bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of Home Infusions in a Multinational Preclinical Alzheimer’s Disease Study
Authors: Velona Isabella , Yaari Roy , Holdridge Karen C. , Brown Cheryl Ann , Cohen Paula , Shaffer‐Bacareza Elizabeth , Arampatzidou Maria , Lizzul Nancy , Weiss Ellen
Published: December 2023

Background

The A4 Study is a Phase 3 clinical trial investigating solanezumab in preclinical Alzheimer’s disease. The COVID‐19 pandemic impacted the delivery of elective health services worldwide and social distancing restrictions created challenges for clinical trial participants to continue monthly infusions. In an effort to retain A4 participants, decentralized clinical trial methods were implemented, including deployment of mobile research nurses to conduct home visits.

Method

The A4 Study is a 4.5 year double‐blind trial, followed by an optional 4 year open‐label treatment period. The study launched in 2014 and 1163 males and females between the ages of 65 and 85 years old have been dosed. Home visits were not originally included in the study protocol, but were implemented in 2020 to mitigate the COVID‐19 pandemic impact on study conduct. PCM Trials offered home visits as an option to allow participants to continue to receive investigational product. Mobile research nurses traveled to participant homes and administered the 30‐ to 60‐minute intravenous infusions every 4 weeks.

Result

To date, more than 1,400 home infusions visits have been conducted in the A4 Study. 124 participants were enrolled in home infusions (99 in the United States; 1 in Canada and 24 in Australia) from 18 sites.

Conclusion

Implementation of home visits led to several positive outcomes, including reduced participant burden (particularly for participants living in rural/remote locations), study continuity and maintenance of treatment regimen, and retention of participants. Considering the length of the study, the infusion frequency, and the age of the participants, home visits have been a valuable option to help study completion and compliance. Data integrity and participant safety were ensured and maintained with the use of home visits in the A4 study.
Personalized nutritional ketosis through a whole‐food low‐carb diet, medium chain triglycerides, and other ketogenic strategies for people with mild cognitive impairment and Alzheimer’s disease
Authors: Newport Mary T
Published: December 2023

Insulin resistance with abnormal brain glucose uptake, a brain‐energy gap, and neuroinflammation are common in the aging brain and are exaggerated in people with Alzheimer’s disease (AD) and in some people with MCI (Cunnane Nature Reviews Drug Discovery 2020). Ketones are an alternative fuel for the brain and ketone uptake is normal in brain regions affected by abnormal glucose uptake in AD (Castellano J Alzheim Dis 2015). Ketones are anti‐inflammatory (Kim Frontiers Immunol 2022) and lessen beta amyloid plaques, tau tangles, and anxiety in animal models (Kashiwaya PNAS 2000; Wu FASEB 2020). Increased brain energy from ketones has been demonstrated using PET imaging in clinical trials of MCT oil (Fortier Alz Dementia 2021), ketogenic diet (KD) (Neth Neurobiol Aging 2020), and exercise (Vandenberghe Appl Physiol Nutr Metab 2019). Recent studies report cognitive and/or other clinical improvements in MCI and/or AD with KD (Brandt J Alzheimers Dis 2019), modified Mediterranean KD (Neth Neurobiol Aging 2020), KD with MCT oil (Taylor Alzheimers Dement 2017), KD with coconut oil in keto study diet recipes (Phillips Alz Research & Therapy 2021), MCT oil with habitual diet (Reger Neurobio Ageing 2004; Constantini Nutri Metab 2009; Maynard Neuropsych Disease Treat 2013; Abe J Nutr Sci Vitaminol 2017; Abe J Nutr 2016; Xu et al. Clin Nutr 2020; Fortier Alz & Dementia 2021), and coconut oil with habitual diet (De la Rubia Orti Nutr Hosp 2017). Case reports of people with AD consuming KD, MCTs, and/or ketone ester also report cognitive improvement (Maynard Neuropsych Disease Treat 2013; Newport Alz Dementia 2015; Stoykovich Alz Dementia 2019; Morrill Diab Metab Syndr:Clin Res & Rev 2019). Ketone esters can rapidly and substantially increase blood ketone levels. Given the lack of any FDA‐approved drug that results in meaningful improvement for people with AD, accumulating evidence suggests that adopting a personalized program for people with AD, aiming for mild to moderate ketosis (blood betahydroxybutyrate levels 0.5‐2 mmol/L), could provide a safe and reasonable therapeutic approach to improve cognitive impairment and other symptoms and could offer a strategy to delay or prevent AD in persons at risk.
Plasma TDP‐43 Levels are Associated with Neuroimaging Measures of Temporal Lobe Structure
Authors: Gold Brian T. , Bauer Christopher E. , Zachariou Valentinos , Sudduth Tiffany L , Van Eldik Linda J. J. , Nelson Peter T , Jicha Gregory A , Wilcock Donna M. , Bauer Christopher
Published: December 2023

Background

Tar DNA binding protein of 43kDa (TDP‐43) proteinopathy is a pathological hallmark of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), with or without comorbid Alzheimer’s disease neuropathologic change (AD‐NC). At present, the diagnosis of LATE neuropathologic change (LATE‐NC) can only be made at autopsy. There is thus an urgent need for a clinical biomarker for LATE and a blood‐based method would be optimal for clinical and economic reasons. Here, we assessed the relationship between plasma TDP‐43 levels with imaging measures of neurodegeneration (volume and cortical thickness).

Method

Participants were 72 nondemented older adults (47 women, age range 60‐94 years). Immunoassays for TDP‐43, phosphorylated threonine‐181 tau (p‐tau181), total tau (t‐tau), amyloid beta‐42 (Aβ42), and amyloid beta‐40 (Aβ40) were quantified (pg/mL) in duplicate for each participant using the Quanterix Simoa HD‐X instrument. Neuroimaging was conducted using a 3 Tesla MRI Siemens Prisma scanner with a 64‐channel head coil. A T1‐weighted MPRAGE sequence with 1 cubic mm voxels covering the entire brain was acquired. FreeSurfer software was used to estimate intracranial volume (ICV) and volumes of the entorhinal cortex (ERC), amygdala, and subiculum of the hippocampus, regions known to harbor TDP‐43 pathology in early stages of LATE‐NC. Multivariate linear regression models controlling for age, sex, and ICV were conducted in SPSS using plasma TDP‐43 as the predictor and volumetric or cortical thickness measurements as dependent variables.

Result

There was a negative association between plasma TDP‐43 concentration and ERC volume, a relationship that remained significant after controlling for plasma markers of AD‐NC (the Aβ42/Aβ40 ratio, p‐tau181/Aβ40 ratio or t‐tau/Aβ40 ratio). Results from subsequent exploratory analyses indicated a negative association between TDP‐43 and cortical thickness in the inferior temporal lobe, a finding which also remained significant after controlling for AD‐NC plasma biomarkers.

Conclusion

High plasma TDP‐43 levels were associated with in vivo imaging measures of neurodegeneration in multiple temporal lobe structures. Plasma TDP‐43 assays may prove useful in clinical trials seeking to enroll individuals at risk for LATE‐NC.
Unlocking cognition with pulsatile GnRH in Down Syndrome: implications for Alzheimer’s disease
Authors: Prevot Vincent
Published: December 2023

Background

There is currently no viable treatment for the cognitive and olfactory deficits of Trisomy 21 and Alzheimer’s disease.

Method

Physiological characterization and epigenetic, cellular, chemogenetic, and pharmacological interventions in male and female Ts65Dn mice (P9‐P360), a mouse model of Down syndrome, and 12‐month‐old THY::TAU22 male mice, a mouse model of Alzheimer’s disease, and their wild‐type littermates. Seven men with Down syndrome (20‐50 years of age) were enrolled in an open‐label pilot study to assess the effect of 6‐month pulsatile GnRH therapy on cognitive and olfactory function.

Result

We show in Ts65Dn mice that olfactory and cognitive neurological symptoms are closely related to a post‐pubertal decrease in hypothalamic and extra‐hypothalamic expression of a master molecule controlling reproduction ‐ gonadotropin‐releasing hormone (GnRH) ‐ and appear to be linked to an imbalance in a microRNA‐gene network known to regulate the maturation of GnRH neurons as well as to an alteration in hippocampal synaptic transmission. Restoring physiological GnRH levels abolishes olfactory and cognitive deficits in Ts65Dn and THY::TAU22 mice, while pulsatile GnRH treatment improves cognition and brain connectivity in adult T21 patients.

Conclusion

We have discovered that GnRH plays a crucial role in olfaction and cognition, and pulsatile GnRH treatment holds promise for improving cognitive deficits in patients with Down syndrome. Such treatment could potentially also be beneficial for mobilizing cognitive reserve in pathological brain aging such as that found in Alzheimer’s disease.
Frequency of social isolation among older adults in Nepal
Authors: Shrestha Prabha , Baral Dikshya
Published: December 2023

Background

Social isolation is a recently documented modifiable risk factors for dementia but little is known about its prevalence in low and middle income countries (LMICs).1 Older adults in Nepal are increasingly at for risk for social isolation given trends of adult child migration to other communities. The resultant social isolation increases risk for depression, psychological distress, and dementia2‐3. This study aimed to estimate the prevalence of social isolation among older adults of Nepal and its associated factors.

Methods

A quantitative cross‐sectional study in Dhulikhel municipality of Nepal. Two geographical regions within the city were randomly selected. Systematic random sampling was used for the selection of respondents. We employed the Lubben Social Network Scale (LSNS‐18), a brief tool validated in LMIC, to quantify social isolation.4 Data were analyzed with Statistical Package for Social Sciences (SPSS) v25.

Results

More than half of respondents (52.3%) were age 60‐70 years, 56.1% were male, 55.1% were illiterate, and 59.8% were living in a nuclear family. More than one third (37.4%) met criteria for socially isolation. Social isolation associated with age (p = 0.026), being a widow (p = 0.002), living in a nuclear family (p = 0.001), and the presence of chronic diseases (p = 0.014). Whereas gender and education were not significantly associated with social isolation.

Conclusion

More than one third of older adults in this representative community met criteria for social isolation despite the family‐based societal norms that are typical of Nepal. Addressing this issue may promote brain health among older adults. Further research is recommended to examine the cognitive health of this isolated population.

References

1. Livingston et al, Dementia prevention, intervention, and care. The Lancet. 2017

2. Xiang X, et al Trajectories of Social Isolation and Dementia in Older Adults J Aging Health. 2021

3. Taylor HO, et al. Social Isolation, Depression, and Psychological Distress Among Older Adults. J Aging Health. 2018

4. Bincy, K. et al. Validation of Expanded form of Lubben Social Network Scale among Community‐Dwelling Geriatric Population in India. Indian Journal of Community Medicine 2022.

Keywords:

Older adults, Social isolation, Dementia
Proteomics Analysis Identifying New Markers Related to Alzheimer’s Disease Pathology In Vivo
Authors: Binette Alexa Pichet , Salvadó Gemma , Spotorno Nicola , Vogel Jacob W , Kumar Atul , Strandberg Olof , Janelidze Shorena , Hansson Oskar
Published: December 2023

Background

To better understand the pathophysiological processes in Alzheimer’s disease (AD), we need to broaden our knowledge on molecular pathways and discover molecular markers that co‐occur with, precipitate and follow the accumulation beta‐amyloid (Aβ) and tau pathology. Using high‐throughput proteomics, we investigated how a wide array of proteins relate to AD pathology in a large cohort spanning the AD continuum.

Method

We included 949 BioFINDER‐2 participants with cerebrospinal fluid (CSF) measurements of 2943 proteins (Olink Explore 3072 assay), and CSF and/or PET measurements of Aβ and tau. We compared CSF proteins between groups based on their Aβ (A) and tau (T) status, defined respectively from CSF Aβ42/40 ratio and tau‐PET RO948 in the temporal meta‐ROI (i.e. A‐T‐ vs. A+T‐ and A+T‐ vs. A+T+). We also compared A+T+ vs. non‐AD neurodegenerative diseases. Then, among the significant proteins identified across all three comparisons, we evaluated their associations with Aβ‐ (flutemetamol) and tau‐PET, both cross‐sectionally and longitudinally (based on rate of change). These latter analyses were restricted to cognitively unimpaired and patients with MCI, who all had Aβ‐ and tau‐PET available (n = 548).

Result

Across all AT comparisons, 85 proteins were significantly different between groups (pFDR<0.05; Fig.1). More advanced pathology was associated with higher protein levels, except ApoE levels that were decreased. The A+T‐ vs. A+T+ comparison revealed most protein differences (n = 74; Fig.1B), compared to A‐T‐ vs. A+T‐ or A+T+ vs. non‐AD neurodegenerative diseases. In cross‐sectional analyses, 32/85 proteins (38%) were significantly associated with Aβ‐ and tau‐PET load, with the strongest ones being microtubule‐associated protein tau (MAPT), neurogranin (NRGN), ITGAM, ITGB2 and SMOC1. When putting both pathologies in the same model, all proteins remained associated with Aβ only, except for ENO2 and GPI, which remained associated with tau only (Table 1). In longitudinal analyses, 19 proteins were associated with greater tau‐PET rate of change (the top five being MAPT, NRGN, ITGB2, FABP3 and CHIT1), whereas only SMOC1 and ITGAM were associated with greater Aβ‐PET rate of change (Table 1).

Conclusion

Through comprehensive proteomics analysis, we identified novel proteins associated with AD pathology, many of which are involved innate immunity, intracellular transport and extracellular matrix binding.
Establishment and application of a microglial phagocytosis/cell health high content assay for Alzheimer’s disease drug discovery targeting microglia
Authors: Mason Emily R , Soni Disha , Chu Shaoyou ,   Cellular Pharmacology lab/TREAD‐AD center, Clinical Pharmacology/Dept. of Medicine
Published: December 2023

Background

Targeting microglial phagocytosis has been proposed as a therapeutic strategy for Alzheimer’s disease drug discovery. A reliable cellular assay capable of measuring drug‐regulated phagocytosis activity while simultaneously measuring treatment‐caused cell stress and toxicity is needed for drug discovery research targeting microglia. This need motivated us to develop and establish a high content microglial phagocytosis/cell health assay to meet the challenge.

Method

The assay uses 384‐well cellular imaging plates, microglial cell lines (HMC3 and BV2) and mouse primary microglia, pHrodo‐myelin/membrane debris as ligand, and a high content imaging system for imaging and analysis. Assay procedures include 1) plate cells on day 1 and incubate cell plates overnight in 37oC; 2) treat cells with compounds on day 2; 3) add pHrodo‐myelin/membrane debris to cell plates on day 3 and incubate in 37oC for 20 hours; 4) stain cell nuclei with Hoechst‐33342 for 30 min before performing high content imaging and analysis on day 4. Three selected parameters are measured from cell images: 1) mean total fluorescence intensity per cell of pHrodo‐myelin/membrane debris in phagocytosis vesicles to quantify phagocytosis; 2) cell counts per well (assessing effects on proliferation and cell death); and 3) average nuclear intensity (detecting induced apoptosis).

Result

Various treatments targeting different mechanisms regulating microglial phagocytosis were tested; we observed that Cytochalasin D inhibited phagocytosis, LPS stimulated phagocytosis in BV2 cells but not HMC3 cells, Idelalisib (PI3Kd inhibitor) inhibited HMC3 cell phagocytosis, and Saracatinib (Src/abl family of kinases inhibitor) stimulated HMC3 phagocytosis. These results validated the assay for use in drug discovery targeting microglial phagocytosis. With the assay, we identified some INPP5D inhibitors and some PLCG2 activators stimulated phagocytosis in a concentration range without significant cell stress/toxicity with all three cell types tested.

Conclusion

A microglial phagocytosis/cell health assay was established. The simultaneous measurement of phagocytosis and cell health allows for the distinction of drug effects on regulation of phagocytosis from cellular stress/toxicity‐related changes, a distinguishing feature of the assay, which helped compound selection of drug discovery projects targeting INPP5D and PLCG2 respectively.
Exploring gray matter volume atrophy associations with hearing in the UK Biobank
Authors: Fitzhugh Megan C , Pa Judy
Published: December 2023

Background

Hearing impairment was recently recognized as a modifiable risk factor for dementia. Theories to explain this relationship propose that hearing impairment results in reduced sensory input across the brain, which negatively affects brain structure. Therefore, large exploratory studies are needed to examine potential relationships between hearing and brain volume.

Method

2,000 participants (age = 63±7 years, 50% female) from the UK Biobank were include in this study. Voxelwise multiple regression models examined the association between hearing and baseline MRI gray matter volume. Hearing was assessed using a speech‐in‐noise task, with positive scores reflecting poorer hearing. Interactions between hearing and sex on brain volume were also explored. Covariates included age, sex (except in model with sex interaction), socioeconomic status, and total intracranial volume. Given the exploratory aim of the analysis, a threshold of p<0.001 was used.

Result

The multiple regression model results showed that poorer hearing is associated with lower gray matter volume in bilateral temporal auditory regions (Heschl’s gyrus, superior temporal gyrus) and left amygdala. While hearing scores did not significantly differ by sex, there were significant hearing‐by‐sex interactions. In women, poorer hearing was associated with lower volume in bilateral auditory regions. In men, poorer hearing was associated with lower volume in right hippocampus and higher volume in posterior cingulate cortex.

Conclusion

This study sought to address a major gap in the current literature and explored voxelwise associations between hearing and brain volume in a large sample. The results show that poorer hearing is associated with lower brain volume in lateral and medial temporal regions, which differed by sex. Poorer hearing in women was associated with lower volume in auditory regions, while in men, poorer hearing was associated with lower volume in regions similarly affected by Alzheimer’s disease and dementia. Together, these data provide support for a potential mechanistic explanation for the association between hearing loss and dementia through increased brain atrophy.
C/EBPβ/δ‐secretase Signaling Drives Neurodegenerative Diseases
Authors: Ye Keqiang
Published: December 2023

Background

C/EBPb/AEP pathway are escalated in the brain in an age‐dependent manner and proteolytically cleaves APP and Tau and a‐Synuclein, facilitating AD and PD pathologies.

Method

C/EBPb/AEP pathway couples different risk factors that elicit inflammation to Alzheimer’s disease. To explore why women are more vulnerable for AD, we investigated different hormones altered during menopause and found FSH (follicle‐stimulating hormone) strongly activated this signalling, leading to AD pathogenesis in different mouse models. Employing immuno‐EM and knockout tissues, we demonstrated that FSHR is expressed in mouse and human brain neurons. Notably, FSH administration drives AD onset in young male and female mice, whereas anti‐FSH robustly diminishes AD progression in overiactomized female 3xTg mice. Moreover, deletion of FSHR or C/EBPb from the neurons of 3xTg mice attenuates AD pathologies.

Result

Elevated FSH during menopause activates C/EBPb/AEP signalling, which subsequently cleaves both APP and Tau, triggering AD onset. Blockade of FSH abrogates overiactomy‐induced AD pathologies and restores the cognitive dysfunctions in AD mouse models.

Conclusion

FSH elevation after menopause elicits women susceptibility to AD via activating C/EBPb/AEP pathway. Inhibition of FSH/FSHR may provide an innovative therapeutic strategy for treating AD.
Sex Differences in Behavioral and Psychological Symptoms in Institutionalized Patients with Advanced Alzheimer’s Disease
Authors: Choudhury Samira , Colman Sarah , Chu Li , Davies Simon , Derkach Peter , Elmi Sarah , Fischer Corinne E. , Gerretsen Philip , Graff‐Guerrero Ariel , Hussain Maria , Ismail Zahinoor , Khan Shehroz , Kim Donna , Krisman Linda , Moghabghab Rola , Mulsant Benoit H. , Nair Vasavan , Pollock Bruce G. , Rej Soham , Rostas Aviva , Streiner David , Van Bussel Lisa , Rajji Tarek K. , Kumar Sanjeev , Burhan Amer M. ,   StaN study Group
Published: December 2023

Background

Behavioral and psychological symptoms in dementia (BPSD) are highly prevalent in patients with Alzheimer’s dementia (AD). We examined sex differences in the frequency and severity of BPSD in patients with advanced AD residing in long term care or admitted to inpatient psychiatric units. Also, sex differences in the frequency and severity of BPSD symptom clusters were explored.

Method

We analyzed data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201). BPSD was assessed with the Neuropsychiatric Inventory Clinician rating scale. Chi‐squared tests and Mann‐Whitney U tests were used to determine sex differences in frequency and severity of BPSD, respectively. Bonferroni correction was used for multiple comparisons. Generalized linear models were performed to examine effect of sex on severity of BPSD while controlling for age and residence. BPSD symptom clusters were defined as: (1) psychosis (hallucinations and delusions), (2) emotional distress (depression and anxiety), and (3) agitation (agitation, aggression, irritability, aberrant motor behavior, and aberrant vocalizations).

Result

194 participants (99 female, 95 male) were included. Females had higher frequency of delusions (X2(N = 176) = 8.47, p = .004) and males had higher frequency of sleep disturbances (X2(N = 176) = 9.89, p = .002). Further, females had greater severity of delusions (N = 176, U = 2976, p = .001), and sleep disturbances (N = 176, U = 2950, p = .002). In generalized linear models, sex was associated with severity of delusions (Wald X2 = 3.97, N = 176, p = .046), but not with sleep disturbances. Examination of clusters revealed that females had higher frequency of psychosis (X2(N = 176) = 4.25, p = .039).

Conclusion

We observed sex differences in the frequency and severity of specific BPSD. Future studies should aim to understand potential mechanisms underlying these differences, and to study their relevance for screening, and individualized management of BPSD.
Findings from IDEA Café, the first pilot intervention for sexual and gender minority older adults living with dementia with no care partner
Authors: Fredriksen‐Goldsen Karen I , Kim Hyun‐Jun , Teri Linda , Jones Brittany R , Petros Ryan , Berridge Clara , Emlet Charles A
Published: December 2023

Background

Due to our aging population and changing demographics, there are an increasing number of older adults with dementia with no care partner in the U.S., a trend more pronounced among sexual and gender minority (SGM) older adults. To our knowledge there are no extant interventions for SGM older adults with dementia and few dementia interventions that do not rely on the presence of a care partner.

Method

We tested an innovative group adaptation of Innovations in Dementia Empowerment and Action (IDEA), IDEA Café. SGM older adults with dementia (including mild cognitive impairment) and no care partner were enrolled and randomly assigned to IDEA Café (n = 15) or routine medical care (RMC; n = 15). IDEA Café participants attended a 9‐session virtual group program emphasizing exercise, pleasant events, social support, and stress management. The goal was to improve the health‐related quality of life of SGM older adults with dementia and no care partner. We aimed to assess the intervention’s feasibility, acceptability, and preliminary efficacy.

Result

We met enrollment goals and had good adherence, compliance, and participation, demonstrating feasibility. Participants and interventionists found the intervention acceptable. Within‐group tests revealed the RMC group showed no statistical changes from pre‐test to post‐test, while the IDEA Café treatment group showed significant improvement in primary outcomes, including physical functioning and depressive symptomology with medium effect sizes, and quality of life with small effect size. Between‐group tests found the IDEA Café group had significantly higher physical functioning and quality of life and lower microaggression scores than the RMC group at posttest, all with large effect sizes. In secondary outcomes, IDEA Café participants’ microaggression scores, perceived stress, and social isolation scores significantly decreased with medium effect size, and informational and social support increased with medium affect size.

Conclusion

Our results offer preliminary evidence for a group‐based virtual intervention for this health disparate, underserved population. Our significant findings support IDEA Café’s mechanisms of change: increasing physical activity and mobilizing social support, while addressing SGM risk and protective factors. Future research should examine treatment effects over time with a larger sample size, and the moderating and mediating effects of background characteristics.
The prevalence of and risk factors for sleep disturbances: a systematic review and meta‐analysis
Authors: Butris Nina , Tang Evan , Pivetta Bianca , He David , Saripella Aparna , Yan Ellene , Englesakis Marina , Boulos Mark I , Nagappa Mahesh , Chung Frances
Published: December 2023

Background

Determining the prevalence and risk factors related to sleep disturbance is beneficial for risk stratification, preventative interventions, and care planning. The objectives of this systematic review and meta‐analysis are to determine the prevalence and risk factors of sleep disturbances and their associated postoperative complications in surgical patients.

Method

A systematic search of the databases MEDLINE, MEDLINE ePubs Ahead of Print and In‐ process, Embase Classic+Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to February 23, 2022, was conducted. The inclusion criteria were: (1) adult patients undergoing a surgical procedure; (2) in‐patient population; (3) assessed for pre‐ and postoperative sleep disturbances using the Pittsburgh Sleep Quality Index (PSQI) and/or objective sleep assessment tools, and (4) English language articles. The pooled prevalence of sleep disturbances was calculated using inverse‐variance random‐effects model. The 95% confidence interval (CI) was calculated using normal approximation calculation. Sensitivity analysis was performed to determine the effect of each study on the meta‐analysis estimates.

Result

The systematic search resulted in 21,951 articles. Twelve studies involving 1,497 patients were included. The pooled prevalence of sleep disturbances at preoperative assessment was 60% (95% CI: 50%, 69%) (Figure). Risk factors for postoperative sleep disturbances were preexisting disturbed sleep and preoperative anxiety. Patients with postoperative delirium had a higher prevalence of pre‐ and postoperative sleep disturbances. Patients with postoperative delirium also had higher wake after sleep onset percentage (WASO%) in preoperative assessment using actigraphy.

Conclusion

The prevalence of preoperative sleep disturbances is high at 60%. In adult surgical patients undergoing inpatient surgery, preoperative sleep disturbance and anxiety were the two main risk factors for postoperative sleep disturbance. Surgical patients with postoperative delirium were associated with a higher prevalence of pre‐and postoperative sleep disturbances. Preventing sleep disturbances in surgical patients may be important for postoperative outcomes.
Assessing caregiver burden
Authors: Bakkali Leen , Renzulli Brenda
Published: December 2023

Caregiver burden is an unfortunate reality which can impact negatively on the health of the caregiver and the appropriate care the patient with dementia needs.

The Zarit Burden interview provides an objective measure of caregiver’s burden which alerts the healthcare provider and the caregiver for the need to intervene to prevent deleterious consequences.

Our practice regularly assesses caregiver’s burden and looks in ways to lessen care giver burden using different tools and approaches.

Caregiver burden can improve by education, emotional support, change in environment and planning.
Do Mouse Data Lie? For Buntanetap, They Totally Predict Human Outcome
Authors: Maccecchini Maria L. , Fang Cheng
Published: December 2023

Background

Overexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function (Chen et al. 2021). By inhibiting the translation of neurotoxic aggregating proteins ‐ amyloid precursor protein, tau, alpha‐synuclein etc., buntanetap restores axonal transport, lowers inflammation, and protects nerve cells from dying. In three double‐blind, placebo controlled, phase 1/2 clinical studies in both Alzheimer (AD) and Parkinson (PD) patients buntanetap showed statistically significant improvement in movement in PD and cognition in AD (Fang et al. 2023).

Method

Here we want to compare our animal data with our human data to evaluate if animal models are predictive of human outcomes. We are comparing data from APP/PS1 AD mice (Teich et al. 2018), Ts65Dn Down Syndrome mice (Chen et al. 2020), and two Phase 1 /2 double‐blind, placebo‐controlled human AD studies: Discover study run by ADCS and AD/PD study run by Annovis.

Result

1. Buntanetap is a translational inhibitor of APP by pulse‐chase experiment in mice and by stable isotope labeling kinetics (SILK) in humans (Galasko et al. 2022).

2. Our drug inhibits APP/Abeta, tau/pTau in a dose‐dependent manner in animals (Lahiri et al. 2007; Teich et al. 2018; Chen et al. 2020) and humans (Maccecchini et al. 2012).

3. The biomarker dose‐response is seen at a much higher dose than the efficacy dose‐response.

4. We see a statistical improvement in cognition in animals and in humans (Teich et al. 2018; Fang et al. 2023).

Conclusion

In all our studies conducted to date in AD mice and humans, we have obtained consistent data on the mechanism of action, consistently lowered levels of neurotoxic aggregating proteins, and consistent improvements in cognition.
Increased neural activity relates to greater neuropsychiatric symptoms and beta‐amyloid plaque load in cognitively normal older adults
Authors: Oh Hwamee , Razlighi Qolamreza R , Rogers Annika , Sharp Elizabeth
Published: December 2023

Background

Epidemiological studies have shown that individuals predisposed to experiencing psychological stress, and those affected with diseases associated with chronic stress such as depression and anxiety have an increased risk of developing Alzheimer’s disease (AD). These findings may imply that poor resilience to psychological stress is not simply a characteristic of dementia, but may reflect mechanisms involved in disease etiology. In this study, we examined the level of neural activity as a potential mechanism of linking individual susceptibility to psychological stress and AD‐related neuropathology across the spectrum of AD.

Methods

A total of 166 participants (mean age = 74.21; 90 Females) spanning diagnostic spectrums along cognitively normal (CN) individuals and AD patients was selected for analysis from the ADNI2 database based on the availability of resting state fMRI and AV45 PET data. Neural activity was quantified by applying the amplitude of low frequency fluctuations (ALFF) method to time series of fMRI blood oxygenation‐level‐dependent signals (in the frequency range of 0.01‐0.08 Hz) obtained during resting‐state fMRI (rsfMRI) scan. Amyloid pathology was quantified by AV45‐SUVR measures that were normalized to the cerebellum. Mini‐Mental State Exam (MMSE) and the total Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores were used as cognitive and stress susceptibility measures.

Results

Behavioral measures of stress were significantly associated with brain Aβ indices and neural activity across the entire cohort, spanning from CN older adults to AD patients (ps<0.05). Relationships between the neural activity, stress responses, and Aβ deposition, however, differ by diagnostic groups. As stress indicators increased, CN subjects exhibited increased activity in several brain regions including the regions within the default mode network (DMN), while AD participants exhibited decreased activity across the brain. Moreover, as brain Aβ load increased, CN participants experienced DMN hyperactivity, while AD participants experienced hypoactivity.

Conclusion

These results indicate a potential link between heightened stress responses and increased susceptibility to the development of AD pathologies through neuronal hyperactivity, especially in the preclinical stage of AD. Alleviating stress and regulating stress responses may be important modifiable factors and intervention strategies that could help prevent and intervene the development of AD pathology.
Development of an Algorithm for Real‐time Delivery of Automated Intervention Boosters to Support Long‐term Use of an Electronic Memory Aid
Authors: Schmitter‐Edgecombe Maureen , Luna Catherine , Farias Sarah Tomaszewski , Cook Diane J
Published: December 2023

Background

Electronic memory aids can facilitate positive health outcomes in older individuals experiencing memory difficulties. Despite this, long‐term maintenance of device use is often limited. Delivery of automated boosters has the potential to enhance use of these aids and retention of compensation training goals, but questions remain regarding optimal timing of boosters. For example, if delivered too frequently recipients will habituate. Here we describe our process for developing an automated schedule that will detect when use of an electronic memory aid has started to decline so that an automated booster can be delivered. We start by unobtrusively observing use patterns and generating initial delivery rules based on clinical judgement, and then apply these rules to develop an automated algorithm.

Methods

We used three months of post‐training data from 28 older adults with mild cognitive impairment who learned to use an electronic memory and management aid (EMMA) application. Two clinicians examined graphs of each users’ daily interactions with EMMA to identify specific days when device interactions had declined and iteratively developed a set of rules that identified the best time points to deliver boosters. The algorithm was then applied to data from an entirely different cohort of 50 older adults engaged in an intervention utilizing the EMMA app. We then compared when the clinician would have boosted vs when the algorithm would deliver a boost.

Results

Following 4 iterations of clinicians examining graphs with possible boost points from the first set of users, an algorithm was developed. When applied to the second data set, the algorithm identified 371 boost points, with a false positive rate of 11% and false negative rate of 3%. It was also deemed that the timing of approximately 28% of the correctly identified boost points by the algorithm were off by +/‐ 2 days.

Conclusion

Next steps will be to further modify the algorithm and then formally test the impact of boosts at different time points to empirically evaluate their impact on usage. Our ultimate goal is to deliver boosters in real time and as early as possible when usage wanes to improve intervention outcomes.
APOE‐4 dependent dysfunctional neutrophil‐microglia crosstalk accelerates Alzheimer’s disease
Authors: Rosenzweig Neta , Kleemann Kilian , Grucci Madeline , Aronchik Micheal , Butovsky Oleg
Published: December 2023

Background

APOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The role of human APOE variants in AD has been studied extensively in the regulation of brain cells but not in peripheral immunity. APOE is also expressed in neutrophils and controls their activation. Moreover, neutrophils have been shown to play a negative role in AD mice via the induction of neutrophil extracellular traps (NETs)

Method

Here we aimed to dissect the impact of APOE4‐neutrophils on AD pathology, using Ly6g‐CRE mice crossed to APOE‐KI(E3 and E4)fl/fl:APP/PS1.

Result

We identified a cell intrinsic role of APOE3 in controlling neutrophil maturation and degranulation, which is exacerbated in APOE4‐KI neutrophils and reduced in APOE4‐KO neutrophils. Moreover, APOE4 neutrophils accumulated in the brains of AD mice and in AD patients, associated with microglia at sites of plaque pathology. Here we show that genetic deletion of APOE4 in neutrophils suppressed their activation and reduced their recruitment to the brains of APP/PS1 mice. RNAseq analysis showed increased proportion of disease associated microglia (DAM/MGnD) in APP/PS1: Ly6g‐CRE:APOE4fl/fl mice, associated with reduced plaque pathology. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers. Our findings show that APOE4‐induced inflammatory neutrophils are recruited to the diseased brain and impair MGnD response leading to accelerated AD pathology.

Conclusion

Taken together, these findings identify a cell‐intrinsic role of APOE4 in the induction of hyperactivated neutrophils recruited to the brain, which may provide new molecular targets to modulate and restore functional microglia in AD.
Domestic Environment of Multisensory Stimulation based on Snoezelen principles pilot study
Authors: Mauricio Beatriz Zima Borsari , Novelli Marcia Maria Pires Camargo
Published: December 2023

Background

Multisensory stimulation (MSS) aims to stimulate the senses such as vision, hearing, touch, taste, smell, vestibular and proprioceptive systems that may be areas affected by dementia. The 24‐hour Snoezelen spaces in home environments aim to offer a proposed MSS intervention for seniors with dementia syndromes. In addition, studies on this therapy, its benefits and effects both for the elderly living in the community and for their caregivers/family members, are scarce.

Objective

To understand and evaluate the benefits of Snoezelen sensory stimulation in home settings of community‐dwelling elderly.

Materials and Methods

The 24‐hour Snoezelen intervention will be conducted over three/four months, in 9 sessions. The sessions will be organized in stages: The 1st stage, involves the evaluation process, performed in the 1st week, which will consist of two evaluation sessions that include home assessment, establishment of sensory preferences and sensory profile of the elderly. The 2nd stage will be carried out from the 2nd to the 5th week with the implementation of the 24‐hour Snoezelen sessions that aim to teach caregivers how to use the Snoezelen space with two focuses: stimulation and relaxation. The initial session will be determined by the demands presented by the caregiver and the elderly regarding the need to start with a relaxation or stimulation session. The third stage involves the follow‐up of the implementation of the post‐training sessions for caregivers that will be developed from the 6th to the 9th week with 3 sessions. The interval between the 3 sessions will be 15 days so that the caregivers can practice what they have learned during the training. To analyze the impact of the Home Spaces of MRE the effect size will be used considering the averages in the NPI before and after the Intervention. Measures of variance will be applied to evaluate the impact of MRE home stimulation in relation to time (pre‐ and post‐intervention). The degree of significance was set to values of p<0.05

Result: And Conclusion

The study in question is in progress and the results and conclusion will be presented at the congress.
Associations of Beta‐amyloid and Alzheimer’s Disease Risk with Patient Age in Over 2,000 Plasma Specimens Analyzed by LC‐MS/MS
Authors: Weber Darren M , Kim Jueun C , Goldman Scott , Clarke Nigel J , Racke Michael K
Published: December 2023

Background

Beta‐amyloid (Aβ) plays an important role in Alzheimer’s disease (AD) pathology with Aβ42/40 ratio being an indicator amyloid deposition. Measurements have been performed using cerebrospinal fluid specimens, but now plasma assays are available as less invasive options. Our objective was to evaluate associations of age with Aβ40, Aβ42, and AD risk assessed using the Aβ42/40 ratio in >2,000 plasma specimens measured by LC‐MS/MS.

Method

Results from plasma specimens submitted to our laboratory for AD risk assessment were used for this analysis. Both peptides were quantitated using a CLIA‐validated LC‐MS/MS assay, and the ratio of Aβ42 to Aβ40 (Aβ42/40) was calculated. Using a ratio cutoff of 0.160, individuals were categorized as being at higher risk (HR) of developing AD (Aβ42/40 <0.160) or lower risk (LR) of developing AD (Aβ42/40 ≥0.160).

Result

Results from 2,235 specimens (58% female) were analyzed. Overall, 987 (44.2%) individuals were classified as being at HR for AD. An inverse relationship between age and the Aβ42/40 ratio (Spearman’s rho = ‐0.249, p <0.001) was observed; on average, the Aβ42/40 ratio decreased 3% per decade of age. Individuals who were HR for AD were older than those who were at LR for AD (mean [SD] age, 74.4 [9.0] vs. 69.2 [12.6], p <0.001). Aβ42 values were lower in the HR group compared to the LR group (38.5 [11.4] pg/mL vs. 44.7 [11.1] pg/mL, p <0.001), whereas Aβ40 values were higher in the HR individuals compared to LR (267.3 [76.3] pg/mL, vs. 245.9 [57.8] pg/mL, p <0.001). Both Aβ40 and Aβ42 values increased with age: on average, Aβ40 increased 7% per decade (Spearman’s rho = 0.415, p < 0.001), and Aβ42 increased 4% per decade (Spearman’s rho = 0.213, p < 0.001).

Conclusion

In this cohort, we found almost 45% of individuals were HR for AD based on Aβ42/40 ratio. With respect to patient age, we found significant associations with risk reflecting decreases in Aβ42/40 ratio in plasma. We also found increases of both Aβ40 and Aβ42 plasma concentrations with age but at different rates; the rate of increase was almost double for Aβ40 compared to Aβ42.
Non‐invasive kinetic modeling of [18F]‐florbetaben and [18F]‐PI‐2620 with total‐body dynamic EXPLORER PET
Authors: Holy Emily Nicole , Li Elizabeth , Alfaro Evelyn Rebekha , Fletcher Evan , Bhattarai Anjan , Spencer Benjamin A. , Cherry Simon R. , Decarli Charles , Fan Audrey
Published: December 2023

Background

This study aims to quantify amyloid and tau buildup in older individuals with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and [18F]‐PI‐2620 total‐body EXPLORER PET.

Method

Fifteen adults (9 CU, 2 MCI, and 3 AD) aged 66‐86 underwent dynamic total‐body 18F‐florbetaben [110min] and PI‐2620 PET [90min] (United Imaging). 3 CU adults also underwent Tau PET for this initial analysis. IDIFs were derived from descending aorta ROIs. PET volumes were motion corrected (FSL‐MCFLIRT) and linearly registered (FSL‐FLIRT) to T1W image. The DKT ATLAS was used to segment brain cortical regions that are involved in neurodegeneration for PET SUVR measurements. PET SUVR means were calculated from 10 index regions and the cerebellar gray matter as the reference. Dynamic time activity curves were fit to the two‐tissue compartment model (2TCM) using joint estimation and population metabolite‐corrected IDIFs (Li, JNM 2021). The Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).

Result

[18F]‐Florbetaben Aβ+/Tau‐ SUVR was the highest in each brain index region, while PI‐2620 showed elevated SUVR in brain regions associated with early Braak stages I‐III in both Aβ‐/Tau‐ and Aβ+/Tau‐ (Fig 2). In our tau‐negative cohort, PI‐2620 signal in both cortical and reference regions, as expected, had low specific distribution volume (Vs) values (1.43 ±0.56) in both HC and AD. [18F]‐Florbetaben cortical Vs values were roughly 4 times higher than cerebellum in the Aβ+/Tau‐ (AD) individual and PI‐2620 cortical Vs values were 3.5 times higher compared to the cerebellum in both HC and AD. Mean k₁ values, which reflect regional blood flow, were similar in both AD and HC in both [18F]‐florbetaben and PI‐2620 PET analyses (Table 1). SUVR and DVR from MRTM kinetic models were correlated for each tracer; with slight overestimation of SUVR compared to DVR.

Conclusion

Absolute quantification of amyloid and tau binding from total‐body PET data is feasible using aorta IDIFs and enables high quality kinetic modeling for accurate measures in clinical research of aging and dementia.
Use of Inflammatory Panels to Distinguish Alzheimer’s Disease in a Down Syndrome Population
Authors: Petersen Melissa , Zhang Fan , Hall James , Mapstone Mark , O'Bryant Sid E.
Published: December 2023

Background

Proteomic profiles conducted among adults with Down Syndrome (DS) have shown to be strongly driven by inflammatory markers particularly for models conducted among those with Alzheimer’s Disease (DS‐AD). This corresponds to other work that has suggested inflammatory markers could serve as non‐A/T/N blood based biomarkers for DS‐AD. To date, no work has examined the utility of specific panels of inflammatory proteins in their ability to distinguish between cognitively unimpaired (CU), mild cognitive impairment (MCI‐DS) and AD dementia (DS‐AD) among adults with DS.

Method

Data were analyzed on n = 598 participants (n = 431 CU, n = 73 MCI‐DS, and n = 94 DS‐AD) from the Alzheimer’s Biomarker Consortium‐ Down Syndrome (ABC‐DS) cohort. Inflammatory blood biomarkers were derived using the Meso Scale Discovery (MSD) platform with ECL. Inflammatory biomarkers were group as follows: Pro‐Inflammatory Panel (Interleukin [IL]‐18, IL‐5, IL‐6, IL‐7, SAA, sICAM1, TARC, TNC, TNFa) and General Inflammatory Panel (A2M, B2M, CRP, Eotaxin3, I‐309). Statistical analyses were conducted using support vector machine (SVM) models with inflammatory blood biomarkers entered as the predictor variable and diagnostic classification entered as the outcome variable.

Result

In distinguishing CU from DS‐AD, the pro‐inflammatory panel produced an area under the curve (AUC) of 88%, sensitivity (SN) of 91%, specificity (SP) of 68%, and negative predictive power (NPV) of 94% with age and gender. The general inflammation panel produced a similar AUC of 88%, SN of 89%, SP of 75%, and NPV of 97% with age and gender. When applied to distinguish CU from DS‐AD and MCI‐DS combined, the pro‐inflammatory panel produced an AUC of 86%, SN of 89%, SP of 67%, and NPV of 94% with age and gender. The general inflammatory panel also distinguished the same groups with an AUC of 85%, SN of 88%, SP of 69%, and NPV of 93%.

Conclusion

Both the pro‐inflammatory and general inflammatory panels produced similar AUCs ranging from 85‐88% in distinguishing either DS‐AD or MCI‐DS and DS‐AD from CU with NPVs ranging from 93‐97%. As most screening tools rely on high NPVs, results support the potential application of an inflammatory driven panel in distinguishing diagnostic cases in this specific population.