bluuebunny/crossref_metadata_2025 huggingface dataset:
A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [18F]flutemetamol PET images
Authors: Farrar Gill , Nordberg Agneta K , Sur Cyrille , Scott David , Lhommel Renaud , Collij Lyduine , Molinuevo Jose Luis , Hansson Oskar , Gunn Roger N , Rowe Christopher C , Dore Vincent , Buckley Chris J
Published: December 2020

Background

[18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation of scans as either negative (equating to none or sparse amyloid plaques in pathology SoT), or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of Nuclear Medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. Data was collected from multiple sources to assess comparability of the two methods of image interpretation.

Method

9 separate studies where visual reading of [18F]flutemetamol and quantitative analysis of images was available were combined to form a single cohort to measure the percentage agreement between the two methods of image interpretation. Scans covered a wide range of cases (eg from cognitively unimpaired subjects to patients attending the memory clinics see table). Methods of quantifying amyloid ranged from using CE marked/510K cleared software (eg Cortex ID), to other research tools (eg PMOD, CapAIBL) as well as newer methods such as AmyloidIQ. Concordance between visual and quantiative imaging used thresholds robustly established using pathology as the standard of truth

Result

A total of 2,566 [18F] flutemetamol images were collected from 9 clinical studies, visually interpreted by readers using the approved reading methodology and compared to quantitative measures using thresholds which had a binary delineation of amyloid. The mean concordance between visual read and quantitation was 95.01% (SD 3.00%), the median was 95.0%, and the range of the 9 studies was from 89.7% to 99.0%. A total of 379 images were compared using CE marked/510k cleared amyloid quantitation software and the percent agreement in these studies was 98.8% to 99.0%.

Conclusion

Given the high concordance of visual and quantitation from over 2500 scans, users are able apply quantitative amyloid PET software methods to supplement visual inspection. The decision to use these methods as an adjunct to visual reading is left to the choice of the physician as both methods of image interpretation are comparable. The European Medicines Agency (EMA) have agreed to update the prescribing instructions for [18F]flutemetamol (Vizamyl) based upon this analysis.
Improved repeatability of amyloid quantitation using FSL: Implications on ability to detect small longitudinal changes
Authors: Msayib Yunus , Buckley Christopher , Battle Mark R , Pillay Lovena Chedumbarum
Published: December 2020

Background

Monitoring changes in amyloid load requires repeatable image quantification methods. Several different brain‐image analysis pipelines are used, including SPM8, PMOD, and FSL [1]. Test‐retest (TRT) repeatability is an important parameter for assessing how useful a given pipeline is for longitudinal within‐subject studies, providing a measure of the pipeline’s likely variability and helping to determine the optimal approach to quantitation [1]. We report the results of a test‐retest study that compared pipelines from relevant software packages

Method

Six pipelines were evaluated: our previously‐published FSL pipeline (FSL1) [1] and a revised version (FSL2), SPM8, PMOD, and two PET‐only pipelines (CortexID** Windows, PMODPET). FSL2 differs from FSL1 by additional heuristic checks that help identify failed registrations, which are then automatically re‐attempted using adjusted registration parameters. The heuristic checks in FSL2 were manually tuned through qualitative evaluation on a large and heterogenous PET‐MR database comprising 812 Alzheimer’s (AD) and non‐AD subjects, for which FSL2 had a final successful registration rate of 98%.For the TRT analyses, 10 subjects [1] with confirmed AD were evaluated. Each subject received an initial (test) [18F]flutemetamol scan, followed by a retest scan within 2 weeks. For each pipeline, TRT variability was calculated for individual subjects and reported as a group mean and standard deviation (SD) (thereby equally weighting each observation): TRT variability of cortical uptake (%) = |retest – test|/0.5*(retest + test). Results were reported on three different scales: SUVRcereb, SUVRcereb‐1, and centiloids (CL).

Result

Figure 1 shows TRT variability for each pipeline. Using CL measures for example, FSL2 exhibited the lowest TRT variability (mean ± SD) (2.6 ± 1.9%), followed by FSL1 (3.0 ± 2.7%), SPM8 (3.1 ± 2.7%), PMOD (3.3 ± 1.6%), and the PET‐only pipelines (CortexID: 5.8 ± 4.7%, PMODPET: 6.8 ± 6.4%). Note that FSL2 and PMOD had relatively low dispersion of TRT variability, whereas the other pipelines exhibited a spread that was at least at least 1.4 times larger.

Conclusion

Our FSL‐based pipeline exhibited higher repeatability than other platforms, thus it may be better‐suited for quantifying small longitudinal changes in cortical amyloid load. [1] Battle et al. EJNMMI Res. 2018;8. **CortexID and its PET‐only adaptive template was used as the core for AmyPype, which outputs centiloid quantification.
Association between use of assistive technologies and activities of daily living in Alzheimer’s disease: Does cognitive score matter?
Authors: Brigola Allan Gustavo , Trucco Ana Paula , Camino Julieta , Mioshi Eneida
Published: December 2020

Background

Assistive technologies (AT) can be useful to support the day‐to‐day care of people with dementia, especially those with Alzheimer’s disease (PwDA). This study investigated the frequency of use of AT in PwDA. We also explored the association of using AT and functional ability, considering age, sex and cognition as covariates.

Method

Cross sectional analyses including 70 PwDA (assessed 2016‐2019). Global cognition was assessed with the Addenbrooke’s Cognitive Examination (ACE‐III). Disability Assessment for Dementia (DAD) assessed performance of basic (BADL) and instrumental (IADL) activities of daily living. Information on use of AT in regards to a) Prompts/Reminders, b) Leisure, c) Communication devices, was collected. Linear regression models were used to explore the association between use of AT and Basic ADLs and Instrumental ADLs. Covariates included global cognition, age and sex of participants.

Results

Overall, sample mean age was 78.8±6.6 years; 60% of participants were male. Average Basic ADL score was 70.5±27.5; Instrumental ADL average score was 34.7±26.8, reflecting greater disability in instrumental ADLs. In terms of AT, 32.9% used Prompts/Reminders; 34.3% reported use of technologies for Leisure; 12.9% reported use of technologies for Communication devices. When controlling by age and sex (model A), the use of Communication technologies was inversely associated with Basic ADLs (β=‐22.81;95%CI:‐43.9;‐1.6;p=0.035), explaining 17% of the variance. When controlling by age, sex and global cognition (model B), the association between use of communication technologies and Basic ADLs was not significant. In regards to instrumental ADLs, use of technologies for Communication, Prompts/Reminders and Leisure were not associated with Instrumental ADL scores in models A and B.

Conclusion

Use of AT for Communication appears to be driven by the greater level of disability of the user in basic ADLs, which seems to fulfil their need for this AT. However, if PwDA's cognitive scores are also low, the use of AT does not influence performance in Basic ADLs any longer. Use of AT for Prompts/Reminders and Leisure was not associated with performance in Basic and Instrumental ADLs, reflecting the need for better understanding the importance of cognitive ability in using AT for maintaining function.
Examining risk of dementia in lifestyle engagement subgroups of community‐dwelling older adults: A latent class approach
Authors: Moored Kyle D , Parisi Jeanine M , Snitz Beth E , DeKosky Steven T , Williamson Jeff D , Fitzpatrick Annette L , Carlson Michelle C
Published: December 2020

Background

Engagement in lifestyle activities may be neuroprotective, but it remains unclear what aspects of engagement are most beneficial. For self‐reported activity inventories, examining response patterns may better characterize both quantitative (e.g., number) and qualitative (e.g., characteristic/motivational) differences in engagement.

Method

Participants were 3069 individuals from the Gingko Evaluation of Memory (GEM) Study who were evaluated for dementia and completed neuropsychiatric testing over 8 years. We used a subset of 18 physical, intellectual, or social activities from the Lifestyle Activity Questionnaire. We performed latent class analysis to characterize subgroups with distinct activity response patterns and examined whether they have differential risk of incident dementia and domain‐specific cognitive impairments over time. Cox proportional hazards models were used to examine subgroup differences in risk of cognitive impairments.

Result

A three‐class model was chosen based on fit statistics and interpretability. Class 1 (Highly intellectually/socially active) participated in more social leisure activities (e.g., movies) than Classes 2 (Socially/less intellectually active) and 3 (Less intellectually/socially active). Class 2 participated in more institutional social activities (e.g., church) than Class 3. In an unadjusted Cox proportional hazard model, Class 1 had a reduced risk of dementia compared to Classes 2 (HR=1.32, 95% CI: [1.1,1.6], p=.013) and 3 (HR=1.53, 95% CI: [1.2,1.9], p<.001). After adjusting for potential demographic and health confounders, Class 1 had a statistically significant reduced risk of dementia compared to Class 3 (HR=1.40, 95% CI: [1.1,1.8], p=.003), but the reduction in risk compared to Class 2 was only trending (HR=1.26,95% CI: [1.0,1.6], p=.051).

Conclusion

These results suggest that subgroups characterized by less engagement in leisure social and intellectual activities have increased risk for dementia. Our findings also highlight subgroup differences in activity types (e.g., participation in social institutions in Class 2) that may be leveraged by further behavioral interventions to reduce risk of dementia with age.
Untangling the roles of amyloid and tau in synaptic and axonal loss in the course of Alzheimer’s disease
Authors: Pereira Joana B. , Janelidze Shorena , Ossenkoppele Rik , Brinkmalm Ann , Mattsson Niklas , Stomrud Erik , Smith Ruben , Zetterberg Henrik , Blennow Kaj , Hansson Oskar
Published: December 2020

Background

It is currently unclear how rising amyloid‐β (Aβ) and tau tangles are linked to changes in synaptic function and axonal structure over the course of Alzheimer’s disease (AD).

Method

Here we assess how presynaptic (synaptosomal‐associated protein 25, SNAP‐25), postsynaptic (neurogranin, Ng) and axonal (neurofilament light chain, NfL) biomarkers change in early and late AD, in individuals with or without Aβ and tau pathology based on Aβ‐PET (18F‐flutemetamol) and tau‐PET (18F‐flortaucipir). In addition, we explore the relationship between these biomarkers with memory and global cognition as well as functional and anatomical brain connectivity.

Result

Our findings show that the synaptic markers SNAP‐25 and Ng are increased in early AD, i.e. in Aβ‐positive individuals without evidence of tau pathology. In this group, higher synaptic levels were associated with more Aβ pathology, worse memory and functional changes in the default‐mode network, but not global cognition or anatomical connectivity. In contrast, NfL levels became abnormal in later disease stages, i.e. in individuals with both Aβ and tau pathology. In this group, higher NfL was associated with more tau and worse global cognition, but not Aβ pathology or default mode network connectivity. Finally, reduced anatomical connectivity was only associated with tau pathology in late AD.

Conclusion

Altogether, these findings support the hypothesis that Aβ and tau have downstream effects on synaptic and axonal function in a stage‐dependent manner. Increases in Aβ are related to presynaptic and postsynaptic markers, which affect functional connectivity in early disease stages. This is followed by an increase of tau, which affects both axonal markers and anatomical connectivity in later disease stages.
Dementia diagnosis disparities by race and ethnicity
Authors: Lin Pei‐Jung , Daly Allan , Olchanski Natalia , Cohen Joshua T , Neumann Peter J , Faul Jessica D , Fillit Howard M , Freund Karen M
Published: December 2020

Background

Dementia is often underdiagnosed, and self‐reported data suggest that this problem may be more common among racial and ethnic minority groups. This study examined racial and ethnic disparities in the timeliness in which individuals receive a formal dementia diagnosis.

Method

This analysis used eight waves of US national surveys from 2000‐2014 Health and Retirement Study, linked with Medicare and Medicaid claims. We identified study participants age ≥70 with dementia using a well‐validated statistical model based on individual’s age, gender, education, cognition, and functional limitations. We assessed the proportion of patients not receiving a coded diagnosis of dementia in their claims by the time the prediction model classified them as having dementia. We used logistic regression models to compare the likelihood of missed or delayed dementia diagnoses in claims by race and ethnicity, adjusting for patient characteristics. We analyzed dementia severity, measured by cognition (TICS scores for self‐respondents; IQCODE scores for proxy‐respondents) and functional limitations, at the time of a dementia diagnosis documented in claims, by race/ethnicity. All analyses adjusted for sampling weights.

Result

Our sample included 3,966 older adults with dementia. Forty‐two percent had a missed or delayed dementia diagnosis in their claims. This proportion was higher among non‐Hispanic blacks and Hispanics than among non‐Hispanic whites (46% and 54% vs. 41%, p<0.001). Logistic regression model indicated more frequent missed/delayed dementia diagnoses among non‐Hispanic blacks (OR=1.27; 95% CI: 1.05‐1.53) and Hispanics (OR=1.83; 95% CI: 1.43‐2.35), compared to non‐Hispanic whites. Over the study period, 76% had a dementia diagnosis documented in their claims. At the time of diagnosis, non‐Hispanic blacks and Hispanics had poorer cognitive function and more functional impairments, compared to non‐Hispanic whites.

Conclusion

Non‐Hispanic blacks and Hispanics may experience missed or delayed diagnoses of dementia more often than non‐Hispanic whites. When they are diagnosed, non‐Hispanic blacks and Hispanics may have more advanced dementia compared to non‐Hispanic whites. Public health efforts such as the Brain Health Initiative should tailor campaigns to different ethnoracial groups when promoting early diagnosis of dementia. The medical community should implement provider training on culturally competent dementia care and improve documentation of dementia diagnostic findings in health insurance claims.
Brain network functional connectivity changes following psychosocial stress in subjective cognitive decline
Authors: Albert Kimberly , Boyd Brian , Newhouse Paul A. , Taylor Warren D.
Published: December 2020

Background

Neurodegenerative processes in early AD may disrupt the coordinated activity of brain networks important for the regulation of endocrine and emotional stress response. Stress reactivity and the effect of psychosocial stress on brain network function may thus be useful markers of neural changes related to early AD processes. The goal of this study was to examine the effect of psychosocial stress on brain network function in older adults with Subjective Cognitive Decline (SCD), a population at increased risk for Alzheimer’s disease.

Method

Participants (n=25) were evaluated to exclude cognitive impairment and significant psychiatric disorders. SCD was operationalized using the Cognitive Complaints Index (CCI) with a required minimum score of 20%.

The Montreal Imaging Stress Task (MIST) was used to induce moderate psychosocial stress. Subjective measures included the stress subscale of the Stress‐Arousal Checklist (SACL) and the Profile of Mood States (POMS).

Resting‐state fMRI scans were completed before and after the MIST. Seed‐based analyses were used to examine changes in functional connectivity (FC) in the default mode (DMN‐posterior cingulate), cognitive control (CCN‐dorsolateral prefrontal cortex), and salience (SN‐anterior insula) networks (p uncorrected <0.005, FDR corrected p <0.05).

Result

Participants had an average CCI of 45% (SD = 10.5%). There was an increase in subjective stress (stress‐SACL; t=6.12, p < 0.0001) and worsening mood symptoms (POMS total score; t=3.23, p=0.004) during the MIST. In the DMN, stress exposure with the MIST resulted in decreased FC between the posterior cingulate cortex and regions of the CCN, (middle and superior frontal gyri). In the SN, stress exposure increased FC between the right anterior insula and the right middle/inferior temporal gyri and DMN regions including the precuneus and posterior cingulate cortex. We did not observe changes in FC in the CCN.

Conclusion

These findings suggest that in SCD stress reduces coordinated activity of the CCN and DMN and increases connectivity between SN and DMN which may reflect impaired regulation of DMN activity and enhanced vigilance for emotional information. Further work is needed to determine how these changes may differ from normal aging and whether network changes may indicate early AD‐related cognitive and emotional disruption.
Complementary analyses of the AMBAR trial: Impact of discontinuations, consistency of results across outcomes and additional adjustments
Authors: Hendrix Suzanne B. , Núñez Laura , Boada Mercè , Lopez Oscar L. , Grifols Carlota , Barceló Miquel , Páez Antonio
Published: December 2020

Background

The AMBAR study enrolled 496 mild‐to‐moderate Alzheimer’s disease (AD) patients from Spain and US centers, 347 of which were randomized [1:1:1:1] to three treatment arms of plasma exchange (PE) with different doses of albumin with or without intravenous immunoglobulin (IVIG) or placebo (sham PE) arm. PE treatment showed slow cognitive and functional decline in AD patients, with variable significance in outcome (primary: ADCS‐ADL, ADAS‐Cog; secondary: CDR‐Sb, ADCS‐CGIC), baseline disease severity, and treatment arm (low‐albumin; low‐albumin+IVIG, high‐albumin+IVIG, and all three combined). The percentage of patient dropouts ranged from 20% in the placebo to 34.9% in the low‐albumin+IVIG group. In this analysis we investigated the effect of possible biases due to discontinuations and baseline imbalances, and assessed the consistency across outcomes.

Method

The impact of discontinuations was determined by least squares mean estimates from the Mixed Model for Repeated Measures (MMRM) analysis using the z‐score carried forward analysis (zLOCF). The overall impact of the treatment on the disease was determined by a global statistical test which combined with equal weighting three outcomes (ADCS‐ADL, ADAS‐Cog, CDR‐Sb) into a single outcome. An analysis of relevant outcomes was performed adjusting for key baseline characteristics.

Result

Analysis of discontinuations suggested that the treatment differences and effect sizes estimated using the primary model MMRM are likely to be conservative and that lowering dropouts is likely to increase effect sizes. Effect sizes were consistent across outcomes (between 51% and 76%). The GST score showed slowing of progression at month 14 with statistically significant differences between all active treatments and placebo from month 9 onward. When the model was adjusted for key baseline characteristics, the analysis showed statistically significant differences against placebo of all treatment groups in most of the relevant outcomes.

Conclusion

Results of this analysis disprove the possible bias of dropout effect in the AMBAR trial. Effect sizes were consistent across outcomes and the Global Statistical Test showed an overall impact of the treatment on the disease. The analysis corrected for baseline factors supports and reinforces the findings that the PE‐treated arms were superior to the placebo group.
Alzheimer’s disease worries, fears, and stigma and their relationship to genetic and interventional research engagement
Authors: Bardach Shoshana H , Kent Saida , Jicha Gregory A
Published: December 2020

Background

Alzheimer’s disease (AD) research increasingly focuses on risk factors, including attention to genetics, and clinical trials in the area of prevention, necessitating the engagement of healthy participants willing to undergo genetic testing and potentially take experimental medications. Objective: This study seeks to: 1) describe older adults’ beliefs about AD genetic testing, worry about AD, and fear of AD stigma, and 2) explore how these constructs relate to various forms of AD research participation.

Method

Surveys were sent via mail both to participants active in AD‐observational research and those that were not. Surveys included questions on benefits and limitations of AD genetic testing, AD worry, and fear of AD stigma. Three measures of research participation were explored: 1) Being a current research participant, 2) Self‐report of clinical trial participation, and 3) Expressing interest in a genetic registry.

Result

Surveys were returned from 502 individuals. The majority of respondents perceived greater benefit than risk associated with AD genetic testing. Overall AD worry and perceptions of AD stigma were low. Higher levels of AD worry and lower perceptions of AD stigma were both associated with being a current AD research volunteer. AD worry and stigma were unrelated to reports of clinical trial participation or genetic registry interest; however, both of these research participation measures were associated with higher ratings of AD genetic testing benefit.

Conclusion

These results demonstrate that beliefs about AD genetic testing, as well as AD worry and stigma, are related to research participation, but these relationships vary based on the form of research participation investigated. Further work needs to be done to identify how best to use these findings to direct outreach and recruitment efforts.
Incident cognitive impairment in a longitudinal cohort of older adults in rural South Africa, 2014‐19
Authors: Kobayashi Lindsay , Farrell Meagan T , Langa Kenneth M , Mahlalehla Nomsa , Wagner Ryan , Berkman Lisa
Published: December 2020

Background

We aimed to determine the incidence of cognitive impairment and its key sociodemographic, social, and health‐related predictors at the first longitudinal follow‐up of the population‐representative “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI) cohort in South Africa.

Method

Data were from 3,861 adults aged ≥40 in rural Agincourt sub‐district, South Africa from 2014‐19, who were free from cognitive impairment at baseline. Cognitive impairment was defined as scoring ≥1.5 SD below the baseline mean composite time orientation and episodic memory score, or requiring a proxy interview with “fair” or “poor” proxy‐reported memory. Limitations to activities of daily living (ADLs) were compared according to incident cognitive impairment status. Incidence rates (IRs), incidence rate ratios (IRRs), and 95% confidence intervals (CIs) for cognitive impairment were estimated according to sociodemographic, social, and health‐related characteristics using modified Poisson regression. IRs and IRRs were weighted to account for mortality over the follow‐up. IRRs were adjusted for age, sex/gender, and country of birth.

Result

Over a mean follow‐up of 3.7 years, 309/3,861 at‐risk participants newly developed cognitive impairment (IR=24.0 per 1000 person‐years (PY); 95% CI: 21.6‐26.8). Incidence increased steadily with age, from IR=9.1 per 1000 PY (95% CI: 5.5‐16.1) among those aged 40‐44 years at baseline to IR=76.5 per 1000 PY (95% CI: 63.2‐93.4) among those aged 80+. At least one ADL limitation was prevalent at follow‐up in 39% of those with an incident cognitive impairment, compared to 7% of non‐cognitively impaired participants. The incidence of cognitive impairment did not vary by sex/gender, HIV infection status, or cardiovascular risk factors, but was strongly graded according to education, literacy, household assets, employment, marital status, and frequency of alcohol consumption. For example, IRR=1.13 (95% CI: 0.91‐1.40) for female vs. male, IRR=1.05 (95% CI: 0.77‐1.43) for HIV‐positive vs. HIV‐negative, IRR=2.40 (95% CI: 1.81‐3.17) for illiterate vs. literate.

Conclusion

This study presents one of the first incidence rate estimates for cognitive impairment in sub‐Saharan Africa, where populations are beginning to rapidly age. Social and socioeconomic disparities in incident cognitive impairment rates were apparent in a similar pattern as in many high‐income countries.
Understanding resistance, resilience and repair: An analysis of electronic medical records to identify ‘successful aging’ free of Alzheimer’s disease and related dementias
Authors: Miller Amber H. , Marra David E. , Anton Stephen , Maraganore Demetrius M.
Published: December 2020

Background

As the number of individuals living with Alzheimer’s disease and related dementias (ADRDs) increases in the United States, it is important to discover ways to preserve and improve brain health across the lifespan through prevention. This is especially important for the rapidly growing over age 90 segment of the population (“oldest old”). This project defined ‘Successful Aging’ and utilized Electronic Medical Records (EMR) to understand the characteristics of successfully aged individuals over 90 throughout the State of Florida. This epidemiological investigation will also discover common lifestyle factors that contribute to the risk management of ADRDs.

Method

A panel of distinguished researches, in the fields of dementia, aging, and biomedical informatics and health outcomes at the University of Florida, convened to develop a computable phenotype of “Successful Aging”, derived from the EMR. Utilizing the OneFlorida Data Trust, a repository of healthcare data for 75% of Floridians (∼15 million patients), researchers computed a successful aging phenotype, using discretely coded demographics, ICD‐9/ICD‐10 diagnostic codes.

Result

The research investigators identified 19 parameters of ‘Successful Aging’ and universally agreed to three primary criteria: over the age of 90, not residing in a nursing home, and free of ADRD. From the OneFlorida Data Trust, 281,927 individuals were identified as residing in Florida, alive and over the age of 90, a 2.01% prevalence. In this over 90s population, 187,514 (66.5%) did not have a diagnosis of ADRD and 94,413 (33.5%) had ADRD diagnosis. Of the 187,514 non‐ADRD individuals, 65,008 (23.1%) did not reside in a nursing home zip code and exhibited the three primary criteria for successful aging. There were 45,710 (16.2%) individuals who demonstrated all 19 parameter criteria (Figure 1).

Conclusion

Florida is the third‐most populous state, with the highest percentage of elders, and the most ADRD per capita. Studies in this special population are crucial to understanding ‘Successful Aging’. Future research will validate the EMR computed phenotype by contacting the ‘Successful Agers’ in Florida to further investigate demographic, medical, and social characteristics that promote resistance, resilience, and repair. This validation will lead to the development of preventive interventions that can reduce the lifestyle risk of developing ADRDs.
Caregiving is associated with worse sleep, and worse sleep‐related health and function
Authors: Sprecher Kate E , Hagen Erika W , Ravelo Laurel A , Barnet Jodi H , Peppard Paul E
Published: December 2020

Background

Disturbed sleep in caregivers of persons with dementia is a leading reason for the decision to institutionalize persons with dementia. Here we quantify the association of caregiving with sleep, and sleep‐related health and function.

Method

In the Retirement and Sleep Trajectories study, 2137 community dwelling adults completed 4 annual mailed surveys (52% female, mean age 64 years (range 46‐86 years)). Caregiving status was determined from questions: (1) How many hours per month do you spend providing unpaid assistance to others? and (2) Indicate how often caring for others kept you up past your intended bedtime. Responses of never or rarely were compared to responses of sometimes, often or always. Participants were asked their usual bedtime, waketime, and sleep need (How many hours and minutes of sleep do you think you currently need each day to feel rested and alert?). Sleep duration was defined as the time from bedtime to waketime, averaged across weekdays and weekends. Sleep debt was defined as the difference between sleep duration and sleep need. A 9‐item version of the functional outcomes of sleep questionnaire (FOSQ) was administered, which reflects general productivity, activity level, vigilance and social outcomes. Mental and physical health were assessed with the SF‐12 Health Survey. Mixed‐effects linear models were used to test associations of caregiving with sleep, health and function, controlling for age.

Result

5.45% of respondents reported that caregiving delayed their bedtime, which was significantly (p<0.001) associated with 11 (95% CI = 6‐16) minutes/day shorter sleep duration, 13 (95% CI = 7‐18) minutes/day greater sleep debt, worse functional outcomes of sleep (beta = ‐0.58, 95% CI= ‐0.87‐ ‐0.30) and worse mental health (beta = ‐1.88, 95% CI = ‐2.67 ‐ ‐1.10). Delayed bedtime due to caregiving was not associated with physical health. Hours spent caregiving was not associated with sleep duration, sleep debt, health or functional outcomes.

Conclusion

Caregiving is associated with disturbed sleep, which is associated with worse daytime function and worse mental health. Interventions to improve caregiver sleep could be a strategy to improve caregiver health, function and quality of life.
Musical Bridges to Memory (MBM): Exploring the effects of a dyadic music‐based group intervention on social engagement and neuropsychiatric symptoms in persons with dementia
Authors: Schafer Rhiana , Karstens Aimee J , Hospelhorn Emma , Wolfe Jeffrey , Ziemba Amanda , Wise Peggy , Crown Rickie , Rook Jenni , Bonakdarpour Borna
Published: December 2020

Background

Music‐based interventions can reduce the severity of neuropsychiatric symptoms in persons with dementia (PWD), and in turn reduce the need for pharmacological interventions (e.g., psychotropic). However, few intervention trials have used a dyadic group approach. We determine the efficacy of a dyadic music‐based intervention on PWD neuropsychiatric symptoms and social engagement. Musical Bridges to Memory (MBM) uses both perceptive and expressive forms of music‐based intervention, administered in a dyadic group setting, to mediate PWD neuropsychiatric symptoms and improve social interaction between dyads (PWDs and their caregivers).

Method

Thirty‐one dyads were recruited from memory care facilities; twenty received the MBM intervention, ten were controls. Groups were comparable in age and level of education. All were assessed at baseline and post‐intervention. Caregiver‐reported PWD behavioral symptoms were assessed using the Neuropsychiatric Inventory (NPI). The Verbal and Nonverbal Interaction Scale (VNVIS) was used to rate PWDs social interactions (10min video recordings of dyads) on sociable, unsociable, verbal and nonverbal behaviors. The 12‐week intervention included weekly sessions, which consisted of caregiver training(30m), live concerts(45m), and breakout groups(30m). Music was chosen based on PWDs’ assessed preferences.

Result

Sociable interactions (e.g. positive affect, eye‐contact, apparent interest/focus), significantly increased (p=0.044) in the MBM intervention group as compared to controls. Caregivers reported a decrease in severity of PWD neuropsychiatric symptoms (p=0.089, indicating a trend) and symptom‐related distress in caregivers (p=0.005) decreased significantly. Analyses controlled for sex and global cognition (Mini Mental State Exam) score at baseline.

Conclusion

Our preliminary results indicate that a dyadic music‐based group intervention approach administered in a memory care facility is effective at improving PWD social engagement, mitigating PWD behavioral symptoms, and reducing associated caregiver distress. These results complement previous literature, highlighting music‐based interventions as a non‐pharmacological approach to managing neuropsychiatric interventions in PWD. In addition, our use of a dyadic group‐based approach and our reported increase in sociable engagement highlights the benefits of including caregiver participation in music‐based interventions. Future work will examine a larger cohort and directly examine caregiver burden.
CO‐registration of proton magnetic resonance spectroscopy (1H‐MRS) and diffusion imaging (DMRI) in healthy aging: A prospective study of cerebral neurochemistry and microstructure
Authors: Hone‐Blanchet Antoine , Shahid Salman Syed , Krishnamurthy Lisa , Lin Qixiang , Levey Allan I , Lah James J , Qiu Deqiang , Crosson Bruce
Published: December 2020

Background

Changes in brain microstructure are markers of aging and implicate changes at the neurochemical level. Prior magnetic resonance spectroscopy (MRS) works have demonstrated effect of aging on gamma‐aminobutyric acid (GABA) and myo‐inositol (mI), suggesting changes in cellular metabolism and neuroinflammation. Diffusion MRI (dMRI) works have shown that neurite density (NDI) is decreased in aging, suggesting a decrease in dendritic and axonal health. We obtained MRS and dMRI indices co‐registered within the same voxel in the medial frontal cortex (MFC) to investigate how tissue microstructure locally influences neurochemistry. We hypothesized that NDI would predict age‐related changes in concentration of GABA and age‐related neuroinflammation with concentration of mI.

Method

Participants: 138 healthy older adults (age 64.8±6.52 years; range 51‐86 years). Informed consent was obtained from all subjects. MRS: acquired on a 3T MRI system with a 32‐channel head coil. PRESS and MEGAPRESS spectra were acquired from a 3x3x3cm voxel positioned in the MFC. GABA and mI levels were estimated with Gannet and LC Model. Segmentation of images was performed with SPM 12. A voxel mask registered to T1 was generated to perform registration of dMRI in the same volume. dMRI: acquired in the axial plane with a multi‐band signal‐shot spin echo echo‐planar sequence (MB acceleration factor = 3). A multi‐shell scheme was used with 3 b0, 10 b150, 10 b350, 64 b1000, 64 b2000, 64 b3000 and 104 b5000 directions. Raw images were processed to reduce signal noise. Analyses: Linear regression analyses were performed: Effect of age with NDI and MRS metabolites as dependent variables. Effect of NDI with MRS metabolites as dependent variables with age as covariate.

Result

Age predicted levels of GABA (B=0.413, P<0.001), mI (B=0.309, P=0.002), and NDI (B=‐0.351, P<0.001). NDI predicted levels of GABA (B=0.24, P=0.005) and mI (B=‐0.236, P=0.022).

Conclusion

This study demonstrates that local microstructure differentially impacts GABA and mI in a healthy aging cohort. It also supports age as a predictor of microstructure and neurochemistry in the MFC. These suggest that neurite density impacts neurochemistry prior to age‐related, clinically significant structural changes and demonstrate relevance of co‐registration of MRS and dMRI in aging.
Microglial activation and brain networks in Alzheimer’s disease: The ActiGliA cohort study
Authors: Rauchmann Boris‐Stephan , Brendel Matthias , Keeser Daniel , Tato Maia , Palleis Carla , Zaganjori Mirlind , Ersözlü Ersin , Janowitz Daniel , Bürger Katharina , Goldhardt Oliver , Grimmer Timo , Levin Johannes , Stöcklein Sophia , Höglinger Günter , Haass Christian , Perneczky Robert
Published: December 2020

Background

Recent research suggests that brain network degeneration and immune response play important roles in Alzheimer’s Dementia (AD). Brain network connectivity become increasingly impaired as AD progresses. Glial activation in the neuropathology of AD has also been widely recognized both as a consequence and as a contributing factor for the formation of Aβ and tau aggregation. Immune surveillance in the brain and microglial activation can be reliably measured by translocator protein (TSPO) positron emission tomography (PET).

Method

To understand better important associations between network degeneration and immune response in AD, we initiated the ActiGliA prospective cohort study. Here we present an analysis of the initial 55 participants, including 20 participants with subjective cognitive declined, 19 patients with mild cognitive impairment and 16 AD patients. Participants were characterized using CSF biomarker information and underwent TSPO‐PET, fMRT and DTI acquisitions. We assessed topographical associations between microglia activity (TSPO‐PET covariance) with resting state functional and DTI structural connectivity changes using a 210 regions parcellation of the neocortex. PET and MRI preprocessing were performed using standard imaging pipelines.

Result

At baseline, elevated microglia activity was found in TSPO‐PET analysis of AD patients. Resting state fMRI graph‐theory analysis showed reduced global efficiency and increased local efficiency in AD compared to controls. No significant group differences were found in the graph‐theory analysis of structural connectivity. In a further analysis, we assessed the association between microglia activity and functional connectivity. A positive correlation of resting state functional connectivity with microglia covariance (r=0.177, p<0.001), but no correlation of structural connectivity and microglia covariance were detected. Network specific TSPO uptake in resting‐state networks, demonstrating increased uptake in the language, default mode network (DMN), and visual network in the AD group compared to controls.

Conclusion

In line with previous findings, we confirm that brain functional connectivity is disrupted and microglial activity is elevated in AD. Preliminary results suggest an association between functional connectivity and microglia activity in AD, furthermore microglia activity is preferentially found in particular resting state networks.
Prediction of Alzheimer’s disease using plasma RNA sequences
Authors: Ibanez Laura , Benitez Bruno A. , Cruchaga Carlos , Harari Oscar , Del‐Aguila Jorge L.
Published: December 2020

Background

Alzheimer’s disease (AD) is inexorable, incurable, and in many cases very difficult to diagnose before symptom onset. Thus, there is a clear need to develop tools to detect the pathological changes that occur before clinical symptoms onset. Historically, proteins have been the preferred biomarker. However, biofluids also contains ribonucleic acid in its free form (cfRNA). The source of cfRNA in plasma is not fully understood, but it is thought to be the result of normal cell death throughout the body, thus providing a mirror of the status of a normal functioning body. Therefore, if some organs are functioning incorrectly, we can detect it by changes in cfRNA. To date, several species of cfRNA have been investigated as biomarkers for cancer, fetal development and AD. In here we tested plasma cell‐free RNA species as biomarker for AD diagnostic.

Method

We generated cfRNA‐Seq data from a discovery dataset (ten pathologically confirmed AD cases and ten sex, age and APOE genotype matched controls) and a replication dataset containing samples at different stages of the disease and controls (N=80) not matched by sex or APOE. Standard quality control and alignment pipeline for RNAseq data was used. Gene expression was quantified with Salmon and corrected by library complexity and log transformed prior to analysis. Predictive models were built using the wrapper algorithm Boruta and the machine learning tool Tensorflow to define the optimal number of RNA transcripts.

Results

Transcriptome‐wide principal component analyses show that cfRNA reflect significant differences between cases and controls (46% of variance explained, p=0.001). Using machine learning, we identified a set of 24 genes that perfectly predicts cases in the discovery dataset. In the replication dataset, the area under the ROC curve for the model with APOE and sex was 0.84 for advanced clinical stage (CDR=1), 0.82 for early stages (CDR=0.5) and 0.86 for presymptomatic. Exclusion of APOE genotype in the predictive model drastically affected the predictive power.

Conclusion

Cell‐free RNA is a promising biomarker for AD with an accuracy comparable to the one obtained using CSF biomarkers. This non‐invasive approach can provide new biomarkers or screening tool for AD.
Large synaptic genes are more frequently affected by somatic mutations and show reduced expression in Alzheimer's disease: Implications for disease etiology
Authors: van der Linden Robert J. , Soheili‐Nezhad Sourena , Sprooten Emma , Poelmans Geert
Published: December 2020

Background

Aging is associated with the accumulation of somatic mutations in post‐mitotic neurons. While this idea is not new, recent advances in single‐cell sequencing techniques have now made it possible to not only unequivocally prove that these mutations occur but also to estimate their occurrence rates. Here, we aimed to investigate whether somatic mutations are associated with Alzheimer’s disease (AD) and gain insight into the potential pathophysiological consequences of such mutations in the brain.

Method

Starting from the average annual somatic variation rate of healthy neurons, we modeled the likelihood of a gene being affected by somatic mutations over time, based on the transcribed length of that gene. Subsequently, we investigated the gene length distribution of genes that are affected by somatic mutations in AD brains and we analyzed differential mRNA expression data from eight AD brain areas, including pathway analysis.

Result

Our model predicted that CNTNAP2, the largest gene in the human genome, has a 50% chance of having acquired at least one somatic mutation by the age of 65, which is in sharp contrast with average‐sized genes, in which there is only 1% chance of somatic mutations at 65. We also found that genes affected by somatic mutations are (much) longer than average and that larger genes are more likely to be reduced in their expression levels in AD‐vulnerable brain regions. Lastly, we found that these larger genes are predominantly expressed in neurons and are involved in synaptogenesis and synaptic adhesion, pathways that are predicted to be inhibited in AD based on the transcriptomic data.

Conclusion

Our findings implicate somatic mutations in large genes as potential contributors to AD pathology through their effect on synaptic function.
Neuropsychological subtypes of incident mild cognitive impairment in Down syndrome
Authors: Hom Christy
Published: December 2020

Background

Past attempts to characterize the earliest cognitive changes as individuals with Down Syndrome (DS) transition from cognitively stable to mild cognitive impairment (MCI) have been equivocal (Garcia‐Alba et al., 2019; Lautarescu et al., 2017). Difficulties identifying MCI in this population are complicated by variability in pre‐morbid cognitive abilities, the use of neuropsychological tests that were created for the neurotypical population, and participants scoring at floor on the baseline assessment (Krinsky‐McHale and Silverman, 2013).

Method

We examined data from 151 individuals with Down Syndrome (M age=50.25, SD age=6.94). Their pre‐morbid level of intellectual impairment ranged from mild to severe. All participants received comprehensive evaluations. Following data collection, the clinical status of each participant was rated at consensus review that considered performance on a core neuropsychological test battery and the clinical data for each participant. Data from the non‐demented and MCI groups are examined: Cognitive Stable (N=107, 70.9%) and MCI‐DS (N=44, 29.1%). The full battery consists of 27 subtests that were hypothesized a priori to measure five cognitive domains: language, memory, executive function, visuospatial reasoning, and motor coordination.

Result

Factor analysis revealed 7 principal components that maximally discriminated between test scores in older adults with DS who have not reached clinical AD status: (1) general intelligence (2) sensorimotor, (3) memory, (4) language comprehension and expression, (5) executive function/speed, (6) attention/language expression, and (7) visuomotor. Cluster analysis for the MCI group produced 3 distinct groups: (1) dysexecutive (n=4), (2) dysnomic/visuospatial impaired (n=28), and (3) amnestic/motor impaired (n=12).

Conclusion

The neuropsychological battery assesses 7 distinct cognitive functions in older adults with DS. It can also capture cognitive decline, as we were able to empirically identify three distinct neuropsychological subtypes of MCI: amnestic/visuomotor impaired, dysexecutive, and dysnomic. These subtypes are generally consistent with those that have been found within the neurotypical population (Edmonds et al., 2015; Dick et al., 2016), strengthening the evidence that AD has a similar course in the DS population and late onset AD.
Using seeding models to understand strain differences from Alzheimer’s disease and pathological aging brains
Authors: Moore Brenda D. , Hampton Hailey , Croft Cara L. , Futch Hunter S. , Moran Corey , Levites Yona , Fromholt Susan , Xu Guilian , Dickson Dennis W. , Lewis Jada , Golde Todd E. , Borchelt David R.
Published: December 2020

Background

Pathological aging (PA) patients are individuals that are cognitively normal prior to death but have abundant and widespread amyloid‐β (Aβ) deposits. These individuals typically have few cored amyloid deposits with variable levels of diffuse parenchymal deposits and/or vascular deposits. There is little or no inflammatory reaction, neuritic pathology or neurofibrillary tangles in the cortex. Previously, we have shown that total Aβ levels in PA brain lysates were similar to the levels in Alzheimer’s disease (AD) brain lysates, with overlap in the length of the Aβ peptides that were deposited and no major differences in SDS‐stable Aβ oligomeric assemblies. Despite these similarities, it is unclear whether PA represents a prodromal phase of AD or if the amyloid pathology of PA patients represents a less pathogenic variant. To explore this idea, we examined the seeding capacity of AD and PA brain homogenates to induce Aβ deposition and to secondarily induce tau pathology.

Method

We determined the seeding capacity of two AD, four PA and two control brain homogenates in transgenic mice expressing APPswe/ind with and without Tau‐P301L by intracerebral injection at neonatal day 0. At either 6, 9, 12 or 18 months, we assessed Aβ deposition and neurofibrillary pathology in all 4 genotypes by immunohistochemical and biochemical methods. Furthermore we examined the seeding activity of human AD brain lysates in brain slice cultures from APP/Tau transgenic mice.

Result

In our newborn mouse injections, we observed widespread Aβ seeding as evidenced by accelerated onset of diffuse parenchymal Aβ deposition that was largely proportional to the burden of parenchyma deposits in patient brains. In all cases, high levels of pial deposition were observed and Aβ42 was the predominant peptide deposited. Tau pathology was not induced in any animal, and with the absence of neuritic plaques there was no induction of tau positive neurites.

Conclusion

This study provides evidence that the Aβ conformers associated with diffuse Aβ deposits in the brains of cognitively normal individuals possess seeding activities similar to those found in the brains of AD patients. The findings are consistent with the idea that pathological aging is on a continuum with AD.