bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual patient data meta‐analysis assessing the adverse event profile of Alzheimer dementia randomized clinical trials
Authors: Langford Oliver , Cummings Jeffrey L , Schneider Lon S , Rafii Michael S , Ernstrom Karin , Aisen Paul S , Raman Rema
Published: December 2021

Background

Regular reporting and monitoring of Adverse Events (AE) and Serious Adverse Event (SAE) are a crucial part of all randomized, controlled clinical trials, providing an assessment of the intervention’s safety profile. This process of adverse event surveillance is critical for participant’s safety and data quality. Knowledge and previous experience from Alzheimer’s disease (AD) trials is necessary in order to assess whether an AE/SAE is currently observed in a trial can occur (and at what frequency) in the placebo arm of the study or may be unique to the test agent. The overarching aim of this project is to evaluate the AE profile observed in the placebo arms in AD randomized clinical trials through a systematic review and meta‐analysis.

Method

We evaluated the safety profiles in placebo‐arm AD trials, we combined Individual Patient Data (IPD) using AE and SAE data from completed randomized clinical trials (RCT) AD trials conducted by the Alzheimer’s Disease Cooperative Study (ADCS). We used descriptive statistics, summarizing baseline participant demographics and AE patient level outcomes at the study level. Meta‐analyses using a Negative‐Binomial model were undertaken to determine the pooled risk ratios (RR) of AE and SAE rates.

Result

The placebo arms of five 18‐month RCTs were included in this meta‐analysis with a pooled sample size of 749 participants. The estimated number of adverse events per participant across the five studies ranged from 1.93 events to 7.05 events per participant. Meta‐analysis of the total number of AEs a participant experiences for the duration of an 18‐month trial was estimated to be 3.85 events (95% confidence interval: (1.54, 9.32)). Similar analyses on the number of SAEs a participant is expected to experience was 0.18 events (0.04, 0.94) per participant.

Conclusion

The IPD meta‐analysis models give an indication of the AE profiles we can expect to observe in the placebo arm of future AD trials. We will extend this work by looking at AE classification types and what common types of AEs occur across trials.
Factors influencing medication adherence among U.S. Medicare beneficiaries with Alzheimer’s disease and related dementia (ADRD)
Authors: Pilonieta Giovanna , Pisu Maria , Martin Roy C , Shan Liang , Kennedy Richard E , Oates Gabriela , Kim Young‐Il , Geldmacher David S
Published: December 2021

Background

For persons with ADRD, access to specialist physicians facilitates appropriate medication use and adherence with treatment. Our objective was to ascertain whether system‐level factors, including availability of specialty physicians predicts ADRD medication adherence among community‐dwelling older adults.

Method

We conducted secondary analyses of claims data for Medicare beneficiaries with ADRD in 2013‐2015. Medication adherence was measured using the proportion of days covered (PDC); i.e., ratio of days with ADRD prescriptions over total days of follow‐up. Adherence was defined as PDC >=0.8. Multivariable‐adjusted Modified Poisson regression was used to examine associations of adherence with physicians' availability (defined as number of neurologists and psychiatrist per 1K county population from Area Health Resources File [AHRF]). Analyses adjusted for predisposing factors (sex, race, and age); enabling factors (Medicare/Medicaid dual eligibility, Area Deprivation Index), need factors Alzheimer's disease vs. other) and comorbidities. Context level characteristics from AHRF included county‐level education, urban/rural residence, income/poverty indicator, and mental health professionals shortage area. Because the “Deep South” (DS) region of the US has a shortfall of specialists, we also considered geographic location.

Result

We identified 54,194 Medicare Beneficiaries. The race/ethnicity distribution of the sample was 81.44% white, 9.17 % black, 6.24 % Hispanic, 2.25 % Asian, and 1% other; 71.8 % were female, and 42.36% were >85 years. Bivariate analyses revealed significant differences between DS and non‐DS in all individual and contextual characteristics except sex and comorbidities. Specialists' availability was not significantly associated with adherence to ADRD medication: Neurologists RR: 1.0080, CI (0.9789‐1.0380) and Psychiatrists RR: 1.0066 CI (0.9948‐1.0186). Age, dual eligibility, and living in non‐large metropolitan areas were associated with a higher probability of adherence. Race, comorbidities, having ≥1 visit with specialists, and context factors such as living in deprived and lower education areas were associated with a lower probability of adherence.

Conclusion

Adherence to ADRD medications was not associated with specialist availability but was related to individual and socioeconomic context factors in community‐dwelling older individuals with ADRD. Research should continue ascertaining factors that may influence medication adherence, particularly communities with a higher prevalence of ADRD risk factors, a greater proportion of minorities and socially at‐risk people, and health disparities.
Six months interim analysis of the phase 2 study of AL001 in frontotemporal dementia patients carrying a granulin mutation
Authors: Jackson Sam , Yeh Felix L , Ward Michael , Rhinn Herve , Huang Julie Y. , Pappalardo Jenna L. , Liao Yijie , Hagey Mackenzie , Long Hua , Paul Robert
Published: December 2021

Background

Frontotemporal dementia (FTD) is a rare, early‐onset form of dementia and loss‐of‐function mutations in the progranulin gene (GRN) are a common cause of familial FTD. In the brain, progranulin (PGRN) is a key regulator of microglia activity and lysosomal function. AL001 is a human monoclonal IgG1 antibody that blocks and downregulates Sortilin, a receptor in the key degradation pathway of PGRN, and is being developed by Alector for the treatment of carriers of GRN mutations causative of FTD (FTD‐GRN). Restoring PGRN levels may be an effective therapeutic approach in FTD, and AL001 was shown to normalize CSF PGRN levels in GRN mutation carriers in a Phase 1 study.

Method

INFRONT‐2 is an open‐label, Phase 2 study in GRN mutation carriers to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL001 administered intravenously every four weeks. Lumbar punctures and MRI scans were performed at baseline and every 6 months. Clinical assessments were done every 3 months. Fluid biomarkers in plasma and CSF were analyzed using multiple platforms.

Result

Preliminary results demonstrated that AL001 was generally safe and well tolerated in FTD‐GRN participants in INFRONT‐2. Chronic dosing led to a sustained increase in PGRN levels to the normal range in FTD‐GRN carriers. Preliminary CSF biomarker data related to key aspects of FTD‐GRN pathophysiology, namely changes in levels of lysosomal proteins and markers of inflammation, will be presented for FTD‐GRN participants who received AL001 for 6 months. In addition, updated biomarker data related to neurodegeneration will be presented.

Conclusion

There is a high unmet need for effective therapies in FTD. AL001 is being developed for the treatment of FTD‐GRN to reduce the rate of neurodegeneration by increasing levels of PGRN and disrupting the pathophysiologic cascade associated with FTD‐GRN. INFRONT‐3 is an ongoing, pivotal Phase 3 study to evaluate if AL001 can slow or stop disease progression in carriers of GRN mutations.
Considerations for drug delivery utilizing encapsulated cells: Factors for optimal cell behavior
Authors: Mitra Sumonto , Wahlberg Lars , Linderoth Bengt , Behbahani Homira , Eriksdotter Maria
Published: December 2021

Background

Drug delivery is an important aspect for clinical therapies, but drug delivery to the brain tissue may be restricted by the blood‐brain barrier (BBB), which limits the passage of many molecules when administered peripherally. To achieve direct brain delivery of biological drugs, various techniques have been developed, including encapsulation of live cells within membranes to limit immune mediated host‐rejection (1,2), forming the basis for cell replacement therapies (3,4). Interestingly, the dynamics of cells within the encapsulated membrane (limited space) have been less understood and determinants (prolonged cell proliferation, contact inhibition, cell death, re‐population, debris clearance) which can affect cellular health and its long‐term biological function need more attention. Studying cells (NGC0211) previously used in encapsulated cell‐biodelivery (ECB) devices to treat Alzheimer’s disease (AD) patients (5), the population dynamics of cells when cultured in limited space were investigated.

Method

Human retinal epithelial cells obtained from the ARPE‐19 cell line and genetically modified to release NGF (termed NGC0211) were cultured in 35mm dishes in different conditions (serum containing or serum free) and monitored overtime using light microscope. Cells were cultured for prolonged periods (3‐4 weeks) continuously without splitting to induce space constraints and monitored under the microscope. Simultaneously, medium was changed at different intervals (weekly or every 2 days) to observe effects of nutrient deprivation. To check debris clearance, dying cells were labelled with CFSE and plated on healthy cells stained with CellMask™ Deep Red plasma membrane stain or dye. To check the impact of inflammation, NGC0211 cells were exposed to inflammatory cytokines for various time points.

Result

Cellular dynamics and morphology of NGC0211 cells changed overtime with repeated cycles of cell death and simultaneous re‐population, indicating the prime role of phasic cell proliferation to maintain a constant population. Inflammatory cytokines affected NGC0211 cell proliferation, indicating the negative impact of inflammation on cellular re‐population.

Conclusion

Long‐term stability and clinical therapy using encapsulated cells can be affected by the internal dynamics of the cells itself. Inflammation may reduce clinical efficacy by affecting cellular re‐population, thereby reducing the number of viable cells within the encapsulated device overtime.
Comparing therapeutic‐focused ultrasound (TFUS) in conjunction with bosutinib versus independent TFUS administration among Alzheimer’s patients
Authors: Habelhah Barshen , Mahdavi Kennedy D , Zielinski Margaret A , Haroon Jonathan , Kuhn Taylor P , Becerra Sergio A , Barrows Hannah R , Evans Natalie E , Spivak Norman , Whitney Michael , Mamoun Michael S , Bystritsky Alexander , Jordan Sheldon E
Published: December 2021

Background

To date, there are limited therapeutic options for the treatment or symptomatic relief of degenerative dementia [1]. There has been growing interest in the class of medications known as tyrosine kinase inhibitors, such as bosutinib, as a therapeutic intervention for dementia [2]. Ongoing clinical and preclinical trials also suggest focused ultrasound may yield therapeutic potential for patients with neurodegenerative conditions such as Alzheimer’s disease [3‐5]. Focused ultrasound may be used as an independent therapeutic intervention or adjunctively to facilitate delivery of medicine. The present study compares the efficacy of focused ultrasound as an independent intervention to the efficacy of focused ultrasound combined with bosutinib, using several outcome measures to demonstrate accuracy.

Methods

Structural and functional imaging were used to navigate cerebral and subcortical ultrasound targets for 13 patients (9 female; Mage = 72.08 years, SDage = 9.30 years), 7 of which received therapeutic ultrasound as an independent intervention, and the remaining 6 received both therapeutic ultrasound in conjunction with bosutinib. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Montreal Cognitive Assessment [MoCA].

Results

The combination of therapeutic ultrasound with bosutinib was associated with 66% of patients maintaining or improving their Clinical Dementia Rating scale during the eight‐week protocol, whereas therapeutic ultrasound as a stand alone intervention showed 43% of patients maintaining or improving their Clinical Dementia Rating scale. Similarly, 67% of patients who underwent the combination intervention maintained or improved their MoCA scores, and of the patients who only received therapeutic ultrasound, 57% maintained or improved their MoCA scores.

Conclusions

The results of these comparisons suggest a combination of medication and therapeutic ultrasound may have a more positive outcome than therapeutic ultrasound alone. Clinical studies have shown that this ultrasound technology has been successfully applied for small molecules [6]. This technique of tailored targeting for each patient’s brain in conjunction with medication may represent a significant advancement to the field. Future studies should explore this combination.
The effect of missing cognitive data on the detection of bias due to hearing impairment in cognitive testing
Authors: Nichols Emma , Deal Jennifer A , Swenor Bonnielin K , Abraham Alison , Griswold Michael E , Lin Frank R , Mosley Thomas H , Reed Nicholas S , Sharrett Richey , Gross Alden L
Published: December 2021

Background

Methods for the detection of bias in cognitive testing disentangle underlying cognitive ability from cognitive test performance. These methods have been previously used to understand how language of administration, sex, education, or sensory impairment status might bias cognitive test scores. Although missing data is common in cognitive testing, prior research on bias in cognitive testing has not addressed or accounted for missing data. This work aims to describe and understand how missing data effects the detection of bias in cognitive testing.

Method

We utilized real‐world data from Visit 6 (2017‐2019) of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC‐NCS) (N = 3580), which included a thorough neuropsychological battery. We used item response theory methods to test for item‐level biases (differential item functioning) by hearing impairment (PTA>25 db in 4 speech frequencies). We examined the effect of imposing 10%, 30%, or 50% missingness in cognitive test items that was either (1) random or (2) related to cognitive performance, among those with hearing impairment.

Result

In the ARIC‐NCS sample (mean age: 79.9, 60% female), 73% had hearing impairment. When we imposed missingness that was unrelated to cognitive status, we saw no systematic error in the detection of item‐level biases. However, imposing missingness that was related to cognitive status did result in systematic error in item‐level bias detection. The magnitude of this error was larger with greater amounts of missing data, such that the median error across all cognitive items in the detection of item‐level bias considered for the scenarios with 10%, 30%, and 50% missing data was 0.03, 0.07 and 0.13 logits respectively, resulting in flipped inferences for 21%, 32% and 44% of tests.

Conclusion

Missing data related to cognitive status may lead to error and incorrect conclusions regarding bias in cognitive testing. This has the potential to result in incorrect decisions regarding the construction and analysis of cognitive testing data in epidemiologic studies of cognition and cognitive decline. When evaluating for item‐level biases in cognitive testing, careful consideration regarding the amount and patterns of missingness present in cognitive test data is necessary.
BMI across the lifespan and midlife cognitive function: The Bogalusa Heart Study
Authors: Bazzano Lydia , Gwizdala Kathryn L , Carmichael Owen T , Newton Robert L
Published: December 2021

Background

Greater adiposity in middle age or earlier has been associated with both poorer and greater cognitive functioning late in life, as well as greater and poorer risk of AD (Buchman et al., 2005; Cournot et al., 2006; Sturman et al., 2008), but prior studies were primarily conducted on populations with low African American representation and have scarce data with adolescent BMI. Therefore, this investigation examined the association between adiposity from early life to mid‐life and mid‐life cognition in a bi‐racial, semi‐rural Deep Southern epidemiological cohort.

Method

The Bogalusa Heart Study has followed participants from childhood to adulthood since 1973. Adiposity (i.e., BMI), was collected at roughly biannual visits from 1973 to today and cognitive measures were collected between 2013‐2016. Cognitive measures (n = 1295) included memory, executive function (EF), and global cognition. BMI was averaged within specific age epochs (<20 (adolescent), 21‐40 (early adulthood) and >40 (adulthood). BMI within adolescence was converted into percentiles (Kuczmarski et al., 2002). Separate linear regression models were run with BMI, sex, race, and education as predictors, and each cognitive measure as outcomes.

Result

Greater BMI within the adolescent and early‐adulthood epochs was associated with greater memory performance (Average Est. 0.006, p ≤ 0.045). None of the BMI measures in any epoch were associated with global cognition or EF.

Conclusion

Although a large body of evidence has shown that greater adiposity is associated with a wide variety of adverse health outcomes, in this study greater adiposity in adolescence and young adulthood was associated with better memory performance in mid‐life. Although paradoxical, these results are aligned with several prior studies of similar longitudinal design and racial composition. Higher‐fidelity measurement of adiposity (e.g., subcutaneous vs. visceral fat) could help clarify the complex relationship between adiposity and cognitive function.
Updated treatment of dementia with bosutinib: An open‐label study of a tyrosine kinase inhibitor
Authors: Zielinski Margaret A , Mahdavi Kennedy D , Kuhn Taylor P , Pereles F. S , Bystritsky Alexander , Whitney Michael , Kesari Santosh , O'Connor Ed , Gross Hyman , Barrows Hannah R , Haroon Jonathan , Habelhah Barshen , Chang Marissa , Jordan Sheldon E
Published: December 2021

Background

A 2020 publication from Mahdavi and colleagues reported on clinical status changes observed among a sample of 31 older adults with neurodegenerative conditions who completed 12 months of bosutinib therapy. This abstract provides updated results for an additional 21 patients who have completed the 12‐month regimen since the time of the initial publication. This study pursues and updates data on an effective therapeutic intervention for dementia using TKI’s such as bosutinib.

Method

52 patients with probable Alzheimer’s dementia (AD) or Parkinson’s spectrum disorder with dementia (PDD) completed 12 months of bosutinib therapy. The Clinical Dementia Rating scale (CDR) as estimated by the Quick Dementia Rating System (QDRS) was the primary cognitive status outcome measure.

Results

For the updated sample size of 52 individuals who have completed the protocol, bosutinib was associated with improved CDR scores for 40% of participants (36% AD, and 46% PDD); bosutinib was also associated with clinically stable CDR scores for 38% of patients (36% AD, and 46% PDD). After completion of the protocol intervention, 29% of the AD population yielded decreased CDR scores while only 8% of PDD patients had decreased CDR scores.

Conclusion

These results update findings from the previously reported study (Mahdavi et al., 2020) and continue to warrant further investigation of bosutinib as a potential therapeutic agent for dementia. The data continue to suggest an overall positive or stable outcome among participants after a year of bosutinib, with a clinical improvement rate of approximately 40% and a 38% rate of clinical stabilization. This observation remains consistent regardless of severity of cognitive impairment at baseline. We expect to report on an update for an additional 30 participants in the next year.
Associations between long‐term air pollution exposure and plasma amyloid beta in very old adults
Authors: Park Christina , Hajat Anjum , Leary Cindy S. , Ilango Sindana , Semmens Erin O. , Adam Claire , Fitzpatrick Annette L. , Lopez Oscar L. , Kaufman Joel D.
Published: December 2021

Background

Animal studies suggest associations between exposure to air pollutants and increased amyloid beta (Aβ) pathology. However, there is limited research evaluating the relationship of air pollution to Aβ levels in human populations. Therefore, this study examined the role of long‐term air pollution exposure in plasma amyloid levels in a US cohort of older adults.

Method

This cross‐sectional study included participants from the Ginkgo Evaluation of Memory Study, a longitudinal cohort of older adults (aged 75 years and older) recruited from four US communities who were dementia free at baseline. Plasma Aβ1‐40 levels were measured in 2000‐2002 and again in 2007‐2008 and log transformed for analyses. We applied validated fine‐scale spatiotemporal models to estimate fine particulate matter (PM2.5), coarse particles (PM10) and nitrogen dioxide (NO2) at participant residential addresses. Address history was constructed up to 20 years prior to visit dates using LexisNexis, a commercial credit reporting company. Exposure to air pollutants was averaged over multiple time periods (from one to 20 years) prior to plasma collection. We estimated percent differences (95% CIs) from ordinary least squares and linear mixed‐effect regression models for baseline and repeated measures data, respectively. All models were adjusted for age, race, gender, site, education, treatment, cystatin c, neighborhood deprivation index, alcohol intake, smoking status, pack‐years of smoking, passive smoke exposure and gait speed.

Result

This study included 3,029 participants with measured Aβ1‐40. A 3 µg/m3 (interquartile range (IQR)) higher PM10 over 10 years was associated with higher levels of Aβ1‐40 at baseline: percent difference 1.80% (95% CI: 0.22%, 3.40%). We also observed a positive association of increased magnitude in repeated measures analyses: percent difference 5.20% (95% CI: 3.69%, 6.72%). Similar associations between PM2.5 (IQR = 2 µg/m3) and NO2 (IQR = 7 ppb) and Aβ1‐40 were found in repeated measures analyses. Findings from other pollutants and exposure periods are presented in Figure 1.

Conclusion

These findings provide some of the first epidemiologic evidence suggesting long‐term concentrations of PM2.5, PM10 and NO2 are associated with increased Aβ1‐40.
A machine learning enrichment strategy for presymptomatic cohorts in Alzheimer’s disease clinical trials
Authors: Tam Angela , Laurent César , Noriega de la Colina Adrián , Gauthier Serge , Dansereau Christian
Published: December 2021

Background

It is challenging for Alzheimer’s disease trials to enroll presymptomatic individuals who are likely to decline cognitively. We propose using a multimodal machine learning approach to discriminate between cognitively normal individuals who progressed to mild cognitive impairment (MCI) and those who remained stable over 48 months.

Method

Patterns of gray matter distribution, derived from structural MRI, associated with either healthy aging or Alzheimer’s disease were extracted from AIBL [1] (n=401). We processed images from 823 individuals deemed cognitively normal at baseline from NACC [2] (n=433), ADNI [3] (n=260), and OASIS‐3 [4] (n=130) and generated scores representing the spatial similarities between the gray matter distribution of each individual to the patterns produced from AIBL. Gray matter scores, MMSE, CDR‐SB, FAQ, APOE4 status, education, age, and sex were used to train a machine learning prognostic pipeline using the Foresight platform (Perceiv Research Inc.) to distinguish individuals who received a MCI diagnosis within 48 months from baseline (progressors) from those who remained stable. The model was trained and tested with 5‐fold inner‐loop cross‐validation.

Result

The model achieved a mean (± std) AUC of 0.752±0.045, accuracy of 70.72±2.44, sensitivity of 62.51±12.12, and specificity of 71.82±3.87. The predicted progressors experienced a steeper cognitive decline, tended to be older, and contained a higher proportion APOE4 carriers and amyloid positive cases, compared to stable individuals. Of the predicted progressors, 33.3% were true progressors. This represents a nearly two‐fold enrichment of progressors over the prevalence of the entire sample where only 17.7% were true progressors.

Conclusion

An automated algorithm can successfully identify presymptomatic individuals with impending cognitive impairment. This tool can enhance trial enrollment by targeting individuals who are at the highest risk of cognitive decline and potentially reduce trial costs by minimizing the need for prohibitively large sample sizes.

[1] Australian Imaging Biomarkers and Lifestyle Study of Ageing (aibl.csiro.au).

[2] National Alzheimer’s Coordinating Center (naccdata.org). [3] Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). [4] Open Access Series of Imaging Studies (oasis‐brains.org).
Significance of the in vivo endocannabinoid level to predict effectiveness of lifestyle multidomain intervention: The SUPERBRAIN study
Authors: Lee Sun Min , Park Sun Ah , Kim Joonseok , Kim Sue Min , Han Song Mi , Song Hong‐sun , Chun Buong‐O , Choi Muncheong , Hong Chang Hyung , Park Yoo Kyoung , Na Hae Ri , Kim Byeong C. , Park Kyung Won , Park Hee Kyung , Jeong Jee Hyang , Choi Seong Hye , Moon So Young
Published: December 2021

Background

In the South Korean study to prevent cognitive impairment and protect brain health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we explored changes of in endocannabinoid after 24‐week intervention and impact of baseline endocannabinoid on cognitive and physical effects of intervention.

Method

A total of 152 participants, aged 60‐79 years without dementia but with ? 1 modifiable dementia risk factor, were randomly assigned to the facility‐based multidomain intervention (FMI), and home‐based MI (HMI), or control groups. Among them, 125 participants (43 FMI, 44 HMI, and 38 control) took measurement for their levels of cortisol, anandamide (N‐arachidonoylethanolamine; AEA), and 2‐AG (2‐arachidonoylglycerol). Plasma levels were determined by liquid chromatography‐selected reaction monitoring quantification using a QTrap5500 mass spectrometer (ABSciex, Foster City, CA, USA). We compared changes of compound levels between intervention and control groups. In addition, we analyzed whether the baseline level of the compound was independent predictor for changes in clinical measures after intervention.

Result

Neither the ratios, cortisol to AEA + 2‐AG, cortisol to AEA, and cortisol to 2‐AG nor the levels in AEA, 2‐AG, and cortisol showed noteworthy differences before and after the SUPERBRAIN program, between control and intervention groups. Some changes in the physical fitness and cognitive function variables were associated with the baseline AEA and cortisol, especially in the intervention group: Figure‐8‐walks (p<0.05),and ‘pre‐contemplation stage’ score of the readiness to change questionnaire for motivational enhancement (p<0.05) for cortisol; Prospective Retrospective Memory Questionnaire (PRMQ) by caregiver (p<0.05), and total scale index score of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, p<0.05) for AEA; ‘Confirmed control’ score of the questionnaire for motivational enhancement (p<0.05) for both. Among them, intervention status and baseline AEA seemed to be possible independent variables for changes in two cognitive function items, PRMQ by caregiver and total scale index score of RBANS. However, further analysis showed no interaction between intervention status and baseline AEA level on cognitive function.

Conclusion

Baseline level of in vivo endocannabinoids may predict the cognitive change after a multidomain dementia prevention intervention program, though its modulation on multidomain dementia prevention intervention for cognitive effects needs to be more revealed.
Using motion‐based technology to measure movement confidence among people with dementia and mild cognitive impairment
Authors: Dove Erica , Zabjek Karl , Wang Rosalie , Astell Arlene J.
Published: December 2021

Background

Movement confidence is defined as “a person’s feeling or sense of adequacy in a movement situation.” It is proposed that those who are ‘movement confident’ are more likely to partake in movement situations (e.g., exercise) and enjoy doing so. However, the concept and measurement of movement confidence has not been explored among people with dementia and MCI, who can benefit from participating in activities involving physical movement, such as exercise.

Method

Participants with dementia and MCI (n=28; 53.6% female) were recruited from four community‐based adult day programs to participate in a 10‐week Xbox Kinect bowling intervention to see whether the intervention impacted their balance, movement confidence, and cognition. As part of the data collection procedure, video recordings were taken during the first, middle, and final week of the intervention and coded using video analysis software, to measure movement confidence. Count and percentage data were examined, and the coding scheme used to create a categorical measure of movement confidence. Count, percentage, and categorical data were analyzed descriptively and also compared across the study using a series of related‐samples Wilcoxon signed rank tests.

Result

Among those who completed the study, movement confidence was high at the start and did not significantly decline over time (Z‐score=‐0.359, p=0.719), suggesting a potential maintenance effect of the intervention. Various behaviours signifying movement confidence during the motion‐based activity, such as hip shifting, knee bending, change in base of support, and willingness to move were captured using both the movement confidence coding scheme and categorial measure. The coding scheme, categorical measure, and implications will be further described.

Conclusion

This study is the first to examine the complex construct of movement confidence among people with dementia and MCI, paving the way for future investigations. This study is also the first to create an observational, categorical measure of movement confidence which could potentially be used by clinicians (e.g., physiotherapists) to quickly score the movement confidence of people with dementia and MCI in various movement situations.
Effect of CSF biomarkers on cortical thickness in males and females
Authors: Sangha Oshin , Lee Sieun , Ma Da , Popuri Karteek , Wang Lei , Beg Mirza Faisal
Published: December 2021

Background

The level of elevated Tau, phosphorylated Tau, and aggregated Amyloid β in the cerebrospinal fluid (CSF) are markers of Alzheimer’s pathology in the brain. In this study, we analyzed how these CSF biomarkers are related to the cortical thickness in males and females, for subjects who are cognitively normal (CN), with mild cognitive impairment (MCI), and diagnosed as Alzheimer’s disease (AD).

Method

We studied the CN (305), MCI (264) and AD (230) subjects from the ADNI dataset at baseline. We first studied the CSF biomarker level differences between males and females in all three groups. The effect of age was controlled using general linear models (GLM) We also looked at the effect of the CSF biomarkers on cortical thickness maps generated separately for males and females for all three groups, also with GLM‐based covariate regression to control the effect of age, ICV, and field strength of the scan.

Result

For the CSF biomarker levels, we observed Tau to be significantly higher in females in the AD group. No other significant sex difference in the biomarker levels were observed. We found MCI males [Figure 1] and AD [Figure 2] females showing a negative relationship between Tau and thickness. When comparing CSF pTau levels to cortical thickness, a negative correlation was found only in males [Figure 3] for the AD group. When comparing Aβ and cortical thickness, negative correlations were found for males in the CN [Figure 4] and AD group [Figure 5], and for females [Figure 6] in the MCI group.

Conclusion

The results suggest that the relationship between cortical thickness and CSF biomarkers is different in males and females in CN, MCI, and AD groups. We found that there is a negative relationship between CSF biomarkers and cortical thickness.
Alzheimer’s disease‐like brain atrophy patterns after mild traumatic brain injury can be predicted based on acute cognitive deficit
Authors: Rostowsky Kenneth A. , Amgalan Anar , Irimia Andrei
Published: December 2021

Background

The neurological events that follow traumatic brain injury (TBI) can include cognitive decline, personality changes, and long‐term structural and functional effects. At the microscale, the neuropathological changes following TBI overlap partially with those seen in Alzheimer’s disease (AD). Nevertheless, our understanding of how mild TBI (mTBI) can lead to AD remains inadequate. The predictive potential of acute mTBI degeneration patterns in prognosticating the risk of AD‐like structural changes is also largely unexplored.

Method

In 66 AD patients, 33 mTBI patients and 72 healthy controls (HCs), diffusion‐weighted imaging (DWI) was used to calculate the fractional anisotropy (FA) of white matter (WM) connections and T1
‐weighted magnetic resonance imaging (MRI) was used to estimate gray matter (GM) thickness. Support vector machines (SVMs) then leveraged acute mTBI data to predict the severity of AD‐like neurodegeneration measured six months after mTBI.

Result

In both AD and mTBI, WM degeneration patterns and their extent are indistinguishable, in a statistical sense, within the fornix, corpus callosum, and corona radiata. In these structures, 78%, 35%, and 56% of their respective voxels have mean FAs which differ significantly from those of HCs for both mTBI and AD cohorts (p < 0.05). The mean FAs of these same sets of voxels are statistically equivalent across the mTBI and AD groups (p < 0.05, two one‐sided tests of statistical equivalence). mTBI and AD participants exhibit statistically significant similarities in their GM degeneration patterns, particularly within temporal poles (memory) and orbitofrontal cortices (executive function). 47% and 75% of voxels in these structures, respectively, exhibit statistical equivalence of mean FA across mTBI and AD (p < 0.05); these sets of voxels’ mean FAs are also statistically significantly different from those of HCs. SVM predictions suggest that acute post‐traumatic cognitive assessments contain information that accurately predicts AD‐like neurodegeneration patterns and severity observed chronically after mTBI (sensitivity: 0.87±0.09, specificity: 0.93±0.09; precision: 0.88±0.2).

Conclusion

Our findings suggest that mTBI‐induced atrophy can relegate the brain onto AD‐like neurodegeneration trajectories and that post‐mTBI cognitive assessments may provide early indications of AD risk after TBI.
Association of ambient air pollution and retinal layer thickness with cognitive impairment in community‐dwelling older adults: A two‐year cohort study
Authors: Fu Shin‐Syuan , Chen Jen‐Hau , Chen Ta‐Fu , Yeh Su‐Ling , Lai Liang‐Chuan , Chiou Jeng‐Min , Chen Jia‐Kun , Chen Yen‐Ching
Published: December 2021

Background

The anatomical structure is close between retina and brain. Our team for the first time found a nonlinear relationship between retinal markers and cognition (Liu et al. 2019). Exposure to ambient air pollution was also known to affect cognition. However, the relationship between long‐term air pollution, retina markers and cognition remains unclear. Therefore, we aimed to clarify this association in a community‐based prospective cohort study.

Method

Participants of this study (2015‐2019) were part of the ongoing Taiwan Initiative for Geriatric Epidemiological Research. A total of 232 older adults (≥ 65 years old) were enrolled at baseline (2015‐2017) with a two‐year follow up. Ganglion cell‐inner plexiform layer (GC‐IPL) and retinal nerve fiber layer (RNFL) thickness were measured by Cirrus High‐Definition Optical Coherence Tomography at baseline. Data of air pollutants were obtained from monitors of Taiwan Environmental Protection Administration between 1993 and 2010. Global cognition and domain‐specific cognition were assessed by a battery of neuropsychological test. Generalized linear mixed model were utilized to assess the association of retinal markers and air pollution with cognition adjusted for important covariates.

Result

We found a nonlinear association between GC‐IPL and poor logical memory over 2 years (immediate theme recall: β=‐0.30×10‐2; immediate free recall: β=‐0.22×10‐2; delayed free recall: β=‐0.17×10‐2). No association was not found between RNFL and cognition. High‐level NO2 (≥ 27.23 ppb) exposure was associated with poor logical memory (immediate theme recall: β=‐0.56; immediate free recall: β=‐0.71; delayed free recall: β=‐0.67). Similarly, high‐level O3 (≥ 41.75 ppb) exposure was associated with poor logical memory (immediate free recall: β=‐0.32). No significant association was found for other air pollutants. After stratification by levels of air pollutants, association remain non‐significant.

Conclusion

Thinning and thickening of GC‐IPL was associated with cognitive impairment over two years. Long‐term high‐level exposure to NO2 or O3 was associated with poor logical memory over the same duration. More studies are need to clarify the association between retinal markers and air pollution on the performance of cognition.
The digital mobile assessment of cognition as a quick comprehensive cognitive test for primary care
Authors: Kumar Suresh , Shah Shalin , Chalamalasetty Prasanth , Kumar Aryan
Published: December 2021

Background

The uniform standardized neuro‐cognitive test is a challenge for the primary care physician due to time constraints, interpretation, and clinical use in the daily practice for dementia care.

Method

The DMAC was given to 318 patients presenting with memory loss in the disease group and 33 patients in the control group. The DMAC was given between 35‐55 minutes after the pre‐screening test. Each domain test was bundled to give a comprehensive average score of each domain in percentage: as the person’s ability to recruit neurons in the neural circuit to perform the cognitive task. The test was given individually. The domains tested include visual, auditory, delayed recall, attention, executive, number recall, disinhibition, and working memory.

Results

Statistical analysis with a series of t‐Tests showed the diseased group (n‐318) had significantly lower scores than the control group (c‐33) with confidence interval of 95% in the following domains: visual (p < 0.001), auditory (p < 0.001), delayed recall ( p < 0.001), disinhibition (p < 0.001), attention (p < 0.001), executive function (p < 0.001), numerical recall ( p < 0.001), and working memory (p < 0.001). The average sensitivity of the DMAC across these eight domains was 84.75% while the average specificity was 59.56%.

Discussion

Neuropsychological test batteries have limitations as it takes 4 to 6 hours, which is not possible for the dementia group due to a short attention span and score interpretation is a challenge due to t‐score and z‐score reporting and selection bias of test battery. In an effort to create a comprehensive, reliable, and simple test for cognitive evaluation by a primary care physician under a controlled environment, we have created a digital mobile cognitive assessment test (DMAC) for memory loss patients with 8 common domains with simple interpretation and guidance to cognitive therapy within one software package. The DMAC has an inbuilt prescreening questionnaire to eliminate and standardize the patient selection.

Conclusion

The DMAC is an ideal cognitive test in an outpatient primary care setting as the results are also translated into cognitive therapy & training in simple digital media.
Cerebrospinal fluid and brain PET measures of synaptic density glycoprotein 2A: Biomarkers of synaptic density in Alzheimer’s disease
Authors: Mecca Adam P. , Ashton Nicholas J. , Chen Ming‐Kai , O'Dell Ryan S. , Naganawa Mika , Toyonaga Takuya , Zhao Wenzhen , Nabulsi Nabeel B. , Brinkmalm Ann , Kvartsberg Hlin , Schöll Michael , Arnsten Amy F.T. , Huang Yiyun , Blennow Kaj , Zetterberg Henrik , Carson Richard E. , van Dyck Christopher H. , Nilsson Johanna
Published: December 2021

Background

Synaptic loss is linked with Alzheimer’s disease (AD) progression and provides a novel target for exploration with fluid and imaging biomarkers. Studies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early AD. The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. This study examined the association between a SV2A measured with brain [11C]UCB‐J–PET and cerebrospinal fluid (CSF) levels of SV2A.

Method

Using [11C]UCB‐J binding to SV2A, synaptic density was measured in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT after a bolus injection of [11C]UCB‐J. Synaptic density was calculated as the distribution volume ratio (DVR) using SRTM2 with a cerebellum reference region. CSF SV2A was measured by an in‐house ELISA method.

Result

As previously demonstrated, synaptic density measured with SV2A PET was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. CSF SV2A was also reduced in participants with AD (762 ± 148) pg/mL) compared to CN participants (935 ± 134 pg/mL, P = 0.01, Figure 1). Within the AD group (n = 21), CSF SV2A was significantly correlated with synaptic density measured with [11C]UCB‐J–PET in a composite of AD‐affected regions (r = 0.65, P = 0.001, Figure 2). A regional analysis showed that CSF and PET measures of SV2A were significantly correlated broadly in the neocortex, but not in medial temporal regions such as the hippocampus, entorhinal cortex, and amygdala.

Conclusion

This study supports a previous report of decreased CSF SV2A in AD. In the primary analysis, SV2A measured in CSF and SV2A measured with brain PET were strongly correlated within a group of individuals with AD, indicating that decreases in both measures may reflect synaptic loss during disease progression. Further studies will focus on longitudinal changes in CSF and PET measures of SV2A, as well as other CSF measures of synaptic and neuronal damage to investigate the neurobiology of AD.
Alzheimer’s disease medication utilization patterns: Disparities in treatment initiation, non‐adherence, and discontinuation
Authors: Lin Paige , Daly Allan , Olchanski Natalia , Zhu Yingying , Cohen Joshua T , Neumann Peter J , Faul Jessica D , Fillit Howard M , Freund Karen M
Published: December 2021

Background

Although currently there is no disease‐modifying treatment for Alzheimer’s disease (AD), several FDA‐approved prescription drugs may ameliorate AD symptoms. This study analyzed AD‐targeted medication utilization patterns in a representative US population overall and by race and ethnicity.

Method

We analyzed use of cholinesterase inhibitors and memantine for AD, using data from the 2000‐2014 Health and Retirement Study (HRS), linked with Medicare and Medicaid claims. We examined medication initiation among newly‐diagnosed AD patients: 1) the proportion filling an AD prescription ≤90 and ≤365 days after diagnosis; 2) mean/median time from diagnosis to first AD prescription fill; and 3) AD symptom severity at treatment initiation, measured by cognitive and functional limitations. We measured AD medication non‐adherence and discontinuation rates in the year following treatment initiation. We used logistic regression to examine whether AD medication initiation, non‐adherence and discontinuation rates differed by race and ethnicity. We used HRS survey reports to compare the proportion of subjects not filling any prescription due to cost, by race and ethnicity.

Result

Among individuals with newly‐diagnosed AD (n=1,299), 26% filled an AD prescription ≤90 days and 36% ≤365 days of diagnosis. These proportions and the median time from an incident AD diagnosis to first AD prescription fill did not vary by race/ethnicity. For 3 of 4 measures, AD severity at treatment initiation did not differ across racial/ethnic groups. Of all individuals who initiated AD‐targeted treatment, 44% were non‐adherent and 24% discontinued the medication during the year following treatment initiation. Non‐Hispanic Blacks were more likely than non‐Hispanic whites to not adhere to AD medication therapy (OR: 1.50 [95% CI: 1.07‐2.09] or discontinue treatment (OR: 1.83 [95% CI: 1.27‐2.63]). More non‐Hispanic Blacks and Hispanics with AD reported ever not filling a prescription due to cost, compared to non‐Hispanic whites (42% and 40% vs. 22%, p<0.01).

Conclusion

Initiation of AD‐targeted medications among newly‐diagnosed patients was suboptimal in all ethnoracial groups, with nearly two‐thirds having no prescription for cholinesterase inhibitors or memantine during the first year post‐diagnosis. Rates of AD medication non‐adherence and discontinuation were substantial and may relate to cost and access to care.
The association of Alzheimer’s disease and cerebrovascular disease biomarkers towards the neurodegeneration of the cholinergic pathways
Authors: Cedres Nira , Ferreira Daniel , Nemy Milan , Machado Alejandra , Pereira Joana B. , Wahlund Lars‐Olof , Zettergren Anna , Teipel Stefan J. , Grothe Michel J. , Eriksdotter Maria , Stepankova Olga , Vyslouzilova Lenka , Blennow Kaj , Zetterberg Henrik , Kern Silke , Skoog Ingmar , Westman Eric
Published: December 2021

Background

To determine the contribution of amyloid pathology and tau pathology in combination with cerebrovascular pathology, towards the neurodegeneration of the cholinergic white matter projections.

Method

We included a sample of 203 cognitively unimpaired individuals derived from the H70 Gothenburg Birth Cohort Studies (all of them 70‐years‐old, 51% female). Amyloid (A) and tau (T) pathology were determined by cerebrospinal fluid levels of Amyloid‐β42/40 ratio, Amyloid‐β38 and phosphorylated tau. Cerebrovascular pathology (V) was determined by automatically segmented white matter lesions detected in magnetic resonance imaging (MRI). Cholinergic white matter projections (i.e. cingulum pathway and external capsule pathway) were modelled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis. To assess association of the markers with the integrity of cholinergic projections we used random forest regression

Result

white matter lesion burden was the most important contributor towards the neurodegeneration of both cholinergic pathways (figure 1). Levels of Amyloid‐β38 and phosphorylated tau also contributed to the cholinergic pathways, especially to the external capsule pathway. Amyloid‐β42/40 ratio levels and APOE ε4 carriership did not show substantial contribution. Females showed poorer integrity in the external capsule pathway.

Conclusion

Underlying cerebrovascular disease (V) in cognitively unimpaired elderly plays a central role in the neurodegeneration (N) of the cholinergic pathways to the cerebral cortex. Future research should elucidate the impact of cerebrovascular pathology to the cholinergic disruption and cognitive impairment in pathological populations.