bluuebunny/crossref_metadata_2025 huggingface dataset:
Framework for disclosing AD biomarker results following cognitive assessment within a pragmatic, multi‐country implementation evaluation
Authors: MacLeod Tim , Baksh Magda Ruth , Filho Otelo Corrêa dos Santos , Govia Ishtar , Robledo Luis Miguel Gutierrez , Kowa Hisatomo , Ritchie Craig W. , Willis Deanna R , Coppinger Justine , Ball Daniel E , Murray James F , Largent Emily A.
Published: December 2022

Background

Blood‐based biomarker tests are critical tools with the potential to change pathways for dementia diagnosis and care. These tests are less invasive than PET scan or lumbar puncture, potentially more affordable, and thus more accessible across more care settings and in more countries. Utilization in primary care settings together with brief cognitive assessments provides a compelling use case that could transform diagnosis, assessment and care.

A critical challenge to the widespread adoption of blood‐based biomarker testing is the issue of disclosure. To date, Alzheimer’s Disease and Related Dementias (ADRD) biomarker disclosure recommendations have primarily focused on disclosure in research and/or specialized‐care settings. Primary care clinicians are well situated to conduct biomarker testing, but they are likely to need training and support to develop confidence and capacity to communicate results.

Method

Review of literature findings involving biomarker disclosure and input from dementia researchers from six countries reflecting diverse health care systems informed development of a disclosure framework to support the inaugural project of the Davos Alzheimer’s Collaborative’s (DAC) Systems Preparedness (DAC‐SP) initiative. This project seeks to promote routine uptake of cognitive screening among people ≥ age 60 and, when cognitive impairment is identified, blood‐based biomarker testing. The biomarker testing is completed using a commercially available, CLIA‐certified test that measures the likelihood of amyloid pathology when cognitive impairment is identified.

Result

The framework recognizes that biomarker disclosure is part of a comprehensive patient evaluation that includes cognitive assessment and a broader discussion of the patient’s health and wellbeing. It divides disclosure into five phases: pre‐test education; consent for and administration of testing; disclosure of results and discussion of treatment plan; provision of educational materials; and follow up (Table 1). This general framework can be adapted for site‐specific factors such as health literacy, health systems operations, legal structures, and cultural relevance.

Conclusion

As part of a pragmatic multisite implementation evaluation of a screening and early detection program including high and middle income countries, the authors have developed a framework to guide biomarker disclosure to patients in primary care settings. This provisional framework represents an important first step towards clinical consensus building on biomarker disclosure.
The association of accelerometer‐measured physical activity, white matter hyperintensity volume, and cognition in normal aging
Authors: Calcetas Amanda T. , Bangen Katherine J. , Thomas Kelsey R. , Smith Christine N. , Bordyug Maria , Brenner Einat K , Zlatar Zvinka
Published: December 2022

Background

White matter hyperintensities (WMH) are an indicator of small vessel cerebrovascular disease, which increases the risk of developing Alzheimer’s disease and related dementia (ADRD). Moderate to vigorous intensity physical activity (MVPA), can help maintain brain structure, function, and cognition in aging. However, the mechanisms by which MVPA may preserve cerebrovascular health remain understudied. To help elucidate the cerebrovascular mechanisms by which MVPA preserves cognition, we examined associations of MVPA and WMH volume, MRI markers of neurodegeneration, and cognition.

Method

Forty‐three adults without cognitive impairment (aged 65–85, 74% female) were recruited from ongoing studies at the University of California, San Diego and underwent MRI exams and comprehensive neuropsychological assessment. Waist‐worn accelerometers objectively measured MVPA for one week. WMH volume was quantified on fluid‐attenuated inversion recovery (FLAIR) scans using semi‐automated procedures and were log transformed and normalized by total intracranial volume (ICV). Hippocampal volume (normalized by ICV) and entorhinal thickness were derived via FreeSurfer. Adjusting for age, sex, and education, ANCOVA models compared participants who had <60 minutes of MVPA per week (n = 18; MVPA<60 group) to those who had ≥60 minutes of MVPA per week (n = 25; MVPA≥60 group) on MRI markers of WMH, hippocampal volume, and entorhinal thickness, and neuropsychological performance on measures of executive function, language, and memory.

Result

Older adults in the MVPA≥60 group had lower WMH volume compared to those in the MVPA<60 group (p = 0.036, ηp
2 = 0.108). There were no significant differences in hippocampal volume (p = 0.157, ηp
2 = 0.052) or entorhinal thickness (p = 0.980, ηp
2 = 0.000) between MVPA groups. The MVPA≥60 group performed better on measures of executive function (Trails B, p = 0.030, ηp
2 = 0.109) and language (category fluency, p = 0.030, ηp
2 = 0.110) than the MVPA<60 group, although the groups did not differ on memory performance (p’s >.05).

Conclusion

Engaging in 60+ minutes of MVPA week may be beneficial for cerebrovascular health and help preserve some aspects of executive and language function performance in older adults. Future work will determine whether better cognitive performance in the MVPA≥60 group is mediated by lower WMH volume. Furthermore, randomized controlled trials that increase MVPA are needed to elucidate cause‐effect associations between MVPA and cognitive and brain health.
End‐of‐life burdensome interventions among Medicare fee‐for‐service beneficiaries with no dementia, non‐advanced dementia, and advanced dementia
Authors: Zhu Yingying , Olchanski Natalia , Freund Karen M , Faul Jessica D , Fillit Howard M , Breslau Rachel M , Cohen Joshua T , Neumann Peter J , Lin Pei‐Jung
Published: December 2022

Background

Older adults with dementia have difficulties communicating their treatment preferences and experience end‐of‐life burdensome interventions with discomfort and limited benefits. This study compared utilization of burdensome interventions during the last 90 days of life among Medicare fee‐for‐service (FFS) beneficiaries with no dementia, non‐advanced dementia, and advanced dementia.

Method

This study utilized data from 2000‐2016 Health and Retirement Study (HRS) linked with Medicare and Medicaid claims, and HRS Exit Interviews. We quantified rates of imaging tests and life‐sustaining treatments during the last 90 days of life among those with no dementia, non‐advanced dementia, and advanced dementia. Life‐sustaining treatments include tube feeding, intensive care unit care, cardiopulmonary resuscitation, and invasive mechanical ventilation. Among patients with a claims‐based diagnosis of dementia, we classified them as having advanced dementia if they had three or more activities of daily living limitations and any diagnosis of malnutrition, pressure ulcer, incontinence, or aspiration pneumonia. We used logistic regression to examine factors associated with end‐of‐life imaging tests and life‐sustaining treatments.

Result

A higher proportion of beneficiaries with non‐advanced dementia (68%) and advanced dementia (79%) had end‐of‐life imaging tests, compared to those without dementia (57%) (p<0.01). Beneficiaries with dementia were more likely than non‐dementia beneficiaries to receive these imaging tests, controlling for patient characteristics (non‐advanced dementia: OR = 2.2 [95% CI 2.0‐2.5]; advanced dementia: OR = 5.4 [4.5‐6.5]). The proportion of receiving end‐of‐life life‐sustaining treatments was lower among the non‐advanced dementia cohort (23%), compared to non‐dementia (27%) and advanced‐dementia (27%) individuals (p<0.01). After adjusting for patient characteristics, beneficiaries with dementia were more likely than those without dementia to receive at least one life‐sustaining treatment (non‐advanced dementia: OR = 1.1 [1.0‐1.2]; advanced dementia: OR = 1.9 [1.6‐2.3]). Younger age, survey self‐respondents, beneficiaries with fewer instrumental activities of daily living limitations and no advance care planning were more likely to have end‐of‐life imaging tests and life‐sustaining treatments.

Conclusion

Our findings suggest that older adults with dementia, especially advanced dementia, are more likely to receive end‐of‐life burdensome interventions compared to individuals without dementia. Advance care planning involving patients with dementia, their families, and physicians about end‐of‐life treatment may improve the quality of care.
Multimodal data collection in Alzheimer’s disease: Participant acceptance of various digital technologies employed in the MEDIA study
Authors: Sorinas Jennifer , Curcic Jelena , Vallejo Vanessa , Sverdlov Oleksandr , Piksa Mateusz , Erdemli Gul , Praestgaard Jens , Snædal Jón , Cha Jang‐Ho , Hannesdottir Kristin , Team MEDIA Study
Published: December 2022

Background

The rate of failed drug trials in Alzheimer’s disease (AD) remains high. Many conventional endpoints currently used to demonstrate success of clinical trials lack sensitivity to drug treatment effects and perform disparately across disease stages. These endpoints tend to be burdensome “single time‐point” assessments that are vulnerable to subjectivity and rater errors.

Novel technologies are rapidly emerging at the same time as our understanding of how to optimally measure drug treatment effects is evolving. Rather than relying on reductionist paper‐pencil assessments, a multimodal approach incorporating more frequent and/or more direct physiological assessments, may result in better detection of true treatment effects. However, will such an approach add too much burden to clinical trials? Are elderly participants in AD trials willing and able to operate new technologies? It is clear that any endpoint that is not well‐accepted by sites or trial participants is unlikely to be successfully adopted for large clinical drug trials.

Method

The MEDIA study was a single‐site study evaluating 10 digital in‐clinic assessments in 38 early AD participants and 12 cognitively healthy controls. The assessments included computerized and augmented reality assessments as well as wearable gait and EEG monitoring. This study additionally included conventional cognitive assessments augmented with unobtrusive digital sensors; such as eye tracking via a tablet camera, speech analytics using voice recordings and physiological assessments using a tablet or pen with built‐in sensors. All participants completed a feedback survey on each of the digital assessments. This feedback survey asked seven questions about ease of use, burden of the assessment and clinical meaningfulness. Responses were recorded on a scale of 0 = strongly disagree to 5 = strongly agree.

Result

The results revealed overall good acceptance of the digital technologies. Although some of the assessments were considered mentally demanding, the majority of participants felt the technologies were easy to use, clinically meaningful and enjoyable.

Conclusion

There is great anticipation for more sensitive clinical endpoints in AD. However, a question remains on the operational feasibility and how acceptable digital endpoints are to trial participants. This presentation discusses early AD participant (from presymptomatic to mild dementia) acceptance of different digital assessments.
Neuropsychological assessment in the multicultural memory clinic: development and feasibility of the TULIPA battery
Authors: Franzen Sanne , van den Berg Esther , Bossenbroek Willemijn , Kranenburg Judi , Scheffers Esther , van Hout Moniek , van de Wiel Lotte , Goudsmit Miriam , van Bruchem‐Visser Rozemarijn L. , van Hemmen Judy , Jiskoot Lize C. , Papma Janne M.
Published: December 2022

Background

Neuropsychological assessment of culturally diverse populations is hindered by barriers in language, culture, education, and a lack of suitable tests. Furthermore, individuals from diverse backgrounds are often unfamiliar with being cognitively tested. The aim of this study was to develop a new neuropsychological test battery and study its feasibility in multicultural memory clinics.

Method

Composition of the TULIPA battery (Towards a Universal Language: Intervention and Psychodiagnostic Assessment) entailed a literature review and consultation with experts and individuals from diverse backgrounds. Feasibility was investigated by examining administration and completion rates and the frequency of factors complicating neuropsychological assessment in 345 patients from 37 countries visiting four multicultural memory clinics in the Netherlands.

Result

The test battery included existing tests such as the Cross‐Cultural Dementia screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), and tests from the European Cross‐Cultural Neuropsychological Test Battery, and newly developed tests. Completion rates for the test battery were generally high (82%‐100%), except for CCD Dots subtest B (58%). Although tests of the ‘core’ TULIPA battery were administered often (median: 6 of 7, IQR: 5–7), supplementary tests were administered less frequently (median: 1 of 9; IQR: 0–3). The number of administered tests correlated with disease severity (RUDAS, ρ = .33, adjusted p<.001), but not with other patient characteristics. Complicating factors were observed frequently, e.g., suboptimal effort (29%‐50%), fatigue (29%), depression (37%‐57%).

Conclusion

The TULIPA test battery is a promising new battery to assess culturally diverse populations in a feasible way, provided that complicating factors are taken into account.
Domain‐specific self‐ and informant‐reported cognitive complaints across the Alzheimer’s disease spectrum
Authors: Cacciamani Federica , Godefroy Valérie , Brambati Simona M , Migliaccio Raffaella , Montembeault Maxime
Published: December 2022

Background

A growing number of studies are currently investigating whether Subjective Cognitive Decline (SCD) may represent an early indicator of Alzheimer’s disease (AD). Due to the high frequency of amnestic AD dementia, SCD research is highly focused on episodic memory. Non‐amnestic complaints are less studied, although patients or their families often report difficulties in retrieving words, planning or spatial orientation, to name a few (e.g., Valech et al., 2018, J Alzheimers Dis). Furthermore, few studies have investigated which source of complaint is the most accurate. In this study, we aimed to measure how accurately self‐ and informant‐reported complaints in different cognitive domains can discriminate individuals along the AD continuum and controls.

Method

We selected four groups of participants from the ADNI cohort: amyloid‐positive (Aβ+) individuals with AD, mild cognitive impairment (MCI) or cognitively normal (CN), and amyloid‐negative (Aβ‐) CN controls. Self‐ and informant‐reported complaints were measured with the Everyday Cognition questionnaire in four domains, namely, memory, language, visuospatial abilities, and executive functions. Receiver operating characteristic curves analysis was performed to evaluate the accuracy of the ECog scores in discriminating the groups.

Result

Self‐ and informant‐reported complaints were distributed as follows: memory, language, executive, and visuospatial (from the most severe to the least severe). ECog‐Subject scores globally distinguished groups little better than chance. The Memory score performed best among the ECog‐Subject scores, but the accuracy was low to moderate. In the other three domains, most AUCs were below 0.70 and specificities always below 70%. All ECog‐StudyPartner scores (i.e., in all four cognitive domains) could discriminate MCI and AD from CN, as well as AD from MCI, with good to excellent accuracy (all AUCs between 0.72 and 0.98). However, no ECog‐StudyPartner score seemed useful in distinguishing Aβ+/CN and Aβ‐/CN subjects (all AUC<0.55, all specificity indices <0.22).

Conclusion

Self‐reported SCD may have limited utility for both early diagnosis and the inclusion of subjects in research protocols. Individuals with early‐stage AD may already present reduced awareness of their cognitive decline (e.g., Cacciamani et al., 2021, Alzheimer’s Res. Ther). For this reason, it seems crucial to consider informant‐reported complaints, both amnestic and non‐amnestic.
Scaling Comprehensive Dementia Care
Authors: Super Nora
Published: December 2022

Background

Despite scientific progress over the last 25 years, dementia remains one of the toughest health‐care challenges. Alzheimer’s disease is the sixth‐leading cause of death in the United States, and the number of deaths from all related dementias may be twice as high.[i] Years of investment and research in Alzheimer’s disease and related dementias (ADRD) are sowing seeds of hope. New treatments aim to slow cognitive decline and manage symptoms. However, because of the complexity of dementia, people living with dementia will likely need a combination of therapeutic treatments, coordinated care, and supportive services to help them live their lives to the fullest post‐diagnosis.

Method

The Milken Institute Alliance to Improve Dementia Care convened a roundtable in June 2021. Leaders across industry, government, research, advocacy, philanthropy, health systems, and community‐based organizations explored ways to improve and pay for comprehensive dementia care. Through a consensus‐driven process, we produced a report that presents actionable recommendations to improve post‐diagnostic care and payment policies under traditional Medicare.[i]

[i] Nora Super, Rajiv Ahuja, and Mac McDermott,” Milken Institute, November 2021: https://milkeninstitute.org/report/dementia‐care‐models‐scaling‐comprehensive

Result

Based on extensive desktop research, the roundtable convening, and consultation with a working group of experts, we identified five high potential action steps.

1. Ensure all dementia‐care models contain a minimum set of core elements for comprehensive care and follow a population‐health approach that tiers services to level of need

2. Implement quality measures to evaluate access, utilization, and outcomes of comprehensive dementia‐care models, particularly for diverse communities disproportionately impacted by dementia and their caregivers

3. Expand dementia‐specific training beyond physicians and nurses to increase interprofessional coordination, provide continuous monitoring and assessment, and expand access to high‐quality, dementia‐care services

4. Test implementation of payment models for comprehensive dementia care in traditional Medicare, especially in underserved communities.

5. Develop mechanisms to pay community‐based organizations (CBOs) for services provided to individuals living with dementia and their caregivers.

Conclusion

Alternative payment models are needed under traditional Medicare to incentivize providers to coordinate care, pay CBOs for the services they provide, align incentives among payers, providers, and patients, and ensure those living with dementia and their caregivers receive more seamless, coordinated health‐ and long‐term care.
Distinct features of rapidly progressive Alzheimer’s disease
Authors: Wang Ping , Lynn Audrey , Song Yeunjoo E. , Haines Jonathan L.
Published: December 2022

Background

Rapidly progressive Alzheimer’s disease (rpAD) has been recognized as a subtype of Late‐Onset Alzheimer’s disease (LOAD) characterized by accelerated cognitive decline and/or reduced survival. The cause of variable progression rates of AD is largely unknown, and information regarding unique clinical features of rpAD is limited in longitudinal cohorts.

Method

A retrospective analysis was performed on AD patients in the National Alzheimer’s Coordinating Center (NACC) database from 2015 to 2021. Patients with rpAD were identified by reduced survival time (time from symptom onset to death < = three years) or accelerated cognition decline (defined as Mini‐Mental State Exam [MMSE] decrease > = 6 points/year or Clinical Dementia Rating scale [CDR] global score increase to 2 or 3 within three years). Demographic, clinical, and neuropsychological measurements were compared between patients with rpAD, typical “slow” progressive AD, and normal controls. rpAD patients and normal controls with Whole Genome Sequencing (WGS) data available from the Alzheimer’s Disease Sequencing Project (ADSP) were selected for a pilot genome‐wide association study (GWAS).

Result

Among 43,746 NACC participants, 983 patients met our criteria for rpAD. rpAD patients had a mean survival of 2.8±0.5 years and their decline in MMSE was 6.4±5.9 points/year. Compared to controls, rpAD patients were older (72.6±8.6 vs 70.0±8.6, p < 0.001), more likely to be male (39% vs 33%, p < 0.001) and had fewer years of education (14.6±3.6 vs 15.9±3.0, p < 0.001). Compared to AD patients who progressed slowly, rpAD patients showed a more rapid decline in neuropsychological tests measuring working memory, language, attention, and executive function (p values < 0.001). GWAS was performed on 175 rpAD patients and 525 age‐ and sex‐matched NACC controls. 49 genetic variants showed significant associations with rpAD (p‐values < 1 × 10−5).

Conclusion

In the longitudinal NACC cohort, rapidly progressive AD constitutes an important subset, featuring a short survival with rapid decline of cognitive and neuropsychological functions. Previously known genetic risk variants for AD were not found in this rpAD cohort. Further examination of rpAD cohort could help identify unique mechanisms that drive the rate progression in AD for different groups of patients.
Clinical and sociodemographic characteristics of patients with Neurocognitive Disorder (NCD) (dementia) at the Ramón de la Fuente Muñiz National Institute of Psychiatry (INPRFM) Psychogeriatrics Clinic in Mexico City, between 2011 and 2020.
Authors: Marin Luis Fernando Collazos , Lopez Guillermo Velazquez , Salas Ismael Aguilar
Published: December 2022

Background

The demographic and epidemiological transition, increased life expectancy and decreased fertility rate have increased the prevalence of dementia that affects 55 million people worldwide; it is estimated to affect 75 million by 2030 and increase three times by 2050. The clinical and sociodemographic characteristics of the studied population are unknown. It is the first study of its kind in the region. It’s also an unaddressed issue where an exploratory type protocol was carried out and a hypothesis was not formulated.

Methods

Descriptive, observational, cross‐sectional, retrospective study. A Mexican population database including subjects from a previous work was created and then a secondary analysis was made. Every patient diagnosed with NCD was included regardless of age and with a clinical, psychiatric and/or geriatric syndrome diagnosis. No instrument or scale was used. There was no funding. Statistical analysis was done in SPSS 20.0.

Results

2056 records were found, 675 met the inclusion criteria. Age 74.71 (±9.02) years, from the urban area 93.78% (n = 633), women 72.15% (n = 487), primary school 49.90% (n = 243), widows 37.99% (n = 185), household occupation 77.21% (n = 376), low socioeconomic status 57.08% (n = 278). 59.86% (n = 404) had a major NCD, MMSE of 18.88 points (±6.68), Alzheimer’s disease was present in 31.56% (n = 213) both in those under 60 years of age 25.64% (n = 10) and in those older than 60 years old 31.92% (n = 203). Mild NCD was present in 9.19% (n = 62), the diagnosis was ruled out in 3.11% (n = 21) and a diagnosis could not be concluded in 25.93% (175). The most common psychiatric pathologies were Depressive and anxious disorder with 80.00% (n = 540) and 9.19% (n = 62) respectively; Clinical diagnosis were Arterial Hypertension 50.07% (n = 338), diabetes mellitus 22.22% (n = 150) and geriatric syndromes in 14.57% (n = 218).

Conclusion

The study analyzes the characteristics of the clinic’s patients. The first of its kind which differentiates it from population based studies. The results are not intended to be extrapolated to the general population. Due to limitations in the diagnostic process of dementias, there were no diagnostic methods such as biomarkers in cerebrospinal fluid, functional or genetic neuroimaging. The intention is to promote dementia research and highlight the extent of the problem to Latinamerican Governments.
Trajectories of cognitive performance in late middle‐aged adults: Bayesian random change point mixed model analysis in WRAP
Authors: Du Lianlian , Koscik Rebecca Langhough , Betthauser Tobey J , Jonaitis Erin M. , Hermann Bruce P , Johnson Sterling C. , Larget Bret , Chappell Richard J.
Published: December 2022

Background

Previous studies indicate that rates of cognitive decline in Alzheimer’s disease (AD) and other dementias may accelerate significantly as brain pathology increases. The objectives of this study included to: 1) characterize changepoints and related slope parameters across four cognitive composites in a longitudinal cohort study; and 2) examine how these parameters varied across predictors of interest.

Methods

Dementia‐free participants at baseline from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) with > = 3 cognitive assessments were eligible (n≈1071; mean(sd) baseline age = 58.4(6.4)). We used newly‐developed Bayesian random change point mixed models (BRCPMM) to estimate fixed (group‐level) and random (person‐level) change points (CPs), slopes pre‐ and post‐CP, and intercepts at CP for four cognitive composites: three‐test preclinical Alzheimer’s cognitive composite (PACC3; primary outcome), immediate learning, delayed learning, and executive function. We used non‐parametric statistics to test whether PACC3 estimates differed by: last cognitive status observed (cognitively unimpaired‐stable or ‐declining (CU‐S, CU‐D), MCI, and dementia); sex/gender, and APOE‐e4 carrier status.

Results

Posterior median fixed and random effect estimates (corresponding 95% credible intervals from 20000 BRCPMM runs) are summarized in Table 1 by outcome. The PACC3 group‐level CP was earliest at ∼75.56 [72.98,78.44] years old with 95% of individuals hitting CP between 59.69 and 91.86. Timing of CP was significantly associated with last observed cognitive status (Table 2); those 37 (3.46%) progressing to MCI/dementia had estimated CP’s before or during study participation while those remaining unimpaired had estimated CP’s after their last visit. All random effects (person‐level) PACC3 estimates differed by worst cognitive status (Figure_1) and sex/gender (Figure_2). For example, while the CU‐D and MCI groups had similar slopes before CP, CP occurred earlier, estimated PACC3 at CP was lower, and post‐CP slope was worse in the MCI group compared to CU‐D (Figure_1). APOE‐e4 random‐effects estimates differed by CP and post‐CP slopes (Figure 3).

Conclusions

The timing and rates of change in different cognitive composites differ by cognitive status, gender, and APOE‐e4 status. Predicting individual cognition trajectories and change points may provide an opportunity for early intervention by diagnosing high‐risk subjects at the right time for treatment and/or enrollment in a clinical trial.
Cognitive Reserve in Mild Cognitive Impairment: structural and functional imaging correlates
Authors: Carbone Chiara , Balboni Erica , Beltrami Daniela , Gasparini Federico , Fiondella Luigi , Salemme Simone , Vinceti Giulia , Molinari Maria Angela , Marti Alessandro , Tondelli Manuela , Chiari Annalisa , Zamboni Giovanna
Published: December 2022

Background

The term “Cognitive Reserve” (CR) refers to the ability of the brain to cope with the damage in order to minimize symptomatology. Several studies have shown controversial data about functional and structural correlates of CR in normal and pathological aging, probably due to the use of different CR proxies (level of education, occupational complexity, participation in leisure activities, IQ, verbal abilities or intelligence, heterogeneous fMRI tasks). The aim of this study was to investigate imaging correlates of different aspects of CR in a sample of patients with Mild Cognitive Impairment (MCI).

Method

Patients with a diagnosis of MCI and young onset of cognitive symptoms (< 65) answered the Cognitive Reserve Index questionnaire (CRIq) aimed at measuring cognitive reserve acquired during lifetime. Patients also underwent multimodal Magnetic Resonance Imaging (MRI) on a 3T scanner including high‐resolution T1 and functional MRI sequences acquired at rest (resting fMRI). CRIq‐Total score and single subscores (CRIq‐Education, ‐WorkingActivity and ‐LeisureTime) were related to regional grey matter (GM) volume, whole brain fractional anisotropy (FA) and functional connectivity of resting‐state networks (RSNs) using, respectively, Voxel Based Morphometry (VBM), Tract‐Based Spatial Statistics (TBSS), and independent component analysis of resting fMRI (MELODIC).

Result

Thirty‐nine patients were recruited. The median CRIq‐Total, ‐Education, ‐WorkingActivity and ‐LeisureTime scores were respectively 102, 97, 105 and 105. VBM correlational analysis showed no significant results. TBSS revealed a negative correlation between CRIq‐LeisureTime and FA of the body of corpus callosum. Resting‐fMRI analyses revealed negative correlations between CRIq scores and functional connectivity, involving particularly frontal and temporal areas.

Conclusion

In patients with MCI, cognitive reserve relates to functional connectivity of fronto‐temporal areas rather than to structural variability (grey matter atrophy or white matter microstructural integrity). The negative correlations found between functional connectivity and CRIq scores shows that patients with high cognitive reserve may not need to increase functional connectivity.
Role strain and COVID‐era burden among South Asian caregivers of individuals with brain health conditions and disabilities
Authors: Tjin Anna , Troy Carol , Vinarti Retno Aulia , Banerjee Debanjan , Goodwin Anna , Yeo Selvie , Saha Sanjib , KRISHNA Murali , Goswami S P , Chen Yaohua Sophie , Leroi Iracema , O'Sullivan Roger
Published: December 2022

Background

The COVID‐19 pandemic has renewed attention to the conflicting demands placed on caregivers worldwide. Nowhere is this more evident than in South Asia, where cultural norms and a scarcity of long‐term care facilities have made the home the locus of caregiving for individuals with brain health conditions and disabilities. A hidden cost of this informal arrangement is the burden experienced by the primary caregiver. This may be exacerbated when traditional caregiving expectations clash with personal aspirations outside the family.

Method

This paper investigates the determinants of burden among 494 informal caregivers in India, Pakistan, and Bangladesh during the COVID‐19 pandemic. The variables, obtained from the Coping with Loneliness, Isolation, and COVID‐19 (CLIC) Global Caregiver study, include caregiver demographic characteristics, features of the caregiving arrangement, and subjective measures of the caregiving experience. The dependent variable in our analysis, the perceived frequency of burden, is rated by respondents on a five‐level scale. Role strain is expected to be greatest among young, educated women living with the care recipient in their own homes. Therefore, burden should exhibit a positive association with female gender, education, and cohabitation, and a negative association with age.

Result

Out of the 494 caregivers included in the study, 33.8% experienced increasing burden and 58% experienced loneliness some of the time during Covid‐19. The ordinal logistic marginal effects are consistent with all four hypotheses. Caregiver Burden is found to be positively correlated with female gender (OR,1.92; 95%CI, 0.35,1,03; P=<0.001), the 18‐39 age range (OR,1.71; 95%CI, 0.114, 0,963; P=0.01), poor finances (OR,2.192; 95%CI,0.22,1.34; P=0.006), poor physical health (OR, 2.24, 95%CI, 0.29,1.32, P=0.002), poor mental health (OR,1.86; 95%CI, 0.14,1.10, P=0.011), and care recipients with dementia/Alzheimer's (OR,2.76; 95%CI, 0.52,1.51, P=<0.001) and/or mental health conditions (OR,1.61; 95%CI, 0.02,0.94, P=0.039).

Conclusion

Role strain may be a significant driver of burden when the caretaker’s educational and professional potential collide with traditional South Asian family obligations. The burden reported by our respondents suggests that role strain may elevate stress among young, educated caregivers. Our results, therefore, provide indirect evidence concerning the changing economic and socio‐cultural context of caregiving in South Asian households.
Tau phosphorylation is more closely associated with amyloid‐β plaques than with tau neurofibrillary tangles
Authors: Vermeiren Marie , Therriault Joseph , Servaes Stijn , Lussier Firoza Z , Tissot Cécile , Pascoal Tharick A , Chamoun Mira , Bezgin Gleb , Benedet Andréa Lessa , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Stevenson Jenna , Rahmouni Nesrine , Kunach Peter , Wang Yi‐Ting , Arias Jaime Fernandez , Massarweh Gassan , Vitali Paolo , Soucy Jean‐Paul , Saha‐Chaudhuri Paramita , Blennow Kaj , Zetterberg Henrik , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2022

Background

While fluid phosphorylated tau (pTau) epitopes are interpreted to be biomarkers of tau pathology according to the A/T/(N) framework, it is unclear to what extent they are preferentially associated with the defining histopathological hallmarks of Alzheimer’s Disease (AD): amyloid‐β plaques and tau neurofibrillary tangles.

Method

We studied 171 individuals, including young adults (n=27), cognitively unimpaired elderly (n=85), individuals with mild cognitive impairment (n=36) and individuals with Alzheimer’s clinical syndrome (n=23), who were evaluated with [18F]AZD4694 amyloid‐PET, [18F]MK6240 tau‐PET, four tau phosphorylation sites in CSF (pTau181, pTau217, pTau231, pTau235) and two phosphorylation sites in plasma (pTau181, pTau231). To better understand the role of soluble biomarkers in AD diagnostic and research purposes, we evaluated associations between soluble pTau sites and cerebral amyloid‐PET and tau‐PET concentrations. Voxel‐wise linear regressions between fluid and imaging biomarkers were performed. Results for plasma and CSF pTau181 were replicated in an independent sample of 258 individuals included in the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI).

Result

We observed that for all plasma and CSF epitopes, pTau is more closely associated with amyloid‐PET than with tau‐PET. Squared correlation coefficients (Spearman’s R2) between CSF pTau epitopes and neocortical [18F]AZD4694 SUVR range from 0.48 to 0.63, while those for the temporal meta‐ROI [18F]MK6240 SUVR vary between 0.33 and 0.45 (p<0.001 for all phosphorylation sites). Using the R package “Cocor”, for CSF pTau181, pTau217 and pTau231 the difference in correlation coefficients between both measures of imaging biomarkers appear significant (p<0.01). Voxel‐wise linear regression analyses further support these results, in particular showing sizable associations for CSF pTau231 with amyloid‐PET. In addition, soluble pTau is more closely correlated with medial temporal than with neocortical tau. All soluble pTau concentrations rise significantly with increasing amyloid‐β plaque load. In contrast, soluble pTau plateau as tau‐PET concentrations increase, starting at Braak stage III. These findings were replicated using plasma and CSF pTau181 in the ADNI cohort.

Conclusion

Phosphorylated tau epitopes measured in CSF and plasma better reflect cerebral amyloidosis than neurofibrillary tangles in the brain. The current findings support careful interpretation of fluid pTau concentrations when implementing the A/T/(N) framework.
Examining the level of test burden in NIA’s Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) clinical trials
Authors: Roper Rebecca Anne , Manohar Rhea , Crespo‐Bellido Mayra , Bui Elise , Jarvis‐Gibson Jeanne , Mitchell Alexandra , Massett Holly A , Miscally Memi
Published: December 2022

Background

The National Institute on Aging (NIA) is working to increase access of its AD/ADRD clinical trials (CT) into community health care settings. Concerns exist in the field regarding the feasibility of conducting AD/ADRD CTs outside of academic settings given the testing required within CT protocols. We evaluated recently awarded NIA CTs to document their types and frequency of diagnostic tests required. Findings provide NIA the opportunity to understand the potential test burden on sites and consented participants.

Method

We conducted a systematic content analysis of recently funded NIA AD/ADRD CTs involving human subjects to assess the commitment required of participants and the number and type of tests required across protocols (start dates: 2/1/20 – 9/30/2021 (N = 115)). Documented tests included: imaging, biospecimen, genetic, sleep, cognitive, and mental health. Findings were analyzed by the CTs’ standardized Common Alzheimer’s and Related Dementias Research Ontology (CADRO) category.

Result

Most CTs (65%) were CADRO C (Translational Research/Clinical Interventions) or E (Dementia Care/Disease Impact; 25%); CADRO E had substantially fewer tests required of participants. Most trials (75%) asked consented participants for less than a year commitment (median = 185 days). Top tests required were cognitive (78% of trials); mental health/well‐being (57%); brain imaging (46%; e.g., MRI, PET, MRS), and blood collection (37%). Fewer CTs required lumbar spinal tap (12%). Initial analyses indicate that potentially 75 unique cognitive tests were documented across the 90 CTs assessing cognition, and that participants were asked to complete a median 8.5 cognitive tests per trial (range: 1 to 71 tests).

Conclusion

This review lays the foundation for understanding the complexity of recently funded NIA AD/ADRD clinical trials. Understanding the required tests will inform the discussion with community health practitioners to identify what and how many tests are feasible, and how such input can be incorporated into the design of future trials in a way that can enhance opportunities and research participation by interested communities, particularly those serving traditionally underserved populations.
Non‐Pharmacologic management: Considerations for Family Caregivers
Authors: Fischer Corinne E. , Hakobyan Narek
Published: December 2022

Background

Agitation is a common symptom of dementia, estimated to occur in upwards of 30% of patients.1 Family caregivers are often the frontline when it comes to management of agitation given that many patients with dementia live at home, and often bear the brunt of caregiver burden. In spite of existing research, which non‐pharmacological interventions should be used when is unclear.

Method

This abstract describes the application of the IPA algorithm to the family‐caregiver setting.

Result

The current IPA algorithm for agitation emphasizes the importance of non‐pharmacological interventions integrated with pharmacological interventions and adapted in an iterative manner dependent on patient response. Data on non‐pharmacological interventions in the family caregiver setting, though sparse, suggest a couple of key themes. Most interventions, including analyses of data from social media platforms, Long Term Care data and clinical trial data emphasize the importance of patient engagement.2 Planning appropriate activities, problem‐solving and teaching communication skills is also paramount. Finally, modification of the environment, reminiscence and engagement with outside support networks is critical. Individualized approaches with multiple components and modified based on follow up are particularly effective. Review of clinical trial data in fact suggests effect sizes comparable to that achieved with medication without the concomitant side effects.2 Finally, interventions that focus on the well‐being of the caregiver and emphasize enhanced self‐efficacy are particularly important, given caregiver burden in family caregivers often exceeds that of professional caregivers. Studies have been limited by lack of standardization, small sample sizes and limited follow‐up.

Conclusion

Further rigorous studies are required to establish which approaches are most effective in family caregivers and how they relate to pharmacological interventions, though data to date suggest interventions that work in other setting (such as Long Term Care) may be adaptable to the family setting.

1. Carrarini C, Russo M, Dono F, et al. Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions. Front Neurol 2021; 12: 644317.

2. Brodaty H, Arasaratnam C. Meta‐analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. The American journal of psychiatry 2012; 169(9): 946‐53.
Sex Differences in Mild Cognitive Impairment Risk by APOE Genotype
Authors: Wang Xinran , Edland Steven D. , Sundermann Erin E. , Banks Sarah J.
Published: December 2022

Background

Male sex is suggested as a risk factor for mild cognitive impairment (MCI), but this association may be influenced by the female verbal memory advantage, and the use of verbal memory tests has been shown to delay MCI diagnosis in women. Moreover, this association may vary by apolipoprotein E (APOE) genotype. The National Alzheimer’s Coordinating Center (NACC) uniform data set (UDS) contains demographic data and annual standardized neuropsychological (with memory being assessed primarily with verbal tests) and clinical diagnostic data obtained by 41 NIA‐funded Alzheimer’s Disease Centers across the U.S. This large database is a rich resource for evaluating sex effects on MCI/Dementia diagnosis by APOE genotype.

Method

We restricted to NACC enrollees above 60 years old, with available APOE genotype, cognitively normal at their initial UDS visit, had at least one follow‐up visit, and without a documented dominantly inherited Alzheimer mutation, leaving 10,461 participants (35.3% men, 77.0% non‐Hispanic White). Cox proportional hazards models of time to incident MCI/dementia controlling for sex, baseline age, years of education, baseline Mini‐Mental Status Exam (MMSE), and interaction terms as indicated were fit separately to APOE E3/E3 homozygotes and E3/E4 heterozygotes. Small sample size precluded analyses of other APOE genotypes. Secondary analyses restricting to non‐Hispanic White participants were also examined.

Result

Among APOE E3/E3 homozygotes, male sex is a risk factor for clinically diagnosed MCI/dementia (Hazard ratio (HR) = 1.27, p < 0.001) independent of age at enrollment. Among APOE E3/E4 heterozygotes, male sex is a risk factor at the lower range of age (age 60–75), while female sex is a risk factor at the higher range (interaction p = 0.006). Similar findings were obtained when restricting to the non‐Hispanic White participants.

Conclusion

The higher risk of MCI/dementia in men in the NACC cohort may reflect previously‐reported sex differences in verbal memory performance at early stage AD pathogenesis and the use of verbal memory diagnostic tests more sensitive in men early in the disease.
Assessment of gray matter microstructure and synaptic density in Alzheimer’s Disease: a multimodal imaging study with DWI and SV2A PET
Authors: Salardini Elaheh , Silva‐Rudberg Jason A , O'Dell Ryan S. , Chen Ming‐Kai , Ra Jocelyn , Georgelos Jamie K , Morehouse Mackenzie R , Melino Kaitlyn P , Nabulsi Nabeel B. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H , Mecca Adam P
Published: December 2022

Background

Diffusion weighted imaging (DWI) is proposed to show alterations to microscopic barriers (O'Donnell, et al. 2011) associated with neurodegeneration (Jacobs, et al. 2013). Positron emission tomography (PET) imaging has also been used to measure synaptic density. Previously, we have shown that synaptic density is lower in Alzheimer’s Disease (AD) participants (Mecca, et al. 2020) and is correlated with cognitive performance in patients with AD. Here, we aim to investigate the relationship between DWI metrics and synaptic density in gray matter in the hope of better understanding of AD neurobiology.

Method

Thirty‐four amyloid positive participants with clinical diagnosis of AD and 18 amyloid negative cognitively normal (CN) participants were included in this study. Early AD‐affected regions (entorhinal cortex, hippocampus, posterior cingulate, and precuneus) were chosen as the primary region of interest (ROI). Synaptic density was measured using [11C]UCB‐J PET where the distribution volume ratio in ROIs was computed using SRTM2 with cerebellum as reference region. Average axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) within each ROIs was computed using Freesurfer 6. Between group comparisons were performed using an unpaired t‐test. Association between gray matter DWI metrics and synaptic density was assessed using univariate regression analyses.

Results

AxD was significantly higher in AD participants in entorhinal cortex and hippocampus bilaterally as well as right posterior cingulate and left precuneus. FA was significantly lower in left hippocampus, and significantly higher in right hippocampus and right posterior cingulate in AD participants. MD was significantly higher in AD participants in bilateral entorhinal cortex, left hippocampus and left precuneus. RD was significantly higher in AD participants in left precuneus, bilateral entorhinal cortex and hippocampus. Within AD participants, synaptic density was inversely correlated with AxD, MD, and RD in the entorhinal cortex and hippocampus bilaterally and positively correlated with FA in the left precuneus. These associations were absent in the CN group.

Conclusion

We found that DWI metrics had significant correlation with synaptic density in Early AD‐affected regions in participants with AD, but not in CN participants. We hypothesize that DWI outcome alterations is reflective of gray matter microstructural changes related to synaptic loss.