bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of Abca7 in late‐onset Alzheimer’s disease animal models
Authors: Oblak Adrian L , Kotredes Kevin P , Ingraham Cynthia , Territo Paul R , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T ,   MODEL‐AD
Published: December 2022

Background

Alzheimer's disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Genome‐wide association studies (GWAS) originally identified ATP‐binding cassette, sub‐family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human‐based studies has extended this association, promoting ABCA7 as one of the most important risk genes of late‐onset AD (LOAD), harboring both common and rare risk variants with relatively large effect on AD risk. Besides associations with disease status, genetic and epigenetic ABCA7 markers show significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human‐based ‐omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism.

Method

To investigate the impact of Abca7 gene expression on microglia biology and disease pathology, we have generated Abca7A1527G mice on an APOE4.Trem2R47H (LOAD1) and APOE4.Trem2R47H.hAß (LOAD2) background. Cohorts of mice were established at JAX and IU and aged to either 4 and 12 months (LOAD1) or 4‐, 12‐, 18‐, and 24‐month. In vivo behavior and wellness assays included continuous activity monitoring, frailty assessment, open field, grip strength, spontaneous alternation, rotarod, delayed spatial novelty, episodic memory, and general health were completed as well as MRI and PET studies. Post‐mortem studies included blood chemistry, immunohistochemistry, and molecular studies. Studies of transcriptomics and proteomics were also completed on brain tissue.

Result

Correlation of transcriptional profiling with human AMP‐AD modules determined individual and synergistic effects with genetic risk factors. At 12 months of age, LOAD1.Abca7A1527G mice show similar correlations to LOAD in Consensus Cluster B (immune system), Consensus Cluster D (cell cycle), and Consensus Cluster E (organelle biogenesis). Neuropathology analysis in brain tissue is in progress, as are cytokine panels in brain homogenates and plasma of LOAD2. Abca7A1527G mice.

Conclusion

Our findings provide evidence that Abca7 plays an important role in LOAD and the addition of Abca7A1527G to a sensitized LOAD model (LOAD1 and LOAD2) more closely align phenotypes in the mouse to outcomes observed in human AD.
Fingolimod (FTY720) offers neuroprotection against AlCl3 induced Experimental Dementia in Rats
Authors: Kumari Shilpa , Agrawal Mohit , Deshmukh Rahul Renukadas
Published: December 2022

Background

Alzheimer’s disease (AD) is an age related progressive neurodegenerative disorder mainly characterized by cognitive decline, synaptic loss, and other mental functions. Extracellular amyloid beta (Aβ) deposits and intracellular accumulation of neurofibrillary tangles of tau protein are the two major hallmarks of AD. Multiple etiological factors have been linked with AD pathophysiology, oxidative stress, neuroinflammation, neurotransmitter deficit and foremost are the dysregulation of lipid metabolism, consistently involve in AD pathology and cognitive deficit.

Method

In the present study, we have explored the neuroprotective potential of Fingolimod (FTY720), against Aluminium Chloride (AlCl3) induced experimental dementia in the rats. AlCl3 at the dose of 175mg/kg, p.o was given daily from 1st to 35th day. Spatial and non‐spatial memory was evaluated by using Morris Water Maze (MWM) and Object Recognition Test (ORT). We further performed biochemical tests to check the levels of different oxidative stress markers.

Result

Administered AlCl3 in rats produced cognitive deficit and caused significant elevation in markers of oxidative stress and showed degenerative changes in hippocampus and cortical brain region. On the contrary, fingolimod treatment attenuate AlCl3 induced cognitive decline, reduced oxidative burden and showed potential of restoring neuronal architecture and prevent neuronal loss in hippocampus and cortical brain region of the rats. The present study suggests that Fingolimod (FTY720) show beneficial effects in treating dementia.

Conclusion

Our data demonstrated that Fingolimod could prove to be a beneficial therapeutic target in the protection of neurotoxicity induced by Aluminium chloride and help in improving memory and other cognitive functions.
Early Discharge from home health therapy services for people with Alzheimer’s Disease and Related Dementias
Authors: Knox Sara , Downer Brian , Haas Allen , Ottenbacher Kenneth J
Published: December 2022

Background

People with Alzheimer’s Disease and Related Dementias (ADRD) experience barriers to accessing care that they need, including home health therapy services (physical, occupational, and speech therapy). Clinicians report difficulty engaging patients with ADRD in therapy sessions, especially during the later stages of the disease. There is limited information about how the existing barriers and challenges impact an individual with ADRD’s likelihood of being discharged from therapy services earlier than planned. The purpose of this study was to examine the relationship between early discharge from home health services and (a) dementia severity, (b) caregiver support, and (c) medication management.

Method

This retrospective study derived data from 100% national Medicare Home Health data files from October 1, 2016 through September 30, 2017. A cohort of 111,537 Medicare Fee‐for‐Service beneficiaries with ADRD was identified. A dementia severity categorization scale was used to classify individuals into one of six severity levels. Early discharge rates with associated 95% confidence intervals (CIs) were calculated for each patient characteristic. Multilevel logistic regression was used to estimate the relative risk (RR) of early discharge, by dementia severity level, caregiver support status, and level of medication assistance and adjusted for patient and clinical characteristics.

Result

The overall early discharge rate was 13.3% (13.1, 13.5). Individuals who were in the most severe ADRD stage were the only group that had an increased likelihood of being discharged early (1.163; 1.003‐1.344) amongst people with ADRD. However, individuals who required assistance with medication demonstrated a decreased likelihood of early discharge at all levels (0.828; 0.741‐0.924) There was no significant difference in likelihood for early discharge across caregiver support levels.

Conclusion

Despite a small increase in the most severe ADRD stage, the number of visits and the risk of early discharge was relatively consistent across severity stages. Further research is needed to assess whether the type and quality of services received varies across dementia stages. Individuals with ADRD who were independent with medication management had an increased likelihood of early discharge. Exploring this relationship in greater detail could inform clinician decisions about frequency and duration of care.
AUC Undermines AD Biomarker Discovery
Authors: Smith Kenneth , Climer Sharlee
Published: December 2022

Background

Efforts are underway to accelerate precision medicine for late‐onset Alzheimer disease (AD). The realization of this endeavor can only be attained by identifying AD subtypes and developing methods to diagnose and treat each subtype. Liquid biopsies offer great potential for mounting this challenge. Identification of promising biomarkers requires evaluation of its ability to diagnose AD, and the area under the receiver operating characteristic curve (AUC) is commonly used for this purpose. This metric is equally weighted on the true positive rate (TPR) and false positive rate (FPR). When a given biomarker represents a single subtype, we expect the TPR to be relatively low as only a subset of AD cases are associated. Consequently, we hypothesized that screening based on AUC may discard valuable subtype biomarkers.

Method

An in silico experiment was conducted in which an ‘ideal’ biomarker for a subtype was modeled and the corresponding AUC was computed. A pseudo biomarker was designed to perfectly identify 20% of the cases and all other individuals were assigned levels near zero. Biomarker levels were generated to create a normal distribution centered on 0, with a standard deviation of 0.01, to represent 1000 controls and 800 cases, and 200 additional cases were represented by a normal distribution centered on 1, with a standard deviation of 0.2, to represent the subtype cases (Figs. 1 and 2). The experiment was conducted 1000 times.

Result

The mean AUC across the 1000 trials was 0.6001, with a maximum of 0.6292 and minimum of 0.5624. The standard deviation for the AUC values was 0.0109. The AUC plot for one of the trials is shown in Fig. 3.

Conclusion

The pseudo biomarker perfectly identified 20% of the cases while having FPR = 0, yet it would likely be discarded due to the low AUC value, indicating that AUC is not a suitable metric for evaluating biomarkers for AD subtypes. Alternative evaluation metrics should be considered while traversing the path towards successful precision medicine for AD.
Targeted bisulfite sequencing analysis of candidate genes associated with Alzheimer’s disease.
Authors: Wheildon Greg , Smith Adam R. , Soanes Darren , Smith Rebecca G. , Moore Karen , O'Neill Paul , Morgan Kevin , Thomas Alan J , Francis Paul T , Love Seth , Mill Jonathan , Pishva Ehsan , Lunnon Katie
Published: December 2022

Background

Recent epigenome‐wide association studies (EWAS) have identified a number of loci in specific genes that show robust and reproducible alterations in DNA methylation in Alzheimer’s disease brain samples. The standard method to assess methylation in EWAS is via microarrays, however, these only target a limited number of methylation sites in each gene. Therefore, further analysis of methylation changes across the entire gene are required to determine the exact extent and pattern of methylation changes in disease. In this study we have performed targeted bisulfite sequencing for candidate genes in the Brains for Dementia Research (BDR) tissue sample resource, which is a highly characterized cohort containing tissue with a high degree of standardized pathological, clinical and administrative data available to allow comparative studies.

Method

Prefrontal cortex brain samples from 60 individuals were selected from the BDR cohort and grouped by Braak stage (Control 0‐II; mild cognitive impairment III‐IV; AD V‐VI). The DNA was extracted, before 30 genomic regions of interest, identified from previous AD EWAS, were captured using Agilent Sure Select target baits. The DNA was next‐generation bisulfite sequenced, before the sequence reads were aligned and the methylation status of cytosine residues were called using the Bismark Bisulfite Mapper program. Differentially methylated positions (DMPs) were then analyzed across the three groups.

Result

The degree and extent of methylation within the targeted genomic regions were identified and quantified for each group before being analyzed using linear regression models.

Conclusion

This study builds on previous work that identified differential methylation in several genomic regions that were associated with Braak stage. By identifying the exact positions that are subjected to differential methylation this work provides further evidence that dysregulation of methylation is associated with pathological changes in AD prefrontal cortex.
Functional role of PLD1 signalosome in Tauopathies
Authors: Natarajan Chandramouli , Phan Phu Cuong , Thomson Bernadette , Krishnan Balaji
Published: December 2022

Background

Phospholipase D (PLD), a lipolytic enzyme for membrane phospholipids, exists in two isoforms of mammalian phosphatidyl choline (PC) specific PLD, inducible PC‐PLD1 and constitutive PC‐PLD2. Elevated PLD activity is well documented in clinical studies involving Alzheimer’s disease (AD). Our lab was the first to show elevated PLD1 facilitates synaptic dysfunction and underlying memory deficits driven by amyloidogenic insults by Aß/tau. We observed preservation of memory in response to PLD1 specific small molecule inhibitor in transgenic mouse models and documented preservation of dendritic spines as a underlying basis. In this study, we explored a role for PLD1 in Frontotemporal Dementia in an attempt to explore its pathological role in this tauopathy‐driven dementia.

Method

We studied altered expression/activity of key F‐actin signaling elements common to PLD1 signalosome in synaptosomal fractions of human post‐mortem FTD brain regions. Synaptic deficits associated with elevated PLD1 expression in human FTD samples was studied by Fluorescence Analysis of Single Synapse Long Term Potentiation (FASS‐LTP). Using immunofluorescence, we studied the association of PLD1 with tau, presynaptic and post‐synaptic receptors, and neuroinflammation markers.

Result

Elevated PLD1 expression in synaptosomal fractions of post‐mortem FTD brain tissues was corroborated by synaptic deficits and association of PLD1 with postsynaptic density protein (PSD95). FASS‐LTP assay indicated relatively lower long‐term potentiation in synaptosomal fractions of FTD brains as compared to the control brains implying synaptic deficits in FTD subjects.

Conclusion

In the light of these observations, we conclude elevated PLD1 expression is associated with toxicity of tau causing memory deficits in FTD patients. This PLD1‐tau interaction alters PLD signaling partners such as mTOR (mammalian target of rapamycin), cofilin and phosphocofilin. This would implicate the actin‐dependent remodeling of synapse to be a key step in the role of PLD1 signalosome in FTD. Delineating the effects of PLD1 signalosome in tauopathies such as FTD will hugely be beneficial in tau‐targeting therapeutics for a multipronged approach in the treatment of neurodegenerative disorders.
Lower novelty‐related locus coeruleus function is associated with entorhinal tau‐mediated memory decline in older individuals.
Authors: Prokopiou Prokopis C. , Engels Nina , Schneider Christoph , Schultz Aaron P. , Sepulcre Jorge , Riphagen Joost M. , Koops Elouise A. , Papp Kathryn V. , Fakhri Georges El , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L.
Published: December 2022

Background

The locus coeruleus (LC) is considered one of the earliest regions accumulating hyperphosphorylated tau before this pathology emerges in the entorhinal cortex (EC). Recent animal work suggested that LC phasic activity, which can be induced with exposure to novelty, can protect the cognitive downstream effects of tauopathy. Here we investigate whether activity of the LC during novelty is associated with memory decline and whether this association is mediated by EC‐tau deposition.

Method

92 participants (51 F, mean age at imaging (baseline) = 69.55±10.17 years) from the Harvard Aging Brain Study underwent both longitudinal memory testing (mean follow‐up = 4.8±1.9 years) and PiB(Aβ)‐, FTP(tau)‐PET, and 3T task‐fMRI scans performed within 1 year of each other (mean time difference = 0.29±0.24 years). The fMRI‐task consisted of novel and repeated face‐name pairs that the participants were instructed to remember. Voxel‐wise mixed‐effects analyses were performed to detect regions exhibiting significant novelty‐related activation. Vertex‐wise linear regression analyses were used to detect significant associations between LC activity and cortical tau deposition. Both analyses were adjusted for age, sex and multiple comparisons (pcl<0.05). The association between LC activity and memory decline (composite, Fig. 3 caption) was evaluated using linear regression adjusted for age, sex and education. Mediation analyses were performed using a quasi‐Bayesian bootstrap (n = 1000) approach to investigate whether EC‐tau mediates the association and whether this mediation effect is moderated by Aβ status.

Result

We observed greater novelty‐related activation within the bilateral LC, amygdala, hippocampus, and fusiform and insular cortices (Fig. 1). LC activation was associated with tau in the EC, inferior‐temporal and fusiform cortices (confirmed by EC‐ROI analyses‐Fig. 2). Lower LC activation was associated with steeper memory decline (p<0.05‐Fig. 3a), and this association was found to be mediated by EC‐tau (p<0.05‐Fig. 3b). This mediation effect was significantly stronger for the Aβ+ compared to the Aβ– group (p<0.05‐Fig. 3c).

Conclusion

This work demonstrates that lower LC activity is associated with tau deposition in the medial‐ and inferior‐temporal lobe, consistent with the spatial patterns of tau observed in preclinical Alzheimer’s disease. Moreover, our observation that EC‐tau mediates the relationship between LC activity and memory decline suggests that lower LC function may indicate risk associated with Alzheimer’s‐related processes.
Inactivity is associated with worse cognition and neurodegeneration in aging adults
Authors: Gogniat Marissa A. , Khan Omair A. , Li Judy , Park Chorong , Robb W Hudson , Moore Elizabeth E. , Houston Michelle , Pechman Kimberly R. , Liu Dandan , Hohman Timothy J. , Gifford Katherine A. , Jefferson Angela L.
Published: December 2022

Background

Greater physical activity is known to be beneficial for healthier brain aging outcomes. However, less is known about how inactivity might influence the aging brain. Inactivity is highly prevalent in older adulthood and may be an important modifiable risk factor. We examined how inactivity relates to cognitive performance and structural imaging variables in community‐dwelling older adults, particularly among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐e4 carriers).

Method

Vanderbilt Memory and Aging Project (n = 265, 74±8 years, 37% female) participants completed at least 7 days of wrist actigraphy, neuropsychological assessment, and 3T brain MRI. Actigraphy data was processed using the GGIR package. Linear regression analyses related average daily minutes spent in inactivity during wake periods to cognition and brain structure adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile score, APOE‐e4 status, cognitive status, actigraphy wear time, and intracranial volume (for MRI outcomes). Models were repeated testing interactions with APOE‐e4 status.

Result

The total sample was inactive for 14±2 hours/day. More minutes of inactivity related to worse episodic memory performance (β = ‐0.001, p = 0.03), a smaller AD‐signature composite of cortical thickness (β = ‐0.0002, p = 0.008), and lower occipital lobe grey matter volume (β = ‐10.01, p = 0.01). Inactivity time interacted with APOE‐e4 status on naming (β = ‐0.01, p = 0.01) and visuospatial performances (β = ‐0.02, p = 0.04); total grey matter volume (β = ‐201.40, p<0.001); and frontal (β = ‐96.24, p = 0.001), temporal (β = ‐27.13, p = 0.03), and parietal lobe volumes (β = ‐54.72, p<0.001). In stratified models, more minutes of inactivity related to worse neuropsychological performance and smaller brain volumes among APOE‐e4 carriers. All stratified models in non‐carriers were null (p‐values>0.12).

Conclusion

Among community‐dwelling older adults, more time spent inactive each day related to worse episodic memory performance and lower cortical thickness in regions susceptible to AD‐related neurodegeneration. Results were stronger among APOE‐e4 carriers. This study supports the importance of not just increasing physical activity but also reducing the time spent inactive each day, particularly among aging adults at genetic risk for AD.

Funding: IIRG‐08‐88733, P20‐AG068082, R01‐AG034962, K24‐AG046373
ICU hospitalization and incident dementia in community‐based cohorts of older adults
Authors: James Bryan D , Grodstein Francine , Barnes Lisa L. , Marquez David X. , Bennett David A
Published: December 2022

Background

Critical illness and intensive care unit (ICU) hospitalization in older patients have been shown to increase risk of long‐term cognitive impairment. However, most data come from patients recruited from the ICU without controls or information on pre‐ICU cognition. We are not aware of a community‐based sample that allows examination of how ICU hospitalization changes risk for dementia.

Method

We used data from 5 diverse epidemiologic cohorts at the Rush Alzheimer’s Disease Center (RADC) linked to Medicare claims data from 1991 to 2018 to observe ICU hospitalizations (both prior to RADC enrollment and during RADC follow‐up) in older adults enrolled without known dementia. Incident Alzheimer’s and all type dementia was assessed using standardized annual cognitive assessment. The association of ICU hospitalization with incident dementia was tested in a time‐varying Cox model allowing hazard rate to change at time of ICU hospitalization during follow‐up. All models were adjusted for age, sex, education, and race. Fully adjusted models also included terms for baseline measures of hypertension, diabetes, BMI, vascular risk factors, vascular disease burden, other chronic medical conditions, functional disabilities, depression, and physical activity.

Result

Participants (n = 3,822; mean age = 77.3, SD = 7.5) were followed for an average of 7.8 years (SD = 5.5) from study enrollment. ICU hospitalization was experienced by 1,992 (52.1%) of participants; 1031 (27.0%) before RADC enrollment, and 961 (25.1%) during follow‐up. In models adjusted for demographics, ICU hospitalization was associated with an increased risk of Alzheimer’s (HR = 1.63, 95% CI = 1.41, 1.88) and all type dementia (HR = 1.71, 95% CI = 1.48, 1.97). In fully adjusted models, the association was stronger with ICU associated with double the risk of Alzheimer’s (HR = 2.10, 95% CI = 1.66, 2.65) and all type dementia (HR = 2.20, 95% CI = 1.75, 2.77).

Conclusion

We found that ICU hospitalization was associated with double the risk of dementia in community‐based older adults compared to those who did not experience ICU hospitalization using standardized annual cognitive assessment. These findings could be significant given the high rate of ICU hospitalization in older persons, and rising ICU hospitalizations more recently during the COVID‐19 pandemic.
Neurotrophic and growth factor response to acute exercise across the lifespan
Authors: Morris Jill K. , Kueck Paul J. , Kemna Riley E. , Green Zachary D. , John Casey S. , White Dreu , Billinger Sandra A , Vidoni Eric D
Published: December 2022

Background

There is evidence that aerobic exercise is beneficial to the brain and may reduce risk for cognitive decline and dementia. However, clinical trials have shown the benefits of exercise programs vary amongst individuals. This variability may occur in part due to differences in the physiological biomarker response to acute exercise. Characteristics such as age, sex, and apolipoprotein E4 (APOE4) genotype may affect these responses, but differences in blood processing protocols may introduce additional variability into the measures.

Method

We characterized the blood biomarker response to acute exercise in 80 individuals, including older adults (n=62, mean age 73y) and 18 young controls (n=18, mean age 37). Participants engaged in an acute, 15 minute bout of moderate intensity exercise (45‐55% HRR) following a 5 minute warm‐up. Blood was collected immediately prior to exercise, immediately post exercise, and 40 minutes post exercise. After collection, each timepoint sample was immediately processed for plasma and platelet poor plasma and frozen; this was done to limit release of growth factors from activated platelets post‐blood draw. Time course responses of brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), insulin like growth factor 1 (IGF1) were measured using ELISA in platelet poor plasma. Lactate was measured in plasma (YSI 2500).

Result

Linear mixed modeling performed with age, sex, and APOE4 genotype as covariates revealed a significant change in BDNF (p<0.001) and lactate (p<0.001) over time, with the highest levels of lactate observed immediately post‐exercise, while BDNF was elevated at 40 minutes post‐exercise in both young and older adults. There was no significant change with either VEGF or IGF1 over time in response to exercise, although older adults had significantly higher VEGF (p=0.01) and lower IGF1 (p<0.001) compared to young controls across all timepoints.

Conclusion

We report here that analysis of the acute exercise response reveals a significant increase in circulating BDNF and lactate, but not VEGF or IGF1, following aerobic exercise in both young controls and older adults. Further investigation into the mechanisms that contribute to these changes and the relevance to additional fluid and imaging brain health biomarkers in this cohort is ongoing.
Relationship between the metabolic hormone response and plasma biomarkers of Alzheimer’s Disease and Related Dementias
Authors: Kueck Paul J. , John Casey S. , Green Zachary D. , Johnson Chelsea N. , Kemna Riley E. , Burns Jeffrey M. , Morris Jill K.
Published: December 2022

Background

Insulin resistance is a known risk factor for Alzheimer’s Disease and related dementias (ADRD). While the role of insulin on peripheral tissue is well understood, it’s effect on the brain remains unclear. Insulin and other gastrointestinal peptides can cross the blood‐brain barrier to form ligands in areas involved in metabolic response. Thus, it’s important to understand the relationship between systemic metabolic outcomes, such as meal‐stimulated hormone responses, and plasma biomarkers of ADRD.

Method

67 Participants (27 ADRD) completed a clinical and cognitive (Uniform Data Set 2.0) examination, meal tolerance test, and MRI scan. Cognitive scores were standardized to z‐scores and averaged to yield a global z‐score. EDTA plasma samples collected during the meal tolerance test were analyzed for glucose and insulin, and responses of peptide tyrosine tyrosine (PYY) and gastric inhibitory polypeptide (GIP) were analyzed in plasma from a subset of samples (n=53) containing DPP4 inhibitor. Further characterization of amyloid beta (Aβ42), pTau 181, Neurofilament light (NFL), and glial fibrillary acidic protein (GFAP) was performed using non‐fasted EDTA plasma on the Simoa HD‐X (Quanterix). We then assessed the relationship between the early metabolic and hormone responses to a mixed meal and baseline plasma ADRD biomarkers.

Result

The study sample consisted of 53.7% females and 43.3% APOE4 carriers with an average age of 74.9±6.3 and 16±3 years of education. All analyses were controlled for age and sex. Aβ42/pTau181, pTau 181, NFL, and GFAP were significantly elevated in ADRD compared to CH individuals (p<0.05) and tracked linearly with global cognitive z score (p=0.004, p<0.001, p<0.01, p=0.02, respectively). Linear regression revealed that both pTau 181 (β=0.334, p=0.009) and NFL (β=0.320, p=0.003) tracked significantly with the early PYY response (0‐30 minute), but not other metabolic responses, across the entire cohort. pTau181 and the Aβ42/pTau181 ratio each tracked significantly with global cognitive z score (p<0.001, p=0.01, respectively).

Conclusion

Early PYY response to a mixed meal tracks with pTau181 and NFL, plasma biomarkers of ADRD neuropathology and neurodegeneration, respectively. The relationship between gut and brain biomarkers warrants additional study, and further characterization of cross‐sectional and longitudinal relationships with other meal‐related hormone responses is ongoing.
Factors associated with high intensity of end‐of‐life care for decedents with dementia in a Medicare Advantage plan
Authors: Nguyen Huong Q , Duan Lewei , Lee Janet S , Wang Susan E , Hou Anthony , Browne Tarah , Carrol Jarrod , Borson Soo
Published: December 2022

Background

There are limited data on end‐of‐life care (EOL) for decedents with dementia enrolled in Medicare Advantage plans. The purpose of this descriptive analysis is to compare socio‐demographic and clinical characteristics and patterns of healthcare utilization for decedents who were hospitalized in the last 30 days of life versus those who were not.

Methods

Data were extracted from electronic health records (EHR) of individuals aged 65+ who had at least one coded ADRD diagnosis and died in 2018‐2019. Decedents with one or more hospital stays in the last 30 days of life were categorized as receiving high‐intensity EOL care (n = 6299, 45%); those with no hospitalizations were classified as receiving low‐intensity EOL care (n = 7571, 55%). We compared socio‐demographic and clinical characteristics and healthcare utilization, including life care planning (LCP) and palliative and hospice care between the two cohorts.

Results

The high‐intensity cohort was minimally younger (85±7.6 vs. 86.6±7.6) and included more men (48% vs. 41%) and people of color (47% vs. 38%) compared to the low‐intensity cohort. Co‐morbidities were also higher in this group (Elixhauser: 11.5±3.6 vs. 9.9±3.7) and dementia was more often first documented in the EHR very “late” [median: 586 (IQR:85.0, 1521.0) vs. 1062 (IQR:391.0, 2012.0) days prior to death]. The high‐intensity group used more outpatient (primary care and specialty visits, 10.3 vs. 6.5), emergency visits (2.7±3.0 vs. 1.8±2.3), and inpatient (1.6±2.2 vs. 1.1±1.5) care in the prior year. Moreover, the first LCP conversation occurred much closer to death in the high‐ vs. low‐intensity group [median: 35 (IQR:10.0, 139.0) vs. 105 (IQR:45.0, 234.0) days from first conversation to death]; an advance directive or POLST were less likely to be completed (71% vs. 81%) as was receipt of home palliative care or hospice (62% vs. 82%) than in the low‐intensity cohort. All comparisons between the two cohorts were significant, p<.01.

Conclusions

We found notable differences in socio‐demographic and clinical characteristics, and utilization patterns in the year prior to death between decedents with dementia who were hospitalized in the last 30 days of life vs. those who were not. Further analyses will assess key, potentially modifiable drivers of high‐intensity EOL care.
Correlation between quantitative and qualitative assessments of white matter hyperintensities inpatients from a multicentric memory clinic population
Authors: dos Santos Clarisse Longo , Cavedo Enrica , Gordon Elizabeth , Samper‐Gonzales Jorge , Schwarz Adam J. ,   MEMENTO study group
Published: December 2022

Background

White matter hyperintensities (WMH) can be visualized as abnormal T2 signal in the periventricular, deep and subcortical white matter on Magnetic Resonance Imaging (MRI). WMH increase with age and are associated with stroke, cognitive decline and dementia. The most common visual rating scale used to assess WMH in the clinical setting is the Fazekas scale (Fazekas et al., 1987). The current study investigated the relationship between WMH volume (expressed as a % of intra‐cranial volume (ICV)) calculated using an automated method included in the QyScore® medical device, and Fazekas scores in a multicentric memory clinic population at baseline.

Method

1959 participants from the MEMENTO cohort (Age 71.02 +/‐ 8.61, 1218 Female, MMSE 27.95 +/‐ 1.91) had 3DT1 and T2 FLAIR MRI scans analyzed with QyScore®, an FDA‐approved and CE‐marked image analysis software. 814 had amyloid status from CSF or PET, of which 216 were Amyloid+. WMH volumes are reported in mL, corrected for %ICV. Correlation between Fazekas deep white matter (DWM) scores and quantitative WMH measurements was ascertained by Spearman’s rank correlation.

Result

There was a significant positive correlation between Fazekas DWM scores and WMH %ICV (0.76 p<0.001) for the total sample, amyloid positive (0.81 p<0.001) and negative (0.72 p<0.001) patients. The correlation was also strong when separated by clinical diagnosis: patients with Subjective Cognitive Complaint (SCC, N= 305, AGE: 69.87 +/‐ 8.03, 197 female, MMSE: 28.86 +/‐ 1.17) and MCI (N = 1638, Age: 71.2 +/‐ 8.69, 1014 Female, MMSE: 27.8 +/‐ 1.95) presented Fazekas DWM scores correlated with WMH %ICV (0.66 p<0.001 for SCC; 0.77 p<0.001 for MCI).

Conclusion

The automated quantification of ICV‐corrected WMH were well‐correlated to Fazekas DWM scores. Considering that visual rating of WMH is time consuming and suffers from intra and inter‐operator variability, the quantitative assessment of WMH load provided by QyScore® may improve the assessment of patients with cognitive impairment.
Increased Bridging Characteristics in Social Networks are Associated with Increasing Amygdala Volume and Grey Matter Density
Authors: Manchella Mohit K. , Logan Paige E. , Perry Brea L , Peng Siyun , Risacher Shannon L. , Saykin Andrew J. , Apostolova Liana G.
Published: December 2022

Background

Social connectedness has been linked to decreased rates of cognitive decline particularly among older adults (Fratiglioni et al., 2004). Several studies have demonstrated that access to an expansive network of diverse, and loosely connected individuals (i.e., social bridging) plays a particularly unique role in conferring resilience against cognitive decline (Perry et al., 2021). We explored the association of social bridging with cortical atrophy measured by gray matter density (GMD) in cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s Disease (AD) participants from the Social Networks and Alzheimer’s Disease (SNAD) at the Indiana Alzheimer Disease Research Center.

Method:

We analyzed baseline data of 176 SNAD participants (63 CN, 54 SCD, 47 MCI, 12 AD). Social bridging metrics were collected via in‐person interviews of egocentric social network data. MCI and AD were combined into a cognitively impaired group, resulting in 3 diagnostic groups (CN, SCD, CI). Demographic and biomarker differences across groups were analyzed using ANOVA. Pooled linear regressions were run with ROIs as the dependent variables and diagnosis, age, sex, education, and social bridging as regressors. A voxel‐wise multiple linear regression of GMD images in SPM12 yielded statistical maps across the pooled sample.

Result

Table 1 shows the demographic and biomarker comparisons of all groups. The linear regression showed greater social bridging was associated with larger left and right amygdala volume (both p=0.01), and trending larger left frontal thickness (p=0.055), and left and right insula thickness (both p=0.09). Figure 1 and Figure 2 show scatterplot distribution of significant and trending brain regions versus bridging by diagnostic group with regression p‐values and lines. Statistical maps show increasing social bridging is associated with increasing GMD lateralized to the left hemisphere with a frontotemporoparietal pattern (Figure 3).

Conclusion

We found that the effects of particular social enrichment on GMD, such as social bridging, are localized to regions primarily involving motivation and emotion. The left lateralization suggests this hemisphere’s propensity for protection against cognitive decline via social mechanisms. Future work should investigate potential associations between social bridging and amyloid and tau deposition.
Genetic contribution to grey matter network disruptions and Alzheimer disease cerebrospinal fluid markers
Authors: Dicks Ellen , Tomassen Jori , ten Kate Mara , Teunissen Charlotte E. , Scheltens Philip , Barkhof Frederik , den Braber Anouk , Visser Pieter Jelle , Tijms Betty M.
Published: December 2022

Background

Grey matter covariance networks become disrupted early in Alzheimer’s disease (AD), when amyloid starts aggregating, and before the onset of irreversible atrophy. However, the precise relationship of grey matter network breakdown and the AD pathophysiological process remains unclear. Here, we studied to what extent shared familial (genes and family environment) or environmental factors unique to a twin contribute to these relationships in a sample of older monozygotic twins with intact cognition.

Method

From the EMIF‐AD PreclinAD study we included monozygotic twins who had at least an MRI scan (n=197) and CSF available (n=124). We assessed the upper limit of genetic contribution to grey matter network measures (size, degree, connectivity density, clustering, path length, small‐world measures) with within‐twin pair correlations. Associations between CSF AD markers (Aβ42/40, t‐tau, p‐tau) and other markers related to AD pathophysiology (neurogranin, Aβ38, Aβ40, BACE1) with grey matter network disruptions were assessed with linear mixed models. Twin analyses (cross‐twin cross‐trait, twin difference analyses) were used to assess the contribution of shared familial and/or unique environmental factors to these associations.

Result

Twenty individuals (16%) had abnormal CSF Aβ42/40 levels. Grey matter network measures were highly correlated within twin pairs (r=0.54‐0.97; all p<0.001, Fig.1), suggesting a moderate to strong genetic background. Across the whole sample, more abnormal Aβ42/40 ratios were moderately related to lower connectivity density (β±SE = 0.176±0.09, p=0.055, Fig.2). The strongest associations with grey matter network measures were observed for t‐tau and p‐tau levels (range β=‐0.344‐0.182), followed by Aβ production markers (Aβ38, Aβ40, BACE1) (range β=‐0.202‐0.165). We observed no relationships between neurogranin and grey matter network measures. Cross‐twin cross‐trait analyses showed that levels for t‐tau, p‐tau and Aβ38 in one twin were associated with grey matter network measures in their co‐twin (r=‐0.27 to ‐0.21; p range=0.02 to 0.07, Fig.3). Within‐pair differences in BACE1 were related to within‐pair differences in normalized path length values (r=0.35; p=0.01; Fig.4).

Conclusion

Our results suggest a shared familial background for the relationship of grey matter network disruptions and AD‐related processes as measured in CSF. In addition, unique environmental factors influencing BACE1 may also affect grey matter network disruptions.
The Assessment of Functional Competence in a Clinical Sample of Older Adults along the Alzheimer’s Continuum
Authors: Rahman Aneela , Pare Nadia , Schmitter‐Edgecombe Maureen , Cunningham Reanne , Behm Lillian , Patel Ved , Schmidt Erica , Warren David E , Rabin Laura
Published: December 2022

Background

Difficulties in performing “Instrumental Activities of Daily Living” (IADL) such as managing finances and medications can lead to loss of independence among older adults. Performance‐based assessments allow for an objective and systematic quantification of IADLs utilizing real life paradigms. In an ongoing NIA‐funded study, we evaluated the association of a recently developed performance‐based assessment of functional ability (Night Out Task, NOT, Schmitter‐Edgecombe, 2021) with a performance‐based measure of financial capacity and an informant‐based measure of functional and decision‐making capacity in non‐demented older adults with varying degrees of cognitive impairment.

Method

Participants (n = 22; mean age = 76) were classified as healthy control (HC, n = 4), subjective cognitive decline (SCD, n = 9), or mild cognitive impairment (MCI, n = 9) based on clinical criteria. The NOT was used to evaluate the ability to efficiently and accurately plan, multitask and complete eight activities in preparation for a night out. The primary outcome variable for the NOT was completion time. Additionally, participants completed the Financial Capacity Instrument (FCI‐SF‐short form), which assesses financial knowledge and problem‐solving skills (Marson, 2015). Meanwhile, informants completed the Assessment of Functional Capacity Interview (AFCI; Pare et al., 2020) which captures decision making related to home safety, financial, medical, and social competence.

Result

NOT scores were normally distributed, as assessed by Shapiro‐Wilk’s test (p > 0.05). We observed a statistical trend for group on NOT completion time such that greater clinical impairment was associated with greater completion time: MCI (M = 916.38s, SD = 218.54) > SCD (M = 741.83s, SD = 212) > HC (M = 728.05s, SD = 167.45). Similar trends were observed for other NOT variables. Correct sequencing and overall efficiency of NOT tasks were negatively correlated with AFCI Financial domain, r(21) = ‐0.606 and r(21) = ‐0.487, both P <0.05, respectively. Overall NOT task accuracy was negatively correlated with FCI‐SF Total Score, r(21) = ‐0.528, P <0.05.

Conclusion

The NOT showed impressive associations with informant reports of functional and decision‐making capacity and objectively assessed financial capacity. The NOT can potentially distinguish among healthy controls and preclinical dementia groups, offering promise for early detection and characterization of cognitive changes.
Microtubule associated protein tau p.R406W patient carriers present with a nonconforming clinical phenotype
Authors: Gossye Helena , Van Mossevelde Sara , Sieben Anne , Bjerke Maria , de Craen Elisabeth Henndrickx Van , van der Zee Julie , De Deyn Peter Paul , De Bleecker Jan , Versijpt Jan , Van den Ende Jenneke , Deryck Olivier , Bourgeois Paul , Bier Jean‐Christophe , Goethals Maarten , Engelborghs Sebastiaan , Van Broeckhoven Christine
Published: December 2022

Background

MAPT p.R406W is an autosomal dominantly inherited missense mutation associated with FTLD with an amnestic, AD‐like phenotype. Our group first described a carrier pedigree (labeled ADG) in 2003, with 47 relatives.

We aim to delineate phenotypic and genetic characteristics of MAPT p.R406W carriers through 19‐year follow‐up, and to provide first data on mutation frequency in FTD and AD.

Method

We extended the ADG pedigree, obtained data over 19 years on symptoms, biomarkers and neuropathology. Furthermore, we screened FTD (n=647) and AD (n=1100) patient cohorts for new carriers.

Result

The ADG family now counts 38 mutation carriers. 7 unrelated carriers were identified in AD and FTD cohorts. Inclusion of additional relatives procured 56 mutation carriers (39 affected).

p.R406W mutation frequencies were 0.62% (FTD) and 0.27% (AD). All probands shared genetic kinship, suggesting a common ancestor.

Average onset age and disease duration were 60.9 and 12.4 years (ranges 54‐69, 5‐25). Remarkably, two distinct phenotypes (clinical AD(n=10) or bvFTD(n=9)) emerged. bvFTD patients had significantly worse prognosis. Disinhibition/aggression were highly common (100% of bvFTD, 40% of AD patients). CSF amyloid‐β1‐42 was decreased in all 5 patients with CSF data, 2/5 with concomitant tau elevation. Neuropathology was FTLD‐tau, notably showing only 3R‐tau‐isoforms.

Conclusion

We are first to report MAPT p.R406W mutation frequencies, unexpectedly high in FTD ànd AD. Contrary to previous reports, we observed a unique phenotypic shift in Belgian p.R406W carriers, with prominent behavioral symptoms, as well as memory decline. Surprisingly, CSF biomarkers showed decreased amyloid‐β1‐42, and neuropathology was FTLD‐tau with isolated 3R‐tau, highly unusual findings for this tauopathy.
Voxel‐wise Staging of Tau Pathology using [18F]RO‐948 PET in the Early AD Continuum
Authors: Shekari Mahnaz , Milà‐Alomà Marta , Falcon Carles , Niñerola‐Baizán Aida , Operto Grégory , Garcia Marina , Sánchez‐Benavides Gonzalo , Brugulat‐Serrat Anna , Tonietto Matteo , Borroni Edilio , Klein Gregory , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Snellman Anniina , Ortiz‐Romero Paula , Vanmechelen Eugeen , Minguillón Carolina , Fauria Karine , Perissinotti Andrés , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Grau‐Rivera Oriol , Suárez‐Calvet Marc , Gispert Juan Domingo
Published: December 2022

Background

Tau positron emission tomography (PET) is a useful biomarker for detecting tau aggregation, one of the hallmark pathological findings in Alzheimer's disease (AD). The goal of this study is to characterize and stage the pattern of spreading of tau pathology across the brain in the early AD continuum.

Method

Forty‐seven cognitively unimpaired individuals from ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted magnetic resonance imaging(MRI), two cognitive assessments, cerebrospinal fluid(CSF), and blood biomarkers. Standardized uptake value ratio(SUVr) maps of [18F]RO‐948 PET images in MNI space created using inferior cerebellum as reference region. Participants were categorized according to the A/T system using pre‐established thresholds for CSF amyloid(A) and tau(T) positivity(Table1). A voxel‐wise hierarchical staging model was constructed based on data from the control group(A‐T‐). Voxel positivity was defined as SUVr higher than mean plus two standard deviations of control group(Figure1). Then, each voxel was assigned to one of 3 stages based on the frequency of its abnormality across the control group, dividing the voxel frequency histogram into 3 equally‐distributed groups. A given stage was assigned to each scan if, at least, 50% of the voxels on the stage mask were positive, hierarchically. That is, to determine stage 2, stage 1 needs to be positive as well. Otherwise, the scan is labeled as non‐stageable. Staging model performance was evaluated by recording the number of non‐stageable scans as well as by performing non‐parametric correlations between tau stages and CSF, blood biomarkers, cortical thickness, Centiloid(CL) as well as changes in cognition composites. Post‐hoc between‐stage comparisons were performed using the Kruskal‐Wallis test followed by a Bonferroni correction.

Results

All scans were stageable. Twenty‐three scans were assigned to stage 0, 11 to stage 1, and 3 to stage 2(Figure2). Significant correlations between tau stages and CSF, blood biomarkers, Centiloid, cortical thickness as well as memory and attention changes were observed(Table2). Between‐group comparisons of tau stages vs biomarkers and changes in memory and attention were statistically significant(Figure3).

Conclusion

Our results suggest that the proposed voxel‐wise staging model is sensitive to capturing the spread of early tau pathology and useful for studying early AD pathophysiological mechanisms.