bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID‐19 and older adults with Down syndrome: Presentation, complications and risk for mortality
Authors: Baksh Asaad , Strydom Andre , Sherman Stephanie , Dierssen Mara , Costa Alberto , Huels Anke ,   T21RS COVID‐19 Initiative
Published: December 2021

Background

Health conditions (including high rates of Alzheimer's disease, AD), immune dysfunction, and premature aging associated with trisomy 21 (Down syndrome, DS) may impact the clinical course of COVID‐19.

Method

The T21RS COVID‐19 Initiative launched an international survey for clinicians or caregivers on patients with COVID‐19 and DS. Data collected between April and October 2020 (N=1046) were analysed and compared with the UK ISARIC4C survey of hospitalized COVID‐19 patients with and without DS.

Result

Mortality rates in individuals with DS diagnosed with COVID‐19 showed a rapid increase from age 40 and were considerably higher in patients with DS (T21RS DS versus non‐DS patients: risk ratio (RR)=3.5 (95%‐CI=2.6;4.4), ISARIC4C DS versus non‐DS patients: RR=2.9 (95%‐CI=2.1;3.8)) even after adjusting for known risk factors for COVID‐19 mortality. Similar to the general population, the most frequent signs and symptoms of COVID‐19 were fever, cough, and shortness of breath. Joint/muscle pain and vomiting or nausea were less frequent (p<0.01), whereas altered consciousness/confusion were more frequent (p<0.01). Risk factors for hospitalization and mortality included age, male gender, diabetes, obesity, and AD, with the addition of congenital heart defects as a risk factor for hospitalization.

Conclusion

Individuals with DS and COVID‐19 present with significantly higher rates of medical complications and mortality compared to general population peers, especially from age 40. The signs/symptoms of COVID‐19 and risk factors for severe disease course are similar to the general population. Those with dementia are at even greater risk, despite being younger than typical patients with AD. Individuals with Down syndrome should be prioritised for SARS‐Cov‐2 vaccination at younger ages than their peers in the general population.
Longitudinal associations of regional cortical tau and apathy in mild cognitive impairment and Alzheimer’s disease dementia: Findings from the Alzheimer’s Disease Neuroimaging Initiative
Authors: Premnath Pranitha Y , Gonzalez Christopher , Properzi Michael J , Rosenberg Paul B. , Marshall Gad A , Gatchel Jennifer R
Published: December 2021

Background

Apathy is among the earliest and most clinically distressing neuropsychiatric symptoms (NPS) in Alzheimer’s Disease (AD). Examining the relationships between apathy and AD pathology is needed to better understand neurobiological mechanisms for therapeutic intervention that could delay disease progression. Research has shown that tau may correlate more closely with cognitive and behavioral manifestations in AD than amyloid. In the current study, we examined the relationship between regional tau burden and longitudinal change in apathy in older adults with mild cognitive impairment (MCI) and AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

Method

A total of 319 ADNI participants (233 with MCI; 86 with AD dementia; age: 75.5 ±8.2; 56% female) underwent flortaucipir (FTP) tau positron emission tomography (PET) and clinical assessment with the Neuropsychiatric Inventory (NPI) every 6‐12 months (average follow up= 39.1 months). The NPI Apathy (NPI‐A) score was examined in relation to tau PET signal in four FreeSurfer defined regions of interest implicated in AD and mood regulation: entorhinal cortex (EC), precuneus, inferior temporal cortex and rostral anterior cingulate cortex (rACC). Separate linear mixed models examined the association between NPI‐A (for each study visit) and FTP SUVR in the above regions and their interactions with time as predictors of interest. Age and sex were included as covariates.

Result

Higher precuneus, EC and inferior temporal cortex tau were each significantly associated with greater NPI‐A over time (precuneus: ß=0.0273; t=5.01; 95 % CI (0.016, 0.04); p<0.001; EC: ß=0.023; t=5.05; 95 % CI (0.014, 0.032); p<0.001; inferior temporal: ß=.018; t=4.92; 95 % CI (0.011, 0.026); p<0.001. rACC tau was marginally associated with higher NPI‐A over time: ß=.013; t=1.93; 95 % CI (‐0.00, 0.027) p=0.05.

Conclusion

These findings suggest that tau burden in brain regions associated with AD, and less so with mood regulation, is associated with increasing apathy over time in individuals with MCI and AD dementia. Further study of emergent apathy in relation to core AD pathology and other neurobiological mechanisms will provide insight into opportunities for interventions that could slow clinical progression and alleviate patient and caregiver burden.
Pharmacodynamic assessment of orally available Mas agonists
Authors: Raman Dhanalakshmi Shankara , Reyes‐Reyes Elsa M , Trial Michael , Hurst Chelsie , Hallquist Austin , Rodgers Kathleen E
Published: December 2021

Background

Oxidative stress (OS) plays a crucial role in driving Alzheimer’s disease (AD) pathogenesis. Angiotensin II (A‐II), the ligand for AT1R (pathological axis of the renin angiotensin system [RAS]), promotes the development of AD in part by increasing OS. Mas receptor and its ligand angiotensin (1‐7) (A(1‐7); protective axis of RAS) inhibits A‐II's pathological actions. Two orally available small molecule Mas agonists, RASRx1902 and RASRx1911, were developed to overcome shortcomings of A(1‐7). Both RASRx1902 and RASRx1911 reduce brain OS 90 days after transaortic constriction surgery (TAC), suggesting that both drugs might reduce neurodegeneration. To understand their pharmacodynamics, RASRx1902 and RASRx1911 were tested in the TAC model to determine their optimal dose and dosing regimen, and biological activity.

Method

C57BL/6J mice underwent TAC or sham surgery. After echocardiography performed, mice were randomized based on their TAC gradient. Mice received one dose of saline, RASRx1902, or RASRx1911 at a range of subcutaneous or oral doses and euthanized at 0.5, 1, 2, 4 and 6 hours post‐treatment. After dose and route of delivery optimization, mice were treated 1x/day, 2x/day, 2x/week or 3x/week for 2 weeks. Brain tissues were isolated and analyzed for pharmacokinetics, functional markers for OS, and Akt/ERK activation.

Results

One to three weeks after TAC surgery, the levels of mitochondrial superoxide were increased in microglia, but not in neurons, oligodendrocytes, and astrocytes compared with sham surgery. Treatment with RASRx1902 and RASRx1911, administered either subcutaneously or orally, reduced microglial superoxide levels compared to saline‐treated TAC mice. RASRx1902 showed a stronger inhibitory activity on TAC‐mediated superoxide production than RASRx1911. RASRx1902 and RASRx1911 treatment reduced the TAC‐mediated decreased Akt/Erk activity in brain compared to saline treatment.

Conclusions

Microglial mitochondrial superoxide is the main contributor to promote OS, a contributor to AD neurodegeneration. Our data clearly show that our metabolically stable small molecule Mas agonists have the capacity to decrease ROS levels in microglia and might mediate neuronal survival through Akt/Erk signaling pathway. Therefore, RASRx1902 and RASRx1911 are promising novel drug for the treatment of AD.
Efficacy of cognitive stimulation therapy virtual program for older adults with dementia in COVID‐19 isolation
Authors: Sanchez Cintia P
Published: December 2021

Background

Cognitive stimulation virtual therapy (CSVT) is an evidence‐based psychosocial intervention for people with mild‐to‐moderate dementia due to various etiological factors.

Objective

The aim of the present study was to assess the efficacy of a cognitive stimulation virtual therapy CSVT program, in individuals who have vascular or Alzheimer dementia in COVID‐19 isolation.

Methods

Older adults with mild vascular or Alzheimer dementia (N = 20) were assigned to one of two programs: one group (N = 10) attended during six months, two sessions per week program of the cognitive stimulation virtual therapy CSVT program, while the other, active control group (N = 10) took part in alternative activities. The following tests were applied to their primary caregivers. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and quality of life (Quality of Life (QoL)

Results

Compared with the active controls, the cognitive stimulation virtual therapy CSVT program showed a greater improvement in general cognitive functioning after the intervention (i.e. score increase on the IQCODE test). A trend towards improvement was also identified in short term/working memory and perceived quality of life (Quality of life (QoL) of elderly with dementia). The primary caregivers also perceived an improvement in mood, stress, anxiety and quality of sleep after the start of the virtual therapy during COVID‐19 isolation.

Conclusion

The present results support the efficacy of cognitive stimulation virtual therapy CSVT program in people with dementia during COVID‐19 isolation.
Targeted microRNA characterization in various brain cell‐derived exosome subtypes to identify novel biomarkers for Alzheimer’s disease
Authors: Kumar Ashish , Su Yixin , Kumar Pawan , Hughes Tim M. , Craft Suzanne , Deep Gagan
Published: December 2021

Background

MicroRNAs (miRs) offer exciting diagnostic and therapeutic opportunities for Alzheimer’s disease (AD). However, most information about human miRs is from either plasma or CSF of uncertain cellular origin or from postmortem AD brain, which suffers significantly for miR integrity and expression. The discovery of brain cells‐derived exosome (BCDEs) in plasma has led to studies examining their role as ‘liquid biopsies’ for AD. Here, we simultaneously isolated 6 BCDE subtypes from plasma and characterized them for specific miRNAs regulating synaptic plasticity, memory, Aβ, tau, ischemia, and neuroinflammation related signaling pathways.

Method

TE were isolated from plasma samples obtained from the Wake Forest Alzheimer’s Disease Research Center: normal cognition (NC; n=8), mild‐cognitive impairment (MCI; n=3), MCI to AD (n=6), and AD (n=11). Next, following 6 BCDE subtypes were extracted using streptavidin‐coated magnetic beads and specific biotin‐tagged antibodies: neuron‐derived exosomes (L1CAM‐biotin antibody), astrocytes‐derived exosomes (GLAST‐biotin antibody), microglia‐derived exosome (TMEM119‐biotin antibody), oligodendrocyte‐derived exosomes (PDGFRα‐biotin antibody), endothelial‐derived exosomes (PECAM1‐biotin antibody), and pericyte‐derived exosomes (PDGFRβ‐biotin antibody). The purity, concentration and size of TE and each BCDE subtype was assessed by flow cytometry, nanoparticle tracking, immunogold labeling, and electron microscopy. The expression of 8 specific miRs (miR‐9a‐5p, miR‐29‐5p, miR‐106‐5p, miR‐107, miR‐125b‐5p, miR‐132‐5p, miR‐135b‐5p, and miR‐210) was measured by TaqMan assays on real‐time PCR.

Result

We observed statistically significant changes in the expression of all 8 miRs in various BCDE subtypes at MCI, MCI‐AD and AD stages. Importantly, we did not observe significant change for most miRNAs in TE, except for miR‐107 and miR‐135b‐5p, highlighting the importance of studying BCDE. Moreover, basal expression of several miRNAs was significantly different between TE and BCDEs. Interestingly, miR‐106b‐5p, miR‐135b‐5p, miR‐107, and miR‐9a‐5b consistently showed significantly higher expression at MCI, MCI‐AD and AD stages for most BCDE subtypes. While the expression of miR‐125b‐5p, miR‐29a‐5p, and miR‐132‐5p showed statistically significant differences based upon BCDE subtype (either an increase or a decrease); for hypoxiamir ‘miR‐210’, expression was higher at MCI stage but decreased with AD progression.

Conclusion

BCDEs characterization in plasma offers a less invasive opportunity to better understand AD pathogenesis at the cellular level, and to discover novel theranostic targets.
Associations between air pollution exposure and subtypes of cognitive performance in older women
Authors: Petkus Andrew J , Wang Xinhui , Younan Diana , Beavers Daniel P , Espeland Mark A , Millstein Joshua , Chui Helena C , Gatz Margaret , Chen Jiu‐Chiuan
Published: December 2021

Background

Air pollution exposure is a novel environmental risk factor in brain aging. It remains unclear whether long‐term exposure in older adulthood is associated with profiles of cognitive performance across multiple domains.

Method

Participants included 2,185 women (aged 66‐83 years) without dementia from the Women’s Health Initiative Study of Cognitive Aging. Baseline neuropsychological assessment included tests of verbal episodic memory (California Verbal Learning Test), figural memory (Benton’s Visual Recognition Test), language (letter and category fluency), attention (Digit Span Forward and Backwards), and visuospatial ability (Card Rotations Test). Testes were adjusted for demographic age, education, and race/ethnicity. Average annual levels of particulate matter of aerodynamic diameter<2.5 (PM2.5) and nitrogen dioxide (NO2) were estimated at the participant’s residence using regionalized national universal kriging models and averaged over the 3‐year period before the baseline assessment. Latent class structural equation models (SEM) were constructed to identify latent classes of women who had similar patterns of performance across cognitive tests. After identifying the number of latent classes extract in the model, we constructed a second SEM to examine associations between air pollution exposure and latent class membership using multinomial regression while adjusting for demographic, lifestyle, and clinical confounders.

Result

Five significant latent classes were identified (Figure 1): multidomain cognitive impairment (n=247; 11%), amnestic cognitive impairment (n=263; 12%), superior memory (n=407; 19%), superior attention (n=351; 16%), and average cognitive ability (n=917; 42%). Women living in locations with higher levels of PM2.5 (per interquartile range [IQR] = 3.63 μg/m3) or NO2 (per IQR = 10.33) were more likely to be classified as having amnestic cognitive impairment compared to having average cognitive ability (OR=1.27; p=.021). One IQR increase in NO2 was also associated with decreased likelihood of having superior memory (OR=.81; p=.024) compared to average cognitive ability.

Conclusion

Our cross‐sectional study illustrates that long‐term exposure to PM2.5 and NO2 may be associated with specific patterns of cognitive performance; mainly worse episodic memory relative to performance in other domains. Our findings provide further evidence that air pollution may exert neurotoxic effects on brain areas underlying episodic memory in older women.
Neuroimaging and clinical characteristics of cognitive migration in community‐dwelling older adults
Authors: Duran Tugce , Bateman James R. , Williams Benjamin J. , Okonmah‐Obazee Stephanie , Craft Suzanne , Lockhart Samuel N.
Published: December 2021

Background

Longitudinal studies in cognitively unimpaired older adults have identified a wide range of neuroimaging and clinical biomarkers that predict cognitive decline and clinical progression to mild cognitive impairment (MCI) or dementia. However, early biomarkers associated with progression from normal to impaired brain functioning and cognition (cognitive migration) in ADRD require further validation. We investigated the impacts of baseline neuroimaging and clinical biomarkers on functional and cognitive migration in a community‐dwelling cohort of older adults.

Method

Participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort who completed their baseline and 1‐year follow‐up clinical visits with available neuropsychological and MRI data were evaluated. Each participant was categorized to a functional/cognitive state based on baseline global CDR (Clinical Dementia Rating); CDR=0 (n=120) indicates normal function and CDR=0.5 (n=57) corresponds to MCI. Cognitive measures included MoCA (Montreal Cognitive Assessment) and preclinical Alzheimer's cognitive composite (PACC5) scores. Oral Glucose Tolerance Testing (OGTT) assessed blood glucose 120‐minute post‐challenge; OGTT >140 mg/dl indicates impaired glucose tolerance. The primary outcome measure was cognitive migration determined by CDR increase/decrease between baseline and follow‐up (mean difference=13.8 months): CDR‐0 Stables (maintained CDR=0), CDR‐0.5 Stables (maintained CDR=0.5), CDR‐0 to CDR‐0.5 (Migrators), and CDR‐0.5 to CDR‐0 (Reverters). Baseline T1 MRI scans were assessed for gray‐matter volume and analyzed using voxel‐based morphometry in SPM12 for group differences. Statistical design was a two‐sample t‐test controlling for age, sex, education and whole brain volume in contrasts of interest (thresholded at k=25 voxels, p<0.01 uncorrected).

Result

Table lists the baseline demographic and clinical characteristics for significant differences between groups. CDR‐0.5 Stables and Migrators had lower gray‐matter density (GMD) than CDR‐0 Stables and Reverters, most significantly in hippocampal (HC), temporal pole (BA38) and angular (BA39) regions (Figure).

Conclusion

Our analyses suggest that lower GMD in HC and BA38/39 may predict cognitive migration in early stages of disease pathology. OGTT tracks cognitive migration status in this cohort with Reverters having the lowest and Migrators having the highest mean OGTT. Validating these biomarkers may guide clinical diagnosis and treatments in ADRD. Cognitive and functional changes identified within one year can inform disease profiling.
Evaluating the relationship between soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and pathological substrates of Alzheimer’s disease (AD)
Authors: Wahdan Malak , Raza Sanara , Livingston Nicholas R. , Nowell Joseph , Edison Paul
Published: December 2021

Background

Developing novel biomarkers of Alzheimer’s disease (AD) is critical for early disease detection and intervention. sTREM2 has proposed to be an early marker of glial activation. However, there has been significant controversy about the function of sTREM2. This study investigated the relationship between cerebral spinal fluid (CSF) sTREM2, and pathological changes in AD.

Method

We included patients with mild cognitive impairment, AD and healthy controls (n= 493, mean age= 73.7, SD= 6.1) were recruited for the Alzheimer’s Disease Neuroimaging Initiative. All participants completed a T1‐weighted MPRAGE MRI, amyloid ([18F]AV45 or [18F]Florbetaben), [18F]AV1451 and [18F]FDG scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within cortical regions. Amyloid status (Aβ positive/Aβ negative) was determined from processed data using a whole brain cerebellar ratio with a cut‐off value of 1.11. Correlations between CSF measurements, ROI, and voxel‐wise analyses were conducted using data from ADNI.

Result

ROI analyses demonstrated that increased CSF sTREM2 was associated with increased amyloid load in the whole brain, temporal, parietal, and occipital lobes of MCI patients. Additionally, increased CSF sTREM2 was associated with decreased glucose metabolism in the Posterior cingulate and parietal lobe in MCI patients. On the other hand, CSF sTREM2 was not significantly correlated with pathological changes in AD patients. However, voxel‐wise analysis comparing Aβ+ MCI patients to Aβ‐ CN subjects showed that increased CSF sTREM2 levels were associated with greater Aβ deposition in temporal and motor regions, increased grey matter volume in frontal and parietal regions, and decreased grey matter volume in the MT gyrus.

Conclusion

sTREM2 levels are associated with amyloid deposition in MCI patients but not in the late stage of AD patients, this suggest that glial activation is associated early on the disease.
Associations between plasma p‐tau217, in vivo brain pathology and cognition in individuals with autosomal‐dominant Alzheimer’s disease: Findings from the Colombia‐Boston (COLBOS) biomarker study
Authors: Aguillon David , Vila‐Castelar Clara , Chen Yinghua , Su Yi , Chen Kewei , Hansson Oskar , Dage Jeffrey L. , Janelidze Shorena , Zetterberg Henrik , Baena Ana Y. , Gómez‐Henck Clara , Fox‐Fuller Joshua T. , Sanchez Justin S. , Sperling Reisa A. , Johnson Keith A. , Blennow Kaj , Reiman Eric M. , Lopera Francisco , Quiroz Yakeel T.
Published: December 2021

Background

Diagnostic methods available for in‐vivo diagnosis of Alzheimer's disease (AD) are expensive and invasive. Interest in plasma P‐tau217 has recently grown as it seems to have higher diagnostic accuracy for clinical AD, compared to other blood biomarkers in preclinical stages. We recently showed that carriers of autosomal dominant AD due to the PSEN1‐E280A mutation had increased plasma P‐tau217 levels, approximately 20 years prior their estimated onset of mild cognitive impairment. Here, we examined whether baseline levels of plasma P‐tau217 may predict subsequent levels of in vivo cortical amyloid‐β, regional tau pathology, and memory performance in PSEN1‐E280A carriers and non‐carriers.

Methods

A total of 24 PSEN1‐E280A carriers (mean age = 31.13 ± 6.81 years), including 18 cognitively‐unimpaired and 6 with MCI, and 20 age‐matched non‐carriers (mean age = 27.55 ± 6.99) from the Colombia‐Boston (COLBOS) biomarker study were included. Participants underwent blood sampling at baseline and PiB‐PET, Flortaucipir‐PET, and memory testing after 8.95±4.19 years of follow‐up. Plasma P‐tau217 concentrations were measured using a highly sensitive immunoassay. Linear regressions were used to examine associations of baseline P‐tau217 levels with subsequent in vivo amyloid, tau levels in the brain and memory scores each, with age, sex, carrier group membership and time from baseline to follow‐up examinations as covariates.

Results

Compared to non‐carriers, mutation carriers had higher P‐tau217 levels (carriers: 5.27±4.69, non‐carriers: 2.53±1.39; p=0.016), greater regional tau (e.g. entorhinal cortex, inferior temporal tau; p <0.0001) and cortical amyloid (p <0.0001), and lower memory scores (e.g. CERAD Word List Recall; p=0.001). Higher baseline P‐tau217 levels were associated with subsequent elevations in in vivo amyloid and tau pathology and memory decline in carriers (Figure 1).

Conclusion

Findings suggest that baseline levels of plasma P‐tau217 may predict subsequent levels of in vivo amyloid and tau burden, as well as memory decline in PSEN1‐E280A carriers and non‐carriers. These findings provide further support for plasma P‐tau217 as a potential non‐invasive diagnostic and prognostic biomarker of AD, which could be useful in clinical practice and trials.
Mapping the human brain metabolome and influences of gut microbiome
Authors: Batra Richa , Heinken Almut , Karu Naama , Arnold Matthias , Kastenmüller Gabi , Hankemeier Thomas , Bennett David A. , Knight Rob , Krumsiek Jan , Thiele Ines , Kaddurah‐Daouk Rima F.
Published: December 2021

Background

There is compelling evidence implying critical role of gut‐brain axis in neuropsychiatric diseases including Alzheimer’s disease (AD). Consequently, microbially‐derived metabolites, e.g., secondary bile acids, have been shown to be altered in blood, faecal and brain tissues of AD patients. The presence of these microbially‐derived products in brain suggests that gut metabolites can cross the blood brain barrier and modify brain function. Yet it remains challenging to disentangle human and microbial contributions to the brain metabolome and to link microbial metabolites back to species of origin.

Method

Based on a literature review effort, a database of over 500 metabolites was manually curated, including microbial metabolites of endogenous and exogenous compounds, as well as their human‐biotransformed products, and health‐reporting compounds which are related to CNS diseases. Human brains (n=514; dorsolateral prefrontal cortex) from the ROSMAP cohort were profiled on the Metabolon TD4 non‐targeted metabolomics platform which measured 1,055 metabolites. Here, by combining the curated database and the metabolic profiling data from the ROSMAP brains, we built a new database of metabolites found in the human brain. In addition, metabolites from both efforts were mapped to the global human reconstruction, Recon3D, and to a resource of 7,206 human microbial reconstructions, AGORA2.

Result

667 (63.2%) metabolites were retained after filtering out metabolites for high missing values. Of these metabolites, 254 were mapped onto genome‐scale metabolic reconstructions (Recon3D and AGORA2) with 67 being found only in human, 13 only in microbes, and 174 in both human and microbes. 12 additional metabolites were of microbial or mainly microbial origin according to our in‐house database. Many of these (13+12) metabolites were associated (adjusted p‐value <0.05) with AD clinical phenotypes including clinical diagnosis at time of death, AD pathology, and cognitive decline.

Conclusion

We developed a database of the human brain metabolome with comprehensive annotations of human and microbial metabolic networks, ranked in order of importance. The human brain database will be a valuable tool for researchers to define metabolic aberrances in Alzheimer’s disease and the contribution of the gut microbiome, genome, and life style influences on brain metabolic states in health and disease.
Effects of dancing on cognition and mobility in Spanish‐speaking older Latinos: findings from the BAILA trial
Authors: Aguiñaga Susan , Kaushal Navin , Wilson Robert S , Marquez David X
Published: December 2021

Background

Despite literature showing the benefits of regular physical activity (PA), 1,2 older Latinos engage in low levels of PA3 putting them at high risk for mobility disability5 and cognitive impairment.2 Engaging Latinos in culturally responsive PA programs is important to improve cognition and physical function. The purpose of the present study was to examine the effect of a 4‐month BAILAMOS™ Latin dance intervention, followed by a 4‐month maintenance program on cognition and mobility in community dwelling older Latinos.

Method

Spanish‐speaking older Latinos were randomized to the dance program (n=167) or health education condition (n=166). Participants completed neuropsychological tests that assessed working memory (WM), executive function, and episodic memory and completed a 400‐meter walk test at baseline, 4‐months, and 8‐months post‐intervention. Repeated analyses of covariance were conducted to test change in the outcomes at 4‐months and 8‐months post‐intervention. Significant findings found at the multivariate level were followed by reporting results from the univariate tests.

Result

A significant difference in WM was found between the two groups [Wilk’s λ = .98 F 2,329 = 3.97, p = 0.034]. Follow‐up univariate tests found that the two groups were not significantly different at 4‐months, [F 1,329 = 3.74, p = 0.235, (d = .13)], but the dance group demonstrated a significant improvement in WM at 8‐months, [F 1,329 = 6.92, p = 0.017, (d = .20)]. No significant differences were found for executive function or episodic memory. For the 400‐meter walk test, findings show a significant difference between the two groups [Wilk’s λ = .98, F 2,329 = 4.37, p = 0.022]. Univariate tests revealed that the two groups were not significantly different at 4‐months, but were significantly different at 8‐months, [F 1,329 = 7.24, p = 0.013], such that the dance group had better mobility than the health education group, (d = ‐.46).

Conclusion

Findings indicate that participants who received the 4‐month maintenance dance program led to changes in WM and mobility. This study highlights the cognitive and physical implications and the importance of creating sustainable community‐based PA programs. Funding: National Institute of Nursing Research: R01NR013151.
Does higher educational attainment influence functional capabilities among African Americans with Alzheimer’s disease?
Authors: Lacroix Faina C , Adams Larry D. , Inciute Jovita D. , Welch Jacob , Starks Takiyah D. , Laux Renee A. , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Cuccaro Michael L. , Vance Jeffery M. , Pericak‐Vance Margaret A. , Rajabli Farid
Published: December 2021

Background

A recent study of educational attainment (EA) in African Americans (AA) demonstrated that it is associated with a decreased risk of AD, as previously described in the Non‐Hispanic White population. Several studies have also suggested that EA is a proxy for the concept of cognitive reserve (CR) or the capacity of the brains of some individuals to compensate clinically for the neurodegenerative processes of AD. If true, then EA should also be associated with other aspects of AD, including functional impairment, often measured using the Clinical Dementia Rating scale (CDR). The aim of this study is to test the hypothesis that higher EA is associated with decreased functional impairment in AA.

Methods

Participants consisted of 158 AA AD cases with known years of completed education, ascertained for a genetics study of AD. Education levels were stratified into three categories:<8 years, 9‐12 years, >12 years. We used a regression model to test the association between years of education and functional impairment (composite score) with the age at onset and sex as covariates. Using the non‐memory components of the CDR: Judgment and Problem solving, Home and Hobbies, Community Involvement, and Personal Care, we formulated a composite score of 12 totaling the individual score of the 4 components. A composite score of 0 is no functional impairment and 12 equals severe functional impairment.

Results

The dataset was 77.2% female with a mean age of exam of 78.8 years and a mean CDR functional composite score of 1.97 and a mean educational attainment of 11.3 years. Our results showed a significant association between education and the composite score ( ). An increase in the years of education was negatively correlated with functional impairment.

Conclusion

Our data support the hypothesis that higher educational attainment is associated with reduced functional impairment. These results extend and support the concept that EA is a measure of CR in AA, extending the role of CR and EA to functional abilities. Further studies on the mechanism by which EA is protective is needed. In addition, our results suggest that EA should be considered when evaluating functional abilities in individuals thought to have AD.
The relationship between subjective cognitive decline and demographic characteristics is moderated by study setting: Findings from the SCD‐I Item Analysis Working Group
Authors: Sikkes Sietske A.M. , Dubbelman Mark A. , Tommet Douglas , Jones Richard N , Crane Paul K. , Rabin Laura ,   SCD‐I Working Group, SCD‐PIA
Published: December 2021

Background

Subjective Cognitive Decline (SCD) in the absence of objective cognitive impairment has been linked to progression to Alzheimer’s Disease and Related Disorders dementia. Demographic characteristics might bias the measurement of SCD, but it remains unclear how these characteristics relate to SCD. As part of the international SCD‐I item analysis working group, we previously harmonized item‐level SCD questionnaires from cognitive aging studies in North America and Europe into a subjective cognition factor (SCF) score. Here, we aimed to investigate the relationship between SCF and demographic characteristics, as well as the potential moderating role of community‐based versus memory specialty clinic settings.

Method

In this cross‐sectional study, data from 13 international aging studies was included (N=4,979 cognitively normal participants, mean age 75±8, 61% female). Over 600 different SCD questionnaire items were harmonized into the SCF score using item response theory modeling. A series of univariate multilevel linear regression analyses were performed to investigate the relationship between age, gender, education and SCF, with setting (community‐based versus memory clinic) included as fixed factor.

Result

After multilevel adjustment for study clustering, lower SCF, indicating worse subjective cognitive functioning, was associated with older age, such that a 10 year difference in age was associated with a 0.05 standard deviation lower SCF (p=.04, see Table 1). Females reported better subjective cognitive functioning (B=.07, p<.01). No association with education was found across settings. When stratified, the relationships between SCF, gender and age were apparent in the community‐based but not the memory clinic‐based settings (see Table 1).

Conclusion

This is the first study using the harmonized SCF score to study the relationship between SCD and demographic characteristics. This SCD metric applicable across studies could serve as a major facilitator in studying SCD. We found men and older individuals to report slightly lower levels of subjective cognitive functioning, driven by the community‐based setting. These findings suggest that relationships between age and SCD may be different among people motivated to seek medical attention for their cognition compared to unselected individuals in the community.
A comparison of multiple platforms for quantifying ATN values in cerebrospinal fluid
Authors: Ramirez Christopher E. , Trombetta Bianca A. , Celia Amanda M. , LaCasse Kathryn , Mattingly Zoe A. , Salloum Lauren , Orusakwe Amanze , Esquivel Rianne N. , Carlyle Becky C. , Kivisäkk Pia , Arnold Steven E.
Published: December 2021

Background

The ATN framework is used to help categorize research subjects as being on the Alzheimer’s disease (AD) spectrum. Analytes commonly used in biofluids to determine ATN status were measured across three platforms to examine the reliability of each technology and inter‐platform variability.

Method

Cerebrospinal fluid (CSF) samples were obtained from 734 patients undergoing diagnostic lumbar punctures at the MGH Neurology Department. Amyloid β 1–40 (Aβ40), Aβ42, total Tau (tTau), and phosphorylated Tau 181 (pTau 181) were measured in all subjects using EuroImmun ELISA kits on a TECAN FreedomEVO liquid handler. 423 of the subjects also had all four biomarkers measured on a Fujirebio Lumipulse G1200 instrument and 164 had levels of Aβ40 and Aβ42 measured on the Quanterix HD‐X platform. 302 of the subjects had Aβ42, tTau, and pTau 181 quantified by Athena ADmark assays as part of their clinical evaluation. Coefficient of Variations (CVs) were calculated, and data was correlated between platforms to determine inter‐platform variability.

Result

The average CV for each analyte was <5% for samples analyzed on the EuroImmun/TECAN platform and <10% on the Fujirebio Lumipulse and Quanterix HD‐X. CVs >20% were not seen in subjects with detectable analyte levels on the EuroImmun/TECAN or Quanterix platforms and the incidence was <5% on the Fujirebio platform. Tight correlations were observed between levels measured on the EuroImmun/TECAN and Fujirebio platforms (R2>0.8), while lower correlations were observed between the EuroImmun/TECAN and Quanterix platforms (R2=0.4‐0.5 for Aβ40 and Aβ42). The lowest correlation was observed comparing Aβ42 analyzed using EuroImmun/TECAN and Athena ADmark (). ICC values were >0.7 for all analytes compared between EuroImmun/TECAN and Fujirebio platforms.

Conclusion

We observed good reliability using all three platforms. to conserve sample. ATN values showed strong correlations between the EuroImmun/TECAN and the Fujirebio platforms and produce . The poor correlation for the Athena ADmark Aβ42 is likely a result of poor control of pre analytical factors in the samples sent for clinical testing and highlights the importance for proper sample handling.
Structural and functional connectivity uniquely contribute to explained variance in episodic memory performance in cognitively normal older adults
Authors: Alm Kylie H. , Soldan Anja , Pettigrew Corinne , Faria Andreia , Hou Xirui , Lu Hanzhang , Mori Susumu , Albert Marilyn S. , Bakker Arnold
Published: December 2021

Background

Given mounting evidence that AD‐related neuropathological changes may be present in cognitively normal individuals, there is a need to examine brain biomarkers related to variability in cognition that may precede cognitive decline. Although prior studies demonstrate age‐related changes in structural connectivity (SC) and functional connectivity (FC) separately (Contreras et al., 2015), few have adopted a multimodal approach to test the potential interplay between SC and FC, and their relative associations with cognition. Here, we examined the independent contributions of SC and FC to individual differences in episodic memory performance in cognitively normal older adults.

Method

This cross‐sectional study included 107 cognitively normal participants from the BIOCARD study. SC was indexed using radial diffusivity (RD) and mean diffusivity (MD) of two limbic white matter tracts (fornix and hippocampal cingulum), as measured by diffusion‐weighted MRI. FC within five large‐scale brain networks (control, default, limbic, dorsal attention, and salience/ventral attention) was derived using resting state fMRI. Hierarchical linear regression was utilized to directly compare the relative contributions of SC and FC to individual variability in a composite delayed episodic memory score, while also accounting for age, sex, cerebrospinal fluid (CSF) Aß42 and total tau, and gray matter volumes of the entorhinal cortex and hippocampus.

Results

When all five FC networks were included in the regression, only the salience network emerged as a significant FC predictor. Therefore, we performed a follow‐up analysis with salience network connectivity as the only FC measure of interest. In this model, the addition of both SC and FC measures (but not CSF or gray matter volumes) significantly increased the proportion of explained variance in memory performance, and all three measures (fornix/hippocampal cingulum microstructure, and salience network connectivity) were significant independent predictors of memory performance.

Conclusion

These findings demonstrate that both connectivity modalities make unique contributions to episodic memory performance, but CSF and gray mater volumes do not. Furthermore, the highest proportion of explained variance was achieved when both modalities were included in the model, suggesting that the combination of SC and FC markers best accounts for individual variability in episodic memory in cognitively normal older adults.
Using cerebrospinal fluid ATN quantification to classify research subjects in a diverse clinical population
Authors: LaCasse Kathryn , Trombetta Bianca A. , El‐Mufti Leena , Ramirez Christopher E. , Mattingly Zoe A , Celia Amanda M. , Salloum Lauren , Carlyle Becky C. , Kivisäkk Pia , Wills Anne‐Marie , Arnold Steven E.
Published: December 2021

Background

The ATN Framework was proposed to better classify subjects on the Alzheimer’s Disease (AD) spectrum for research purposes. The role of the MassGeneral Institute for Neurodegenerative Disease (MIND) Tissue bank is to collect cerebrospinal fluid (CSF), plasma, and associated clinical data from a diverse neurological subject population. Ab40, Ab42, p‐tau 181, and t‐tau were quantified in CSF samples from the MIND Bank and classified according to the ATN framework to assess the utility of this research framework in a clinical trial relevant, non‐cohort setting.

Method

750 CSF samples were collected from clinically indicated lumbar punctures at the Massachusetts General Hospital Outpatient and Inpatient Neurology Services. The CSF samples were analyzed using Eurolmmun ELISA assays on a semi‐automated TECAN FreedomEVO liquid handler to obtain ATN values. To optimize sensitivity and specificity we plotted these value across varying thresholds, and selected the value at which both were maximized. Assessment of cognitive impairment and neurological diagnosis was performed by chart review by an experienced neurologist.

Result

After sliding threshold analysis of clear cognitively unimpaired versus AD‐Dementia cases, a threshold value for Ab42/40 Ratio (0.082, 92% sensitivity, 91% specificity), pTau (41.8 pg/mL, 91% sensitivity, 91% specificity), and tTau (280 pg/mL, 88% sensitivity, 88% specificity) was determined. 25% of the MIND bank was classified as likely AD from chart review and a similar proportion was biofluid A+T+N+. The overlap of these two subgroups was extensive but not complete. Out of the 188 A+T+N+ subjects, 152 presented clinically with a form of AD, 6 had other neurodegenerative diseases, 23 had other forms of cognitive impairment, and 7 were cognitively unimpaired. 8 of the 419 A‐T‐N‐ subjects had a clinical diagnosis of AD or mixed AD.

Conclusion

The ATN framework can be used to provide an extra level of certainty with regards to diagnosis of likely AD in a clinical trial relevant subject population. Even in this population with clinical indication for LP, there is a small number of resilient cognitively unimpaired individuals that have AD positive biomarkers but no cognitive impairment.
Apathy may be a key link between depressive symptoms and subjective cognitive decline
Authors: Joyce Jillian L , Chapman Silvia , Barker Megan S , Sunderaraman Preeti , Rizer Sandra , Huey Edward D. , Kreisl William Charles , Cosentino Stephanie
Published: December 2021

Background

Subjective Cognitive Decline (SCD), a potential marker of pre‐clinical AD, is frequently linked to mood disturbances, such as depression and apathy. These associations are thought to hinder the utility of SCD as a predictor of impending disease. However, recent evidence suggests that depression and apathy are separate constructs that may pose differential risk for cognitive impairment and neurodegeneration. Further, some studies have reported apathy to be a more sensitive predictor of cognitive decline than depression. Therefore, understanding the associations between SCD and mood will help refine SCD’s utility as a marker of pre‐clinical AD. This study examines those associations with particular focus on whether apathy mediates the association between depressive symptoms and SCD.

Method

151 cognitively normal older adults (68% female, mean age 73±7) were assessed for level of SCD, apathy, and depressive symptoms using a 20‐item age‐anchored SCD questionnaire (i.e., “in comparison to others your age”), the Apathy Evaluation Scale and the Geriatric Depression Scale (GDS), respectively. Regression analyses examined the main effects of apathy and depressive symptoms on SCD, and apathy as a mediator between SCD and depressive symptoms. Regression analyses were also conducted after removing three GDS items previously shown to form an apathy factor.

Result

Apathy (b=.84, p=.001) and depressive symptoms (b=4.57, p=.002) independently predicted SCD. In the mediation model, depressive symptoms predicted apathy (b=2.91, p<.001) but not SCD (b=2.14, p=.183). Apathy mediated the relationship between depressive symptoms and SCD (Indirect effect: b=2.44 SE=.80, CI(1.07, 4.30), accounting for 53% of the total effect. Apathy still remained a significant mediator even after eliminating the apathy‐related items from the GDS (Indirect effect: b=1.52 SE=.65, CI(.40, 2.92)), accounting for 40% of the total effect.

Conclusion

Apathy mediated the relationship between depressive symptoms and memory complaints, even when the GDS only included the dysphoric and anxious elements of depression. These results underscore the relevance of apathy in preclinical stages of disease and is in line with previous studies indicating apathy’s unique association with cognitive impairment and neurodegeneration. Longitudinal studies are required to further disentangle the temporality and potential additive risk for dementia of SCD and apathy.
Analysis of the ACE‐R’s sub‐items that best differentiate healthy controls, amnestic MCI and non‐amnestic MCI
Authors: de Oliveira Maira Okada , Tres Eduardo sturzeneker , Cassimiro Luciana , Avolio Isabella B , Brucki Sonia Maria Dozzi
Published: December 2021

Background

The Addenbrooke's Cognitive Examination‐Revised (ACE‐R) is a brief yet reliable test battery that provides evaluation of six cognitive domains (orientation, attention, memory, verbal fluency, language and visuospatial ability) and widely used to measure cognition. It was developed and revised to provide a brief test sensitive to the early stages of dementia, and is also effective for differentiating the subtypes of dementia, such as Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy, and other forms of dementia associated with parkinsonism. Our objective was to identify which sub‐items of ACE‐R could differentiate health controls, amMCI and non‐amMCI.

Method

Data originated from Brazilian Aging Memory Study (BRAMS).110 subjects: health controls (HC) (n=22; age 73.6±6y; schooling 14±4y; 77.2% female), amnestic MCI (amMCI) patients (n=64; age 73±6y; schooling 11±5y; 81.2% female) and non‐amnestic (non‐amnMCI) patients (n=24; age 70±7y; schooling 12±45y; 83.3% female) assessed by neurological exam and neuropsychological assessment. The Brazilian version of ACE‐R was applied as part of the cognitive assessment in all participants, but was not used to determine diagnosis.

Result

The following items differentiated between HC and amMCI: 3‐words recall (p=0.04), name/address recall (p=0.02), Verbal Fluency Letter P (p=0.01) and Verbal Fluency Animals (p<0.01); No differences were found between HC and non‐amMCI and non‐amMCI and amMCI.

Conclusion

Identifying sub‐items that best differentiates groups could add more information to the clinician regarding the diagnosis and progression of the disease.
Resilience and perceived stress in cognitively normal older adults during the COVID‐19 pandemic
Authors: Kuppe Madeline K , Gagliardi Geoffroy , Gatchel Jennifer R , Munro Catherine E , Marshall Gad A , Sperling Reisa A. , Amariglio Rebecca E. , Vannini Patrizia
Published: December 2021

Background

Psychological resilience, a construct representing a person’s ability to return to their baseline when difficulties occur, can play an important role in determining outcomes in the face of stressors. Resilience is a crucial component to consider during times of prolonged stress, such as experienced during the coronavirus disease (COVID‐19) pandemic, given that chronic stress has been associated with cognitive decline and dementia. Here, we investigated whether psychological resilience modified levels of perceived stress (assessed over 7 months), as well as examined the influence of demographic variables and Alzheimer’s disease biomarkers on this relationship.

Method

In May‐November 2020 of the COVID‐19 pandemic, 39 cognitively normal participants (mean age=78.38; 53.85% female) in the Harvard Aging Brain Study (HABS) completed questionnaires assessing stress (Perceived Stress Scale, PSS) and resilience (only at baseline; Connor‐Davidson Resilience Scale), higher scores on each measure indicating greater stress and increased resilience, respectively. We used previously collected data to better characterize the cohort, with the Preclinical Alzheimer Cognitive Composite (PACC;mean=0.46, SD=0.79) to assess cognition, and PET imaging data to assess Aß burden. A hierarchical regression model was used to assess whether resilience could predict baseline perceived stress. A separate linear mixed effect model (LME) was used to explore how resilience, time, and their interaction may affect stress. Both models also included age, sex, education, cognition, and Aß status (SUVR>1.324).

Result

Perceived stress levels were generally low (mean=13.54, SD=8.65, range=0‐35), and did not significantly vary over the study period (p>0.5; mean number of timepoints=3.13). Both models demonstrated a main effect of resilience, such that higher resilience was associated with lower stress levels (p<0.001;Figure 1). Perceived stress was not influenced by demographic factors, cognition or Aß status. No significant interaction was found between resilience and time in predicting stress levels longitudinally.

Conclusion

Our findings confirm that resilience is critical for coping with stress during the COVID‐19 pandemic, suggesting that resilience could be an important target for potential interventions in the future. Efforts at increasing resilience could not only help support older adults navigating stressful situations, but may also mitigate negative effects of stress on neurocognitive and mental health.