increased aerobic glycolysis and excess pro‐inflammatory cytokine secretion.

Conclusion

Our findings reveal that inflammatory stimulation, age, and amyloid each induce a distinct metabolic response in E4 microglia. The accumulation of lactate and succinate and increased glycolysis in E4 microglia indicate altered metabolic preference conducive to pro‐inflammatory activation, whereas the decreased mitochondrial respiration may preclude effective anti‐inflammatory responses. We propose that this altered metabolism skews E4 microglia towards a phenotype that favors chronic neuroinflammation and neurodegeneration. Thus, reprogramming metabolism in E4 microglia may provide a novel therapeutic avenue for the treatment of AD.
Out‐of‐the box automated computation of cortical thickness of the medial perirhinal cortex does not replace segmentation by hand
Authors: Henzen Nicolas A. , Abdulkadir Ahmed , Reinhardt Julia , Blatow Maria , Kressig Reto W. , Krumm Sabine
Published: December 2023

Background

Cortical thickness of the medial perirhinal cortex (mPRC) is a promising marker of early, potentially pre‐clinical Alzheimer’s disease (AD) because atrophy of this region is causally linked to intracellular neurofibrillary tangles. Neurofibrillary pathology, a major neuropathological characteristic of AD, typically starts in the mPRC, also referred to as the transentorhinal cortex. From there it spreads to the entorhinal cortex and eventually to the hippocampus. To date, no tools exist that automatically compute the cortical thickness of the mPRC, most likely because of the novelty and complexity of the manual segmentation protocol and the large variability of the morphology of the mPRC. Herein, we aimed to develop an automated segmentation algorithm for the mPRC.

Method

An experienced rater (SK) manually segmented the mPRC from two data sets (train: n = 103; test: n = 44) using the FreeSurfer segmentation tools. The train data set (mean age = 76.4 ± 7.0 years; normal controls and patients with AD) was used to train the native FreeSurfer segmentation algorithm with the custom region as well as a voxel‐based deep convolutional neural network based on nnUNet with minimal adaptations to the training protocol. In a next step, the trained models were applied to the test data set (mean age = 69.2 ± 10.4 years; normal controls, AD, major depression, and mild cognitive impairment or dementia due to other etiologies than AD) and cortical thickness values were extracted. Finally, cortical thickness values of both segmentations were compared individually to the manual segmentation.

Results

Intraclass correlation coefficients (ICCs) between FreeSurfer and the manual segmentation reached .768 for the left hemisphere (lh) and .835 for the right hemisphere (rh). The deep learning method compared to the manual segmentation achieved ICCs of .840 for lh and .896 for rh.

Conclusion

The deep learning based procedure outperformed the native FreeSurfer segmentation in this complicated segmentation task. Nevertheless, it did not reach inter‐human reliability (SK vs. unexperienced rater (NAH): lh = .953 and rh = .986). Next steps are customization of the deep learning algorithm and validation of clinical usefulness.
Immune regulatory roles for Kv1.3 channels in Microglia in Alzheimer’s Disease
Authors: Bowen Christine A , Lin Young Qingyang , Zeng Hollis , Nguyen Hai Minh , Xiao Hailian , Kumar Prateek , Duong Duc M. , Espinosa‐Garcia Claudia , Wulff Heike , Seyfried Nicholas T , Rangaraju Srikant
Published: December 2023

Background

In Alzheimer’s Disease (AD), a sub‐population of disease associated microglia present increased Kv1.3 channel abundance. Pharmacological blockade of Kv1.3 reduces Aβ pathology and dampens pro‐inflammatory function of microglia. To identify Kv1.3‐regulated neuroinflammatory mechanisms in microglia, we examined the interactome of Kv1.3 channels in vitro, and Kv1.3 deletion and inhibition in vivo.

Methods

TurboID, a proximity‐dependent biotin ligase, was fused to the N‐term or C‐term of Kv1.3 and transduced in BV2 microglia. Kv1.3 and TurboID presence and activity were confirmed via qPCR, electrophysiology, flow cytometry, and western blot. Mass spectrometry(MS) of biotinylated proteins, under resting and lipopolysaccharide(LPS)‐treated conditions, identified Kv1.3 interactomes. Kcna3(Kv1.3)‐floxed mice were generated and crossed to CMV‐Cre mice for global Kv1.3 deletion. Three and six month old 5xFAD mice were treated with PAP1, a small molecule intracellular blockade of Kv1.3, for three months. At nine months of age behavioral tests were performed. Aβ pathology was evaluated using ELISA and Immunofluorescence. Brain nuclei were isolated for snRNAseq. CSF, plasma, and brain were processed for MS.

Results

Proteomics of BV2‐Kv1.3‐TurboID microglia identified distinct N‐term (n = 991) and C‐term Kv1.3 (n = 849) interactors. Kv1.3 N‐term interacts with plasma membrane proteins (e.g. Cars1, Psma2) and mitochondrial trafficking proteins (Timm23). C‐term interactors were modified by LPS‐stimulation (C3, STAT1, Oasl1) (n = 36), and partly dependent on a PDZ‐binding motif (Snx3, ND3, n = 70). Predicted by MS, western blot confirmed mitochondrial Kv1.3 presence. In vivo global Kv1.3 deletion was verified by qPCR. 9month 5xFAD mice with the Kv1.3 blockade show a reduction in Aβ pathology and a rescue of fear conditioning. Brain cell type‐specific and tissue‐level effects of Kv1.3 blockade will be evaluated by snRNAseq and MS.

Conclusions

We identified N and C‐term domain‐specific and context‐dependent interactors of Kv1.3 channels in microglia, including several pro‐inflammatory C‐term interactors. We developed and validated a novel Kv1.3‐floxed line for global, and conditional, Kv1.3 deletion studies in mouse models of AD pathology. Kv1.3 blockers reduce Aβ pathology and correct behavioral deficits in 5xFAD mice. The transcriptomic and proteomic studies of brain and biofluids from this cohort will provide mechanistic insights and identify novel biomarkers of therapeutic efficacy of Kv1.3 blockers.
Relationships between AD‐related neuroanatomy and cognitive, physical, and social aging in vervet monkeys
Authors: Frye Brett M. , Negrey Jacob D. , Craft Suzanne , Register Thomas C. , Baxter Mark G. , Jorgensen Matthew J. , Kim Jeongchul , Barcus Richard A. , Whitlow Christopher T. , Shively Carol A.
Published: December 2023

Background

In humans, social integration wanes with age, a pattern hypothesized to stem from cognitive or physical decrements. Social isolation increases dementia risk. Nonhuman primates provide important translational opportunities to study brain‐body relationships that may promote healthy or pathological aging. Vervet monkeys (Chlorocebus sabaeus), like humans, have complex central nervous systems and naturally experience cognitive, functional, and neuroanatomical changes with age. These changes often recapitulate characteristics of early Alzheimer’s disease (AD), including Aβ accumulation in the brain, reduced CSF Aβ, and greater Aβ plaque burdens accompanied by reduced brain volumes.

Method

We studied 25 females, aged 8‐29 years (middle to very old‐aged), living in long term, stable, social groups. Using a cross‐sectional study design, we tested whether cognitive (executive function and working memory) or physical (gait speed) function mediated the effects of age on social behavior. We also used T1‐weighted structural MRI to test whether the cortical thickness of an AD‐signature region of interest (“meta‐ROI”) predicted social participation at one year follow‐up.

Result

Cognitive (executive function: b = ‐0.603; p = 0.038; working memory: b = ‐0.537; p<0.001) and physical (gait speed: (b = ‐1.005; p = 0.043) function were negatively associated with age. Time spent in affiliative behavior was inversely related to age (b = ‐0.723; p = 0.009), whereas time spent alone was higher for older‐aged monkeys (b = 0.723; p = 0.009). Time spent grooming others decreased with age (b = ‐0.217; p<0.001), but time receiving grooming did not (b = ‐0.057; p = 0.333). The number of social partners groomed diminished in aged subjects (b = ‐0.145; p<0.001). The relationships between age and sociality were mediated, in part, by cognitive function: higher degrees of executive function had a positive mediating effect on time spent in grooming interactions (b = 0.120; p = 0.047). Conversely, social participation was not mediated by physical performance. Finally, thinner cortices in the meta‐ROI predicted greater social isolation (t = ‐2.199; p = 0.038) and fewer numbers of social partners (z = ‐2.319; p = 0.020) at one year follow‐up.

Conclusion

These results suggest that: 1) cognitive, physical, and social function of vervets decline with age like humans; 2) aging vervets are not socially excluded but decreasingly engage in social behavior; and 3) cognitive deficits stemming from cortical gray matter deficits may underlie the relationship between aging and social decline.
Sleep Disturbances predict cognitive decline in cognitively healthy adults
Authors: Mattos Meghan K , Zawar Ifrah , Manning Carol A , Quigg Mark S
Published: December 2023

Background

Sleep disturbances, including insomnia, poor sleep quality, and sleep fragmentation, are implicated in the development and progression of Alzheimer’s disease and related dementias in older adults. However, the effect of sleep disturbances on lifespan in those with cognitive impairment has not been studied independently from other neuropsychiatric symptoms such as disinhibition. The purpose of this study was to determine if sleep disturbances predict increased risk of earlier mortality across cognitive status (e.g., normal, mild cognitive impairment [MCI] and dementia) and risk of mortality independent from other neuropsychiatric symptoms known to predict dementia.

Method

The National Alzheimer’s Coordinating Center database was used to evaluate the mortality risk conferred by nighttime behaviors as determined by the neuropsychiatric inventory questionnaire (NPI‐Q). The effect of nighttime behaviors was used as a surrogate for sleep disturbances at the participant’s baseline assessment. Based on previous work, cognitive status was stratified by normal cognitive, MCI, and dementia using Montreal Cognitive Assessment scores. Covariates of age, sex, education, race, and other NPI‐Q items on mortality risk were analyzed using Cox regression.

Result

The sample was comprised of 31,288 participants, of whom 10,329 (33%) died during follow‐up and lasted a median [interquartile range] of 56.5 [30.2 – 88.8] months for deaths and 39.5 [23.1 – 75.1] months for survivors. One‐fifth of patients (n = 6509) experienced nighttime behaviors (e.g., nighttime awakenings). Worse cognitive status, older age, female sex, lower education, and increased neuropsychiatric burden increased mortality risk (ps≤.02). However, when explored independently, nighttime behaviors were found to predict earlier mortality (hazard ratio [HR]: 1.11 95% CI: [1.06,1.16], p<.001).

Conclusion

Findings expand on current evidence that the cross‐sectional prevalence of sleep disturbances increases with worsening cognition. Sleep disturbances predicted a higher risk of mortality while controlling for other variables. Potential mechanisms by which sleep disturbances may play a role in cognitive impairment or earlier mortality should be explored, including circadian rhythm disturbances and alteration in homeostatic and motivational processes.
In vitro antioxidant and anticholinesterase activity of Aegle marmelos fruit: implications for Alzheimer’s disease treatment
Authors: Sood Parul , Shri Richa , Kaur Gagandeep
Published: December 2023

Background

Increased antioxidant and anticholinesterase activity are key pathological hallmarks of Alzheimer’s disease (AD). In various Ayurvedic formulations Aegle marmelos (AM) belonging to family Rutaceae have traditionally been used as a brain tonic. However, there was no scientific validate proof of it. Hence, the present study was aimed to identify bioactive extract/fraction/constituent of AM fruit having potential to treat AD.

Method

Four different crude extracts of AM fruits by using different solvents on basis of increasing polarity‐such as petroleum ether, chloroform, methanol and distilled water‐by successive Soxhlet extraction were prepared and evaluated for in‐vitro antioxidant and anticholinesterase inhibition assay by using DPPH and Ellman’s assay respectively. Most bioactive extract was further subjected to fractionation by using solvent‐solvent partioning followed by flash chromatography for further sub fractionation of most bioactive fraction. Total phenolic (TPC) and flavonoid content (TFC) was also calculated

Result

Comparative evaluation of all four prepared extracts for in‐vitro antioxidant and anticholinesterase inhibition assays showed that the methanol extract (ME) was most bioactive. Furthermore, bioactivity‐guided fractionation of this bioactive ME revealed that Dichloromethane (DCM) fraction evinced highest antioxidant and anticholinesterase activity with IC50 value 74.56±1.43 µg/ml and 47.65±2.76 µg/ml due to presence of higher phenolic and flavonoid content. However, further sub‐fractionation of DCM fraction showed significantly higher IC50 values thus decreased activity.

Conclusion

This preliminary study clearly suggested that the DCM fraction from the ME of A. marmelos may prove to be potential candidate for the treatment of AD may be due to synergistic effect of phenolic and flavonoid content present in it. However, to validate the neuroprotective effect of DCM fraction of AM fruit against AD further exploration at cellular and molecular level is required to underlying its pharmacological mechanism as well as identification of the active phytoconstituents responsible for anti‐Alzheimer’s effect.
A comparative study of medication profiles from AD, MCI, and non‐demented patients
Authors: Sharoar Md Golam , Koganti Bhavya , Falki Vaibhavkumar , Zaman Zakia , Osentoski Tammy , Graham Stewart F
Published: December 2023

Background

The ever‐increasing incidence of Alzheimer’s disease (AD) and the lack of effective therapeutics to treat the disease are leading to a “silver tsunami”. Current FDA‐approved drugs to treat the disease are limited as their benefit is simply momentary relief of the symptoms. Due to the chronic and progressive nature of AD, patients are routinely prescribed multiple non‐AD medications to preserve their ability to perform daily activities and to improve their quality of life. However, how those medications affect AD pathology remains unknown. In the present study, we have compared medication profiles of AD (n = 135), mild cognitive declined (MCI; n = 120), and non‐demented (n = 259) patients, with an aim to determine the effects of top‐ranked drugs on AD pathology.

Methods

Study subjects (≥65 years) were recruited from an academic geriatric practice that is heavily focused on memory disorders. All subjects underwent for the following cognitive assessments: a) Clinical dementia rating scale (CDR), b) Mini‐Mental Status Examination (MMSE), c) logical memory test, d) digit span forward and backward, e) category fluency test, f) ordering test, g) trails A&B, and finally the Geriatric Depression Scale. Individual medication for each subject was listed and they were categorized into major drug classes. Statistical analysis was performed to determine the frequency of each drug in each class.

Results

Eight top‐ranked drug classes were categorized from a list of 453 individual medications. Vitamins (30‐40%) and anti‐inflammatory (∼30%) drugs were the major categories for each cohort. Interestingly, 11% of drugs were proton pump inhibitors in non‐demented patients, and this decreased by 8% in MCI, and 5% in AD. We found a reduced (8%) Lipitor prescriptions for AD patients compared MCI (11%) and non‐demented (13%) patients. We are investigating the effects of these highly prescribed drugs on β‐amyloid production/aggregation, cytotoxicity, plaque load, and tau phosphorylation in vitro and in vivo using cell culture and AD mouse models.

Conclusion

While the effects of routinely prescribed drugs on AD pathology are not well known, we found reduced vitamins, proton pump inhibitors, and Lipitor in the medication profiles of AD patients compared to the non‐AD population.
Developing a residual cognitive reserve index in a paediatric cohort with ADHD
Authors: Irani Zubin , Sheridan Andrew , Anderson Vicki , Silk Timothy J , Weinborn Michael , Gavett Brandon E
Published: December 2023

Background

Cognitive reserve (CR) is thought to be protective against late‐life cognitive decline induced by neurodegenerative disease and other forms of neurological insult. Although CR is thought to be influenced by early life experiences, information about its development during childhood and adolescence is lacking. The current study operationalised CR with a residual index approach (Reed et al., 2010) optimised for a diverse paediatric cohort. Criterion and construct validity of the index was also assessed.

Method

Data collected across 2011‐2019 from N = 115 children (MAge= 10.48, SDAge= 0.61, n = 72 [63%] male, n = 43 [37%] with ADHD) were acquired from the Murdoch Children’s Research Institute. Elastic‐net regularised linear regression was used to generate baseline and longitudinal CR indices that represented residual variance in (change in) fluid intellect (Matrix Reasoning) not explained by demographics (i.e., sex and age) or MRI‐based brain variables (i.e., cortical surface areas and cerebellar/subcortical volumes); brain regions were selected with the aim of partialling maximal variance out of the CR residual index. Outcome variables, including word reading, math computation, and Conners 3 ADHD Index were then regressed onto baseline and longitudinal CR indices.

Results

Baseline CR predicted baseline math computation (p<.001), while change in CR predicted change in word reading ability (p<.001). Further, in individuals with low grey matter volume, higher CR was associated with higher word reading score (p = .019) and lower ADHD Index (p = .047) compared to those with lower CR, at baseline. Higher change in CR also protected word reading trajectory in individuals with higher change in WMH volumes (p = .048).

Conclusion

These results suggest that individual differences in CR, as operationalised through a residual index, may be detectable in school‐age children. While findings regarding criterion and construct validity of the CR index are stronger than previous research featuring an unoptimised residual model (Irani, 2022), support for the validity of the index remains incomplete compared to established geriatric models – possibly due in part to a relatively less predictable relationship between brain structure and cognition in children versus adults. Future research would benefit from longer‐term follow‐up in paediatric samples with greater variability in neuropathological indices, cognitive functioning, academic achievement, and functional outcomes.
The influence of genetic predisposition to Alzheimer’s disease in cognitive decline differs among sex in cognitively unimpaired individuals in the Alzheimer’s continuum
Authors: Brugulat‐Serrat Anna , Genius Patricia , Rodríguez‐Fernández Blanca , Sánchez‐Benavides Gonzalo , López‐Martos David , Grau‐Rivera Oriol , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia ,   for the ALFA study
Published: December 2023

Background

Evidence shows sex differences in cognitive performance in Alzheimer’s disease (AD). However, studies exploring whether genetic predisposition to AD differs in cognition among sex are scarce. We aimed to evaluate whether the influence of AD genetic liability in cognition differs among sex in cognitively unimpaired (CU) individuals in the AD continuum.

Method

We included 318 CU individuals from the ALFA+ cohort (Table 1). Cognitive change (∼3‐year follow‐up) was measured with a PACC and for individual cognitive domains. Polygenic scores estimating each participant’s genetic predisposition to AD were calculated with (PRS‐AD) and without (PRS‐ADnoAPOE) considering the APOE region (threshold = 5×10‐6). Amyloid positivity (Aβ+) was defined as cerebrospinal fluid (CSF) Aβ42/40<0.0071. Generalized linear models stratified by sex and amyloid status were performed to assess the association between cognitive change and genetic predisposition to AD. Models were corrected by age, years of education, and time between visits. Models were additionally corrected by baseline Jack’s cortical thickness AD signature as a marker of neurodegeneration.

Result

In Aβ+ women (n = 65), a higher genetic predisposition to AD was associated with steeper memory (p
PRS_AD = 0.04; pPRS_ADnoAPOE = 0.01) and executive function (p
PRS_ADnoAPOE = 0.001) decline after correcting by brain AD signature. In Aβ+ men (n = 44), a higher genetic predisposition to AD was associated with worse follow‐up performance on attention (p
PRS_AD = 0.05, pPRS_ADnoAPOE = 0.04), and results did not remain significant after correcting by brain AD signature (Figure 1). In Aβ‐, genetic predisposition to AD was also associated with executive function decline in women (n = 122) (p
PRS_AD = 0.16, p
PRS_ADnoAPOE = 0.02), while Aβ‐ men (n = 87) showed worse follow‐up performance on visual processing (p
PRS_AD = 0.251, pPRS_ADnoAPOE = 0.001). Results remained significant after correcting by brain AD signature (Figure 2).

Conclusion

Our results showed that genetic predisposition to AD is associated with changes in different cognitive domains in men and women. These findings will contribute to developing precision medicine approaches in AD encompassing sex‐sensitive strategies for prevention.
Investigating the social and environmental contexts of habitual walking ACTIVities in older adult DYADs: A mixed methods protocol for the ActivDyad study
Authors: Ardle Ríona Mc , Ryan Leigh James , McCarthy Louis , Wilson Cameron , Hamilton Calum Alexander , Tangen Gro Gujord , Farina Nicolas , Ireson Neil , Lanfranchi Vita , Hicks Ben , Bayat Sayeh
Published: December 2023

Background

Mobility‐related ambulatory activity (e.g., walking) is essential to healthy cognitive and functional ageing. Wearable technology (e.g., accelerometers/inertial measurement units; IMUs) allows us to objectively and continuously capture digital mobility outcomes (DMOs), e.g. volume, pattern and variability of walking activities. Continuous digital mobility assessment has been shown as feasible and acceptable to older adults with and without dementia. However, interpretation of DMOs is limited as we do not yet understand the impact of different social and environmental contexts on walking activity. For example, DMOs may be influenced by the volume of walking that one’s partner participates in, or by the walkability of their local area. Understanding the impact of social and environmental contexts on DMOs will support development of socio‐ecological strategies to support mobility in ageing. We aim to conduct a feasibility study in older adults with the following objectives: (1). Objectively assess DMOs in older adult dyads using digital mobility tools (i.e., IMUs/GPS); (2). Identify key social and environmental influences on DMOs through mixed‐methods exploration; (3). Develop a novel analytical approach combining DMOs with GPS data to assess independence/interdependence in dyads’ walking activities.

Method

We will recruit 20 older adult dyads in North‐East England for an observational cross‐sectional study. Walking activities will be recorded continuously for seven days using an IMU attached to participants’ lower backs. DMOs include volume (e.g., daily steps), pattern (e.g. mean bout length) and variability (of bout length) of walking activities. Simultaneously, participants will carry a GPS device (i.e., smartphone) to monitor excursions outside the home. Questionnaires will capture information on cognition, function, falls risk, exercise motivation, wellbeing, relationship mutuality, spatial navigation, and walkability of local area. Participants will complete a “mobility diary” for the assessment period (e.g., daily journeys, motivations/perceptions/familiarity of journeys).

Result

Preliminary results will be presented regarding associations between social/environmental contexts with DMOs via flexible Bayesian statistical models and thematic qualitative analysis.

Conclusion

This study will assess the feasibility of the protocol and analysis strategies, with intentions of developing further research to examine the impact of social and environmental influences on DMOs in people with dementia and their carers.
Performance of the CANTAB ‐ Paired Associates Learning task in an unsupervised online setting: Results from the Brain Health Registry
Authors: Ashford Miriam T. , Aaronson Anna , Kwang Winnie , Eichenbaum Joseph , Gummadi Shilpa L , Jin Chengshi , Cashdollar Nathan , Thorp Emily , Wragg Elizabeth , Zavitz Kenton , Cormack Francesca K , Banh Timothy , Neuhaus John , Ulbricht Aaron , Camacho Monica R , Fockler Juliet , Flenniken Derek , Truran‐Sacrey Diana , Mackin Scott R , Weiner Michael S. W. , Nosheny Rachel L
Published: December 2023

Background

The aim of this study was to evaluate the feasibility and usability of collecting data from an unsupervised online version of the Paired Associates Learning (PAL) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB™) in adults enrolled in the Brain Health Registry (BHR).

Method

BHR is an online cognitive aging registry for referral and longitudinal unsupervised assessment. The PAL assesses visual associative learning and memory and was administered in BHR between 03/2021‐07/2022. PAL variables included in this analysis were ‘Memory Score’ (patterns correctly identified at first attempt for each difficulty level) and ‘Total Errors’, adjusted for level reached. We analyzed PAL task completion rate and characteristics of PAL completers and used linear regressions to assess whether cross‐sectional PAL Memory Score and PAL Total Errors were associated with participant data (age, gender, education, self‐ and study partner‐reported cognitive complaints (Everyday Cognition scale (ECog)), self‐reported memory concern, and self‐reported depressive symptom severity (PHQ‐9), self‐report of Mild Cognitive Impairment (MCI)).

Result

As of July 2022, 14,520 participants aged 18+ years have completed PAL at least once. Participants were on average 66.3 years old (SD = 11.3), 72.4% female gender, 92.8% self‐identified as White, and had a mean of 16.6 years of education (SD = 2.27). BHR received 374 requests for study support regarding PAL, of which 36% (135) were related to device compatibility. Mean PAL scores were similar to those of previous, supervised studies (Figure 1). Worse PAL performance was significantly associated with being older, female gender, having less education, more self‐ and study partner‐reported ECog, self‐reported memory concern, more depressive symptoms, and self‐report of MCI (Table 1).

Conclusion

Our findings provide evidence for the feasibility of collecting PAL data in an unsupervised online setting and construct validity of cross‐sectional BHR PAL. In terms of usability, there was a minimal need for support. Future studies will investigate the predictive value of BHR PAL in identifying adults with self‐reported MCI, longitudinal BHR PAL performance and associations with in‐clinic assessments and Alzheimer’s disease biomarkers. Our sample lacked diversity. Therefore, a future direction is to increase accessibility of PAL to ethnoculturally and socioeconomically diverse communities.
Differences in Dementia Caregiver Distress Based on Caregiver Gender and Care Recipient Neuropsychiatric Symptoms
Authors: Bell Sophie A. , Gallagher Virginia , Reilly Shannon , Manning Carol A
Published: December 2023

Background

Our healthcare system relies on unpaid family caregivers (e.g., spouses) for care of individuals with Alzheimer’s disease and related dementias (ADRD). Several caregiver and care recipient characteristics are known to be associated with caregiver burden and psychological outcomes in dementia caregivers. Research suggests that caregiver emotional distress is higher among women versus men, and that it increases with elevated care recipient neuropsychiatric symptoms (NPS). However, it is unclear whether gender differences in caregiver distress are independent of care recipient characteristics.

Method

Caregivers completed the Neuropsychiatric Inventory‐ Questionnaire (NPI‐Q). Presence of NPS in care recipients was summed across 12 NPI‐Q domains. Using one‐way analyses of covariance (ANCOVAs), we assessed how caregiver gender (woman/man) and care recipient NPS are associated with caregiver burden (Zarit Burden Interview), anxiety (Geriatric Anxiety Index), quality of life (WHO‐5 Well‐Being Index), preparedness for caregiving (Preparedness for Caregiving Scale), and self‐efficacy (General Self‐Efficacy Scale) in a sample of 112 unpaid family caregivers. Covariates included caregiver age and co‐living status. Bonferroni corrections were used to adjust for multiple comparisons. The sample was comprised of 73.2% women with a mean age of 64.6 ± 12.2 years. Caregivers were primarily spouses (68.5%) and daughters (20.7%) of care recipients.

Result

Relative to men caregivers, women caregivers reported higher levels of burden (F(1,103) = 24.4, p<.005) and anxiety (F(1,103) = 8.60, p<.005) and lower quality of life (F(1,103) = 9.85, p <.005). Caregivers who rated their care recipients as having more NPS also reported greater burden (F(1,103) = 27.2, p<.005), higher anxiety (F(1,103) = 26.0, p<.005), and lower quality of life (F(1,103) = 34.9, p <.005). There were no significant interactions between gender and NPS. Gender and presence of NPS were not associated with caregivers’ preparedness for caregiving or general self‐efficacy.

Conclusion

While women and men caregivers in this sample reported similar levels of preparedness and self‐efficacy, women endorsed greater levels of emotional distress in the form of caregiver burden, anxiety, and decreased quality of life. Across caregiver gender, age, and co‐living status, NPS in care recipients predicted poor psychosocial outcomes in our sample. Our data suggest the need for interventions to support women caregivers, and mitigate the burden associated with neuropsychiatric disturbances.
DNA methylation alterations in Lewy Body Dementia
Authors: Chouliaras Leonidas , Thomas Alan J , Clark Graeme , Donaghy Paul C , Swann Peter , Malpetti Maura , Mak Elijah , Savulich George , Prats‐Sedano Maria A , Low Audrey , Su Li , Rowe James B. , O'Brien John T
Published: December 2023

Background

The epigenetic mechanism of DNA methylation has been implicated in the pathophysiology of neurodegenerative disorders such as Lewy body dementia (LBD). DNA methylation profiling may help to identify novel treatment targets and early disease markers. We hypothesized that DNA methylation alterations are detectable in blood due the influence of genetic and environmental factors as well as immune system changes associated with LBD.

Method

Genome‐wide DNA methylation profiling was carried out using reduced representation bisulfite sequencing in blood samples from 89 LBD patients and 67 controls. Fifty five LBD patients had amyloid PET imaging. Data processing was performed using FastQC, TrimGalore, Bismark and MethylKit. DNA methylation alterations at specific CpG sites as well as at promoter, CpG island and CpG shore regions were compared between LBD cases and controls. A log odds logistic regression was used to identify differential DNA methylation after adjusting for age, sex and smoking status. The false discovery rate (FDR) was used for correction for multiple testing. We also tested the diagnostic classification performance of the differentially methylated regions using receiver operating characteristic (ROC) curve analysis and examined the potential of DNA methylation as a predictor of amyloid PET positivity in LBD.

Result

Two single CpG sites at TNFRSF1B and EMC6 and three CpG shore regions at ABCG5, ETAA1 and TENM4 reached genome‐wide significance in the differential DNA methylation analysis comparing LBD cases and controls. The combined panel of the top three differentially methylated CpG shores reached an area under the curve (AUC) of 0.91 for the diagnosis of LBD compared to controls (sensitivity 0.89, specificity 0.85). DNA methylation at TENM4 was associated with amyloid PET positivity in LBD with an AUC of 0.84 (sensitivity 0.99, specificity 0.55).

Conclusion

Our data suggest that DNA methylation alterations in blood are observed in a cohort of LBD patients compared to controls. Our findings need to be replicated in larger cohorts and tested for specificity in LBD in order to explore their future potential as diagnostic markers and/or targets for novel therapeutics.
Investigations of altered neutrophil apoptosis in Alzheimer’s disease
Authors: Aries Michelle , Cook Makayla , Hensley‐McBain Tiffany
Published: December 2023

Background

There is strong evidence that neutrophils are dysregulated in Alzheimer’s disease (AD) and exacerbate disease pathogenesis. Under homeostatic conditions, neutrophils are short‐lived, and the least inflammatory mechanism of neutrophil clearance from tissues is caspase‐3 mediated apoptosis followed by engulfment by macrophages. However, in pathological conditions, neutrophil apoptosis is delayed, resulting in cell death mechanisms that exacerbate inflammation, including necrosis, pyroptosis, and the release of neutrophil extracellular traps (NETosis). Here we address the hypothesis that neutrophil apoptosis is delayed in AD, contributing to increased NET release.

Method

We assessed neutrophil apoptosis, frequency, and activation in blood from 4‐5 month old mice with 5 familial mutations for AD (5xFAD; n = 8) compared with C57BL6/J (B6; n = 8) as controls. Active caspase‐3 was stained in neutrophils using a fluorescent probe and distinguished from secondary necrosis via a membrane impermeable viability stain. Activation was assessed as the percentage of neutrophils expressing low levels of CD62L. Neutrophils were assessed fresh and after 4 hours of rest in complete culture medium. In addition, we investigated the ability of the osmolyte ectoine to rescue neutrophil apoptosis by incubating blood with 1mM ectoine for 4 hours. Finally, plasma was assessed for neutrophil elastase (NE) via ELISA as a marker of NET release.

Result

In 5xFAD blood, we found significantly decreased neutrophil apoptosis and increased total neutrophils compared to B6 blood. Upon resting for 4 hours in complete culture media (R10), neutrophil apoptosis nearly normalized in 5xFAD mice compared to controls, suggesting a continual in vivo stimulus is required. We observed significantly increased NE in plasma of the 5xFAD mice compared with controls that correlated with neutrophil apoptosis. Using a level of ectoine previously demonstrated to promote neutrophil apoptosis, we observed increased neutrophil apoptosis and reduced neutrophil frequencies in blood from B6 mice but not 5xFAD mice after 4 hours.

Conclusion

These data provide evidence of dysregulated neutrophil apoptosis in AD that associates with increased NET release. These data also suggest that AD neutrophils may be resistant to some apoptosis promoting agents, prompting further research into the mechanisms involved in delayed neutrophil apoptosis in AD.
Influence of physiological glucose levels on SIM‐A9 microglial cell immune response
Authors: Bruno Lucrezia , Mackenzie Francesca Elizabeth , Stolinski Michael
Published: December 2023

Background

Microglia play an important role in the early onset of Alzheimer’s disease pathology1. They are responsible for maintaining brain homeostasis, where changes in energy metabolism alter microglial metabolic profile and function2. The majority of cell culture‐based studies have relied on growing microglia under optimal media conditions, not reflecting the brain’s physiological levels of key metabolites. This study aims to define a suitable experimental culture system that reflects the brain’s physiological glucose level, approximately 1mM3, so the effects of altered glucose concentration can be tested.

Method

SIM‐A9 mouse immortalised microglial cells were initially grown in DMEM/F‐12 medium (17.5mM glucose) containing 10% FBS and 0.1% Penicillin/Streptomycin (Gibco, UK). After 20 hours cells were re‐seeded in Neurobasal medium containing 1x B‐27 supplement (Gibco, UK) and either 1mM or 5mM glucose and grown for 20 hours. Cell proliferation and viability was assessed over 40 hours using an Incucyte imaging system (Essen BioScience, UK) and Trypan Blue assay. Media glucose concentration, cellular glucose uptake (Promega, UK), microglia activation and metabolic marker expression using qRT‐PCR were measured following stimulation of cells with Lipopolysaccharide (LPS) (2.5ng/ml)

Result

Maintaining SIM‐A9 cells in 1mM and 5mM glucose medium showed static proliferation but similar viability over 20 hours compared to growth in DMEM/F12. LPS treatment increased TNFa and IL1b expression in SIM‐A9 cells in all glucose conditions, indicating the cells’ competency to produce a pro‐inflammatory response. No change in pro‐inflammatory activation markers (TNFa, IL1b) was seen after maintenance in 1mM, but in 5mM glucose for 20 hours, compared to LPS treated cells. Media glucose concentration was 0.7mM over 20 hours in 1mM and 1mM in 5mM glucose media. Expression of glucose transporters Glut1 and Glut3 and glycolysis marker PFKFB3 under these glucose conditions was investigated.

Conclusion

Until now microglial metabolic studies have not always reflected the physiological concentrations of glucose in the brain. The results show that culturing microglia in 1mM glucose medium does not induce pro‐inflammatory activation, while maintaining minimal cell death and unvaried confluency.

References: Yoshiyama Y et al (2007) Neuron 53(3): 337‐351. 2. Bernier L et al(2020) Trends in Neurosci43(11):854‐869. 3. Van de Ven K et al (2012) Diabetes 61
Feasibility of real world end‐points of functional neurophysiology in Alzheimer’s disease dementia
Authors: Rueda‐Delgado Laura M , Buick Alison R , Hardiman Orla , Muhammed Kinan , Nolan Hugh , Rowe James B. , Waninger Shani , Murphy Brian
Published: December 2023

Background

Clinic‐based biomarkers are effective in tracking disease progression in clinical research, but do not scale to support public health needs or large‐scale real‐world studies. Purely digital markers are scalable but lack the objectivity and neurobiological grounding of clinical measures. These first results of a real‐world feasibility study demonstrate that objective measures of a range of domains including EEG (Figure 1) are user‐friendly and suitable for repeated at‐home use by patients and older controls.

Method

60 patients and 60 matched controls are being recruited for a 1‐year repeated sampling study in the UK. Patients were clinically assessed to have mild Alzheimer’s type dementia. Participants were asked to complete about 30 minutes of behavioral tasks including memory, executive function, affective processing and language, while synchronized EEG was recorded using a self‐applied dry‐sensor headset. This interim data is from an initial 2‐week burst sampling period, for the first half of the cohorts.

Result

Adherence was 76% for the dementia group (N = 29, mean age = 75; ADAS = Cog 24.3) and 88% for the control group (N = 36, mean age = 71; ADAS = Cog 7.8). A symbol substitution task (executive function) differentiated strongly between groups (t(53) = 6.9), and correlated highly with a conventional pen‐and‐paper DSST benchmark (rho = 0.79). An associative memory task also patterned strongly with disease status (t(54) = 5.7) and correlated with the Verbal Paired Associates benchmark (rho = 0.76). The grand average P300 ERP, elicited by a gamified 2‐stimulus oddball task, showed characteristic features of sensory and higher cognitive processing (Figure 2). As expected in the patient group, the P300 was reduced and delayed; and the resting‐state EEG theta and alpha power were enhanced and reduced, respectively. Radar plots (Figure 3), illustrate the pattern observed across domains in one representative Alzheimer’s patient and one control. Data from a fronto‐temporal dementia sister study is included for comparison.

Conclusion

Interim data from this first‐in‐class study suggest that patients with mild Alzheimer’s disease dementia are capable and willing to participate in intensive home‐based functional neurophysiology studies, if technology is designed to be engaging and easy to use. Initial examination of the data aligns with established benchmarks, constituting positive early evidence for construct validity and technical feasibility.
Physical function predicts declarative memory
Authors: Gray Michelle , Jones Megan , Campitelli Anthony , Gills Joshua L. , Paulson Sally , Glenn Jordan M.
Published: December 2023

Background

No cure currently exists for Alzheimer’s disease; however, early detection may help create therapies and treatments to slow cognitive decline. The concept of early detection is simple, but is complicated by the inability of primary care physicians to recognize symptoms until late disease manifestation and failure to provide appropriate screening tools for disease detection. Thus, the purpose of the present investigation was to determine predictors of cognitive performance among community‐dwelling older adults.

Method

63 community‐dwelling older adults (80.0 ± 5.5 years) participated in the present investigation. Declarative memory was used as the measure of cognition. Physical function was measured using the Short Physical Performance Battery (SPPB), dual‐task fast walking time, and sit‐to‐stand velocity. Linear regression analysis was used to predict cognition from physical function. Odds ratios were used to determine the magnitude of influence of physical function on cognitive function. ANOVA was used to determine differences in individual physical function variable between low and high cognitive groups.

Results

The linear regression model included dual‐task fast 10‐m walking time, sex, education, and SPPB score and accounted for 39% of the variance in cognitive ability (p<.001). The physical function variables accounted for 8.8% and 8.5% of unique variance in cognition, respectively. For participants performing below the 50th percentile for dual‐task fast walking time, there was a 3.6‐fold increase in declarative memory scores (CI: 1.44‐9.35). Similarly, SPPB values indicative of mobility dysfunction was associated with a 3.2‐times increase in cognitive impairment (CI: 1.31‐7.87). Results of the one‐way ANOVA revealed significant differences in SPPB (p = .002), peak sit‐to‐stand velocity (p = .007), and dual‐task fast walking time (p = .001). The high cognitive group had significantly better physical function compared to the lower cognitive group.

Conclusion

Results from the present investigation support the use of physical function in predicting current declarative memory among a sample of community‐dwelling adults with no diagnosed cognitive impairment. Future research is needed to determine the ability to predict changes in cognition longitudinally.