bluuebunny/crossref_metadata_2025 huggingface dataset:
Cultural differences in end‐of‐life care planning for persons with dementia: Comparison of U.S. and Korean cases
Authors: Ha Jung‐Hwa , Lee Changsook
Published: December 2020

Background

Providing good quality care at the end of life is important not only for cognitively‐intact patients but also for people who have dementia. In order to respect the patients’ preferences for end‐of‐life care (EOLC) among persons with dementia (PwD), it is critical to engage in advance care planning before PwDs lose cognitive functioning. However, even if health practitioners perceive such needs, they may be constrained by social and cultural factors in initiating conversations about EOLC. This study examined cultural differences in EOLC planning for PwDs using the case study method. We conducted in‐depth interviews with 7 social workers who work in South Korea, 2 Korean American social workers working with Korean‐American older adults in the US, and 3 American social workers who work in the community and hospice settings serving diverse populations. We asked about participants’ opinion about advance care planning(or EOLC) for PwDs, whether and how they engage in discussions on EOLC, obstacles in their efforts to engage in these discussions, suggestions for improving EOLC and decision making for PwDs. We conducted content analysis and extracted themes relevant to our research questions. Results show that social workers in Korea feel reluctant to engage in advance care planning for PwDs because older adults as well as their caregivers do not want to talk about death. Compared to social workers in Korea, social workers working in the Korean American communities in the US engage in EOLC planning with their clients more frequently, but they wait until they find opportunities to talk about EOLC, such as death of their client’s family of friends. On the other hand, social workers working in the non‐immigrant communities in the US perceived advance care planning as a way to ensure self‐determination and autonomy in EOLC decision making and offered opportunities to prepare for EOLC even when their clients did not bring up the issues. Implications for culturally sensitive practice and ways to improve awareness on the importance of EOLC planning in death‐avoiding cultures are discussed.
Regional variability and solubility of apolipoprotein E in brains from patients with Alzheimer’s and Parkinson’s disease
Authors: Twohig Daniel , Karampatsi Dimitra , Edlund Anna K. , Nielsen Henrietta M.
Published: December 2020

Background

APOEε4 is the strongest genetic risk factor for both Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and increases the severity of Lewy pathology in Parkinson’s disease (PD) and DLB1. Interestingly, nearly all familial PSEN1 mutation‐carrying AD patients exhibit Lewy pathology specifically in the amygdala2 and higher CSF α‐synuclein levels in APOEε4‐carrying asymptomatic familial AD patients were linked to amyloid‐β pathology3. Further, brain‐area specific intraneuronal accumulation of soluble α‐synuclein was previously reported in AD patients4 and an enrichment of ApoE was described in dopaminergic neurons of PD patients5. Together the accumulating evidence suggests an intricate interplay between APOEε4, ApoE and α‐synuclein in both PD/DLB and AD. Here we investigated the levels and molecular size distribution of ApoE4 and total ApoE in three different brain areas from PD and AD patients.

Method

Fresh‐frozen tissue (Netherlands Brain Bank) from the medial frontal lobe, medial temporal lobe and amygdala of neuropathologically confirmed AD (n=3) and PD (n=3) patients with an APOEε3/ε4 genotype was lysed and fractionated to yield tris‐buffered saline (TBS) soluble and TBS‐Triton X‐100 (TBX) soluble protein fractions. Western blotting, densitometry and statistical analysis were then used to identify, quantify and compare levels of total ApoE and ApoE4 in the two fractions from each brain area.

Result

TBS‐soluble levels of monomeric ApoE4 were higher in PD patients versus AD patients specifically within the amygdala (p=0.046), the same fractions also contained high molecular weight ApoE bands (90‐95kDa) that were significantly enriched in the AD patients (p=0.028) The TBX‐soluble fractions from the frontal gyrus of PD patients exhibited lower levels of fragmented (28‐30kDa) ApoE4 (p=0.047) and total ApoE compared to AD patients.

Conclusion

Elevated levels of TBS‐soluble monomeric ApoE4 in the amygdala of PD patients compared to AD patients and increased fragmentation of TBX‐soluble ApoE and specifically ApoE4 in AD patients together suggest an implication of ApoE4‐specific processes that differ between PD and AD.
Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s disease‐like symptom and pathology progression through increased turnover of amyloid precursor protein machinery
Authors: Pickering Andrew
Published: December 2020

Background

The proteasome has key roles in neuronal proteostasis, including removal of misfolded or oxidized proteins, presynaptic protein turnover, as well as synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD). Artificial impairment of proteasome function can mimic many neurodegenerative phenotypes.

Methods

We created transgenic mice and flies as well as novel proteasome activating drugs to examine whether proteasome augmentation can reduce AD like symptoms in animal models of the disease.

Results

We report that manipulation of proteasome activity can influence the rate of AD‐like progression. We show that augmentation of proteasome function in fly and cell culture models of AD delays mortality, cell death, and AD‐like cognitive deficits. We developed a transgenic mouse with neuronal‐specific proteasome overexpression which, when crossed with a mouse model of AD, reduced mortality and diminished AD‐like cognitive deficits. To establish translational relevance, we developed a set of novel proteasome‐activating peptidomimetics based on modifications of proteasome binding fragments derived from the viral protein HIV‐1 Tat. These agonists stably penetrate the blood‐brain‐barrier and enhance 20S as well as 26S proteasome activity. We show that treatment with these agonists protects against cell death in a cell culture model of AD as well as both cognitive decline and mortality in fly and mouse models of AD. The protective effects observed from proteasome overexpression in our models appear to be driven at least in part by increased turnover of the amyloid precursor protein (APP) and β‐secretase enzyme (BACE1) by the proteasome.

Conclusion

We conclude that the proteasome plays an important role in AD‐like progression. Furthermore augmentation of proteasome function is protective against AD‐like pathogenesis in diverse models of the disease, potentially representing a new therapeutic target for treatment of AD.
Big data and dementia in New Zealand
Authors: Yates Susan , Rodriguez Claudia Rivera , Martinez‐Ruiz Adrian , Coomarasamy Christin , Whittington Rosie , Krishnamurthi Rita , Cheung Gary , Kerse Ngaire , Cullum Sarah
Published: December 2020

Background

Research is increasingly looking at how routinely collected health and social care data can be used to influence policy and service design, however the accuracy of such data in New Zealand is not known. Estimates suggest there are 62,000 people living with dementia in NZ, projected to reach 170,000 by 2050, however these figures are extrapolated from overseas prevalence data and do not take into account a variety of factors including NZ’s unique demography, specifically Māori and Pacific Islanders who are at higher risk of dementia. Ideally, we would conduct a NZ based dementia prevalence study to obtain accurate data in all the major NZ ethnic groups, however the time and cost required to do this could be prohibitive. The use of routinely collected data may provide a cost‐effective alternative or parallel process to assess and monitor dementia in NZ, as well as examine other characteristics which potentially modify the risk of dementia and adverse outcomes. It is unclear whether routinely collected data is a good proxy‐measure, given approximately a third of people with dementia never receive a specialist diagnosis, dementia coding is poor even for those who are diagnosed, and there are inequities in how non‐European’s access services.

Method

A small‐scale dementia prevalence study is currently being completed in two geographic areas of South Auckland. Interviews are being completed by bi‐cultural bi‐lingual interviewers in a number of different ethnic groups including Asian, Maori, NZ European, and Pacific Islanders. Routinely collected health and social care data for the same geographic areas are also being collected.

Result

Data collection is due to be completed in the first half of 2019, following which the sensitivity and positive predictive value of the routinely collected dataset will be assessed.

Conclusion

Routinely collected data can be a rich source of information, particularly in populations which are little researched or where further information is needed. In NZ little is known about the extent of dementia, and whether this differs across the major ethnic groups. It is hoped that this research will provide a starting point for robust collection of dementia healthcare information in NZ.
Anemia and the risk of dementia in the oldest‐old: The Monzino 80‐plus population‐based study
Authors: Lucca Ugo , Tettamanti Mauro , Riva Emma , Mandelli Sara , Forloni Gianluigi , Galbussera Alessia A.
Published: December 2020

Background

Hemoglobin concentration tends to decline and prevalence of anemia to increase with age. In recent years anemia has been repeatedly linked to a number of adverse outcomes. Anemia has also been proposed as a potential risk factor for cognitive impairment and dementia. Chronic reduction of oxygen supply to the brain could account for this association. However, evidence from prospective population‐based cohorts is very limited. Aim of the present study was to investigate the association of anemia with prevalent and incident dementia among the oldest‐old participants in the Monzino 80‐plus study.

Method

Consent to blood sampling was obtained in 1,115 participants in a door‐to‐door, prospective population‐based study on the prevalence and incidence of dementia among 80‐years and older residents in the province of Varese, Italy. Anemia was defined according to WHO criteria as a hemoglobin concentration <120 g/L in women and <130 g/L in men. Diagnosis of dementia fulfilled DSM‐IV criteria. Potential confounders included in "fully”‐adjusted models: age, sex, education, smoking history, alcohol consumption, hospital admission during the previous year, history of diabetes, hypertension, myocardial infarction, heart failure, respiratory failure, renal failure, stroke, TIA, parkinsonism, cancer.

Result

Participants were 90.3 (5.6) years old on average, 74.5% women, and had a mean (SD) 5.1 (2.5) years of education. 374 subjects (33.5%) were anemic. Mean hemoglobin concentration decreased and prevalence of anemia increased with age (both p<0.0001). Anemic oldest‐old had a lower mean MMSE score (18.3 ± 9.1) than non anemic (20.8 ± 8.0; fully‐adjusted p=0.0130). In univariate analysis, anemia status was significantly associated with increased odds of having dementia (OR: 1.62; 95%CI: 1.26‐2.08; p=0.0002). When adjusted for confounders, this cross‐sectional association was marginally non significant (fully‐adjusted OR: 1.339; 95%CI: 0.999‐1.794; p=0.0508). Over a 15‐year follow‐up period 318 subjects were diagnosed with dementia out of 614 participants without at baseline. Oldest‐old with anemia did not have a significantly increased risk of incident dementia with respect to those without (univariate analysis, HR: 1.12; 95%CI: 0.85‐1.46; p=0.4306).

Conclusion

In the present prospective population‐based study in the oldest‐old, anemia was not significantly associated with an increased risk of developing dementia.
Using cohort data to emulate lifestyle interventions: Long‐term beneficial effects of initiating physical activity on cognitive decline and dementia
Authors: Leist Anja , Terrera Graciela Muniz , Solomon Alina
Published: December 2020

Background

Intervention studies have shown beneficial short‐term effects of physical activity on cognitive decline and reduced risk of dementia. However, randomized controlled trial data of lifestyle interventions over long time spans are not available due to lack of resources, feasibility or ethical reasons. Drawing from the principles of emulating a ‘target trial’, which apply design principles of randomized trials to the analysis of observational data, cohort data of a large European survey were analyzed to understand the long‐term effects of physical activity changes.

Method

Biennial assessments of the economic, social, and health situation of respondents aged 50 and older came from the Survey of Health, Ageing and Retirement in Europe (2004‐2017). Cognitive functioning (immediate recall, delayed recall, and verbal fluency) and self‐reported diagnosis of dementia were assessed at each follow‐up. The target trial included sedentary respondents at t1 who, at follow‐up (t2), stayed sedentary (“control group”) or newly reported vigorous physical activity more often than once a week (initiators, “treatment group”). Inclusion and exclusion criteria were implemented as close as possible to those of the FINGER trial. Inverse‐probability weighting accounted for the probability of initiating physical activity with a large set of predictor variables. Selecting respondents aged 50‐85 years old who met the target trial inclusion and exclusion criteria, assessments of cognitive functioning and self‐reported diagnosis of dementia were available for 8,781 respondents at t3 (on average 3.02 years later), 3,858 respondents at t4 (5.84 years), and 2,304 respondents at t5 (7.72 years). A total of 304 respondents reported a diagnosis of dementia.

Result

Initiators of vigorous physical activity had higher cognitive functioning at two follow‐ups compared to non‐initiators (t3: “average treatment effect on the treated”, ATET=0.059, CI: 0.028, 0.090), which remained significant after implementing inclusion and exclusion criteria. Initiators had lower risk of dementia compared to non‐initiators at all three follow‐ups (t3: ATET=‐0.009, CI: ‐0.015, ‐0.005, relative risk decrease ‐46.7%), remaining significant after implementing inclusion and exclusion criteria.

Conclusion

Emulating a target trial showed long‐term benefits of initiating physical activity for cognitive functioning and dementia risk. Multidomain interventions related to nutrition, social, cognitive activities etc. can be similarly emulated.
Alzheimer‐like glucose hypometabolism predicts subsequent dementia in amyloid‐negative mild cognitive impairment
Authors: Malotaux Vincent , Dricot Laurence , Quenon Lisa , Ivanoiu Adrian , Lhommel Renaud , Hanseeuw Bernard
Published: December 2020

Background

Patients with mild cognitive impairment (MCI) are at‐risk of progression to Alzheimer’s dementia (AD), particularly if they have elevated amyloid (Aβ), the hallmark pathology of AD. However, a proportion of Aβ‐negative MCI also progress to dementia in clinical practice. We sought to investigate (1) whether subthreshold Aβ load, brain metabolism, or atrophy could predict progression to dementia in patients with Aβ‐negative MCI, and (2) whether the regional pattern was distinct from patients with Aβ‐positive MCI.

Method

Seventy‐nine older adults underwent [18F]‐FDG‐PET to estimate their brain metabolism, [18F]‐Flutemetamol‐PET to assess their Aβ load, and 3D‐T1 MRI. Aβ load was expressed in Centiloids and a threshold of 43 corresponding to visual assessment was used to define Aβ positivity. FDG data were expressed as Standardized Uptake Value ratios (SUVr) scaled on pons with partial volume correction. MRI‐PET co‐registration was performed with PetSurfer. Eight Aβ‐negative MCI progressed to dementia after four years. We compared their FDG and thicknesses maps to 25 Aβ‐negative normal older adults, 31 Aβ‐negative stable MCI, and 15 Aβ‐positive MCI who also progressed to AD dementia after four years. Demographics and follow‐up durations are provided in Table1.

Result

Subthreshold Aβ did not predict progression to dementia among Aβ‐negative MCI (p=0.81). Vertex‐wise analyses highlighted temporo‐parietal hypometabolism in the Aβ‐negative MCI who progressed to dementia, compared to stable Aβ‐negative controls (Fig. 1), and to a lesser extent compared to stable Aβ‐negative MCI patients (Fig. 2). However, their cerebral metabolism was similar to the one observed in Aβ‐positive MCI (Fig.3). Finally, the regional pattern of cortical thinning in progressive Aβ‐negative MCI was less typical of AD (Fig.4). Adjusting for age, sex, e4 status, or Aβ did not modify these observations.

Conclusion

Temporoparietal FDG predicts subsequent dementia in Aβ‐negative MCI patients, suggesting a close association with clinical progression. The FDG regional pattern is however not specific of Aβ pathophysiology.
Assessment of SORL1 rare variants segregation in Alzheimer disease families and in vitro models suggests diverse penetrance and oligogenic inheritance
Authors: Nicolas Gaël , Schramm Catherine , Miguel Laetitia , Lacour Morgane , Rousseau Stéphane , Wallon David , Charbonnier Camille , Zarea Aline , Campion Dominique , Rovelet‐Lecrux Anne , Lecourtois Magalie
Published: December 2020

Background

SORL1 rare (allele frequency <1%) loss‐of‐function (LOF) and missense predicted damaging (Mis3) variants have first been identified in early‐onset Alzheimer disease (EOAD, onset before 66 years) patients with a positive family history. However, segregation data in families are still missing to assess the actual pattern of inheritance. Since then, we and others have shown an increased burden of SORL1 rare LOF and Mis3 variants in EOAD patients, whatever the family history, and in late onset AD patients, with a lower effect size. In addition, although the interpretation of the biological effect of LOF variants is rather straightforward, no formal evidence of a functional effect of Mis3 variants can be inferred from bioinformatics predictions only.

Method

We gathered data from French families with a rare LOF or Mis3 variant and developed a cellular model to assess the role of SORL1 missense variants.

Result

We studied 20 families with a LOF variant (mean age at onset (AAO) in probands, 55.4 years, range: [48‐65]). Seventeen showed a positive family history. Mean AAO in affected relatives was 66.3 (range: [50‐80]). One patient carried two LOF compound heterozygous variants. DNA was available in 18 relatives: 5/6 affected relatives carried the familial variant (AAO = [61‐78]) while 3/12 unaffected were also carriers, aged 42, 71 and 95, respectively. Strikingly, 57% affected carriers were APOE4+ including one homozygous, who was also a carrier of a LOF rare ABCA7 risk variant.

We developed a functional assay using CRISPR/Cas9 introduction of variants in iPSCs. We succeeded in introducing a homozygous LOF variant showing increased levels of Aβ in the supernatant. We are now inducing neuronal differentiation and introducing missense variants to better sort missense variants for penetrance studies and understand mechanisms. Interestingly, in one family with a Mis3 variant associated with increased Aβ secretion, the proband was APOE4+ and carried a LOF rare ABCA7 risk variant. Additional families and variants are currently being studied.

Conclusion

Our data support incomplete penetrance and oligogenic determinism in SORL1 families, making genetic counseling difficult. The development of cellular models will help us understand how and which missense variants result in reduced SORL1 functions.
Left amygdala volume moderates the relationship between nocturnal high‐frequency heart rate variability and verbal memory retention in older adults with amnestic mild cognitive impairment
Authors: Kong Shawn Dexiao , Hoyos Camilla M , Phillips Craig L , McKinnon Andrew C , Palmer Jake R , Duffy Shantel L , Mowszowski Loren , Lin Pinghsiu , Gordon Christopher J , Naismith Sharon L
Published: December 2020

Background

Nocturnal high‐frequency heart rate variability (HF‐HRV), an indicator of parasympathetic tone, is decreased in older adults with amnestic mild cognitive impairment (aMCI) during slow wave sleep. However, it is unclear whether or how this parasympathetic dysfunction relates to early cognitive decline. We therefore aimed to explore associations between nocturnal HF‐HRV during slow wave sleep and verbal memory retention in older adults at risk for dementia, and whether this relationship is related to amygdala volume, a sub‐cortical brain region linked to both verbal memory and parasympathetic modulation.

Method

Older adults attending a memory clinic for cognitive concerns (n=313, mean age 67 years, SD 8.51) completed medical and neuropsychological assessments (including Rey Auditory Verbal Learning Test to assess verbal memory retention). Participants were classified by clinical consensus as aMCI (n=99), non‐amnestic mild cognitive impairment (naMCI; n=134), or subjective cognitive impairment (SCI; n=80). Participants also underwent overnight polysomnography with continuous heart rate recordings. Power spectral analysis of HF‐HRV was analysed for slow wave sleep periods. T1‐weighted magnetic resonance imaging was performed in a sub‐set of participants (n=210) and amygdala (left and right) volumes were derived. All statistical analyses were adjusted for known confounders (age, education).

Result

A significant association between lower slow wave sleep HF‐HRV and poorer verbal memory retention was evident in aMCI group (r=0.393, p=0.004) only, (SCI: r=‐0.092, p=0.464; naMCI: r=0.038, p=0.759). Multiple regression analysis (R2=0.440; p<0.001) revealed poorer verbal memory retention in the aMCI group was predicted by reduced HF‐HRV (7.5%), older age (6.3%), and lower levels of education (6.8%). While left amygdala volume (3%) did not independently predict verbal memory retention, a significant interaction indicated that those with larger left amygdala volumes and greater HF‐HRV had superior verbal memory retention (HF_HRV*left amygdala; 7.1%).

Conclusion

Specific to older adults with aMCI, our data showed that parasympathetic modulation during slow wave sleep, particularly for those with larger amygdala volume, may play a key role in memory consolidation. Given that older adults with aMCI are at greater risk of developing dementia due to Alzheimer’s disease, reduced nocturnal parasympathetic activity may be an early marker of cognitive decline in Alzheimer’s disease.
Tau passive immunotherapy efficacy is modulated by antibody Fc domain
Authors: Nisbet Rebecca M. , Brici David , Götz Jürgen
Published: December 2020

Background

Passive immunotherapy targeting tau is a promising strategy for the treatment of Alzheimer's disease. The proposed mechanisms of action for some tau antibodies is to engage with and clear extracellular pathogenic forms of tau, facilitated by microglial phagocytosis through antibody Fc receptor (FcR) binding. As FcR binding is mediated by the shape of the antibody Fc domain, this suggests that the antibody isotype affects the efficacy of these tau antibodies. We therefore aimed to directly compare the efficacy of a tau‐specific antibody cloned into a murine IgG1 framework, which has low‐affinity FcR binding, to that cloned into a murine IgG2a framework, which has high‐affinity FcR binding.

Method

The variable domains of our 2N‐tau specific antibody, RN2N (Nisbet et al., Brain 2017), were cloned into the murine IgG1 and IgG2a heavy chain frameworks. To investigate the ability of the two IgGs to stimulate microglial phagocytosis of recombinant tau, tau was labelled with pH‐Rodo and incubated with and without RN2N IgG, and then placed onto BV2 microglial cells. Phagocytosis was assessed by microscopy and flow cytometry. For the in vivo analysis, P301L tau transgenic pR5 mice were treated with 50 mg/kg RN2N IgG i.p. once a week for 10 weeks. Following treatment, brain pathology was assessed by western blot and immunohistochemistry.

Result

Although the RN2N IgG1 and IgG2a had consistent binding affinities to tau, the RN2N IgG2a, which has a higher binding affinity to FcR, significantly increased the phagocytosis of extracellular tau compared to RN2N IgG1. In vivo, however, passive immunisation of pR5 mice with RN2N IgG1, but not RN2N IgG2a, reduced pathogenic tau levels in the brains of treated mice.

Conclusion

Taken together, our results demonstrate that although enhanced microglial activation via the RN2N IgG2a isotype increases extracellular tau phagocytosis in vitro, it is not required for antibody efficacy in vivo. This suggests that an antibody with a reduced affinity for FcRs may be beneficial in human clinical trials due to its low activation of pro‐inflammatory cytokine production. Furthermore, as RN2N‐mediated pathological tau reduction in this study was only minimal, targeting intracellular tau might be a better strategy.
Perspectives of people with dementia and family caregivers about dementia clinical research
Authors: Bouranis Nicole , Gelmon Sherril B , Lindauer Allison , Waddell Elizabeth N , Richardson Dawn M , Woo Hyeyoung
Published: December 2020

Background

The National Institute on Aging’s (NIA) national strategy to increase ADRD clinical research participation recommends continued research on identifying barriers and facilitators for ADRD study recruitment. This study builds upon its work by identifying factors affecting dementia research participation according to people with ADRD and their family caregivers in Portland, Oregon.

Method

A community advisory board (CAB) comprised of clinicians, researchers, advocates, people with dementia, family caregivers, and older African Americans was established for this project. Semi‐structured dyadic interviews were conducted with individuals living with MCI or ADRD and their family caregivers, half of whom had participated in ADRD clinical research. Dyad members were interviewed separately. Interviews were audio‐recorded, coded and analyzed through thematic analysis where themes emerged from the data organically. The investigator was the single coder; the CAB interpreted findings by identifying what was most important, surprising, or missing from the interviews.

Result

There is a lack of knowledge about opportunities in the Portland area. Many interviewees were unaware of dementia studies, which was surprising as many interviewees were recruited from organizations with rich knowledge of research opportunities. One’s perceived value of ADRD research did not increase their likelihood of joining a study. Many caregivers either do not have or did not want to use limited free time to be a study partner; however, several caregivers noted that they would participate in the study if provided some sort of caregiver benefit to ease their burden, such as support, education, or respite. The number of people who avoid research because it involves taking study drugs was substantial among interviewees.

Conclusion

Several recommendations can be made based on this study. Researchers can partner with other healthcare and ADRD resource providers to share study opportunities. Study partners should be recognized as full participants who deserve compensation for their time and effort. Research organizations could develop strategies to remove or reduce the time spent and distance traveled in order to participate in research. Researchers could highlight the benefits of helping others by partnering with people with ADRD and caregivers to share the experience of participating in research.
Higher fronto‐parietal metabolism parallels a greater impact of amyloid and anxiety on medial temporal areas in women versus men
Authors: Arenaza‐Urquijo Eider M , Salvadó Gemma , Milà‐Alomà Marta , Shekari Mahnaz , Sánchez‐Benavides Gonzalo , Cacciaglia Raffaele , Minguillón Carolina , Vilor‐Tejedor Natalia , Crous‐Bou Marta , Grau‐Rivera Oriol , Sala‐Vila Aleix , Eichenlaub Udo , Kollmorgen Gwendlyn , Suárez‐Calvet Marc , Blennow Kaj , Zetterberg Henrik , Gispert Juan Domingo , Molinuevo Jose Luis , Study ALFA , Consortium EPAD
Published: December 2020

Background

The higher prevalence of anxiety‐related disorders in women, as well as the lower opportunities for higher education, may explain differences in brain resilience to AD pathologies. The objectives were to (1) test sex‐differences on brain metabolism and (2) evaluate whether the effects of amyloid, tau, education and anxiety on brain metabolism and structure differ by sex.

Method

We included a total of 1327 non‐demented participants, 235 cognitively unimpaired adults from the ALFA+ study (50‐74 years, 66% women) and 1092 non‐demented older adults from EPAD (50‐88 years, 57% women). Participants had available Aβ42 and p‐tau CSF biomarkers (Roche NeuroToolKit robust prototype assays and Elecsys®), anxiety assessments, FDG‐PET (ALFA+) or hippocampal volumes (EPAD). First, in ALFA+, we ran voxel‐wise multiple regression models to assess the effects of sex, and sex*amyloid, sex*p‐tau, sex*education and sex*anxiety interactions on FDG‐PET scans (adjusted by age). Second, in EPAD, we ran the same models with TIV‐adjusted hippocampal volumes as outcome measures.

Result

In the ALFA+ cohort, there were no sex‐differences in age (p=0.09), or CSF biomarkers (all p>0.7). Women showed lower education (p=0.001) and higher anxiety scores (p<0.001) than men. In the EPAD cohort, women were younger (p=0.003), lower educated p=0.003) and showed higher anxiety levels (p=0.002); men showed lower CSF Aβ42 levels (p=0.02). In voxel‐wise multiple regression analyses (ALFA+), women showed higher FDG‐PET uptake than men in medial fronto‐parietal regions, irrespective of their age, education, anxiety and CSF biomarkers levels (Fig1). There was a sex*Aβ and sex*anxiety interaction, such that with increasing Aβ deposition or anxiety levels, women showed lower metabolism in the parahippocampus and hippocampus than men (Fig2, 3). There was no sex*p‐tau or sex*education interaction. In the EPAD cohort, we did not observe any interactions. However, sex‐stratified analyses showed an association of CSF Aβ42, p‐tau and anxiety levels with lower hippocampal volumes in women but not men (Table 1, Fig4).

Conclusion

Our results suggest higher fronto‐parietal metabolism coupled with lower metabolic and structural resilience in medial temporal regions in women. The effects of anxiety and AD pathologies converged in memory‐related brain areas. Brain resilience mechanisms may differ between women and men.
TBI and increased risk of non‐Alzheimer’s disease dementia in older male twins
Authors: Chanti‐Ketterl Marianne , Pieper Carl F , Yaffe Kristine , Plassman Brenda L
Published: December 2020

Background

Several studies have reported an association between traumatic brain injury(TBI) and increased risk of Alzheimer’s disease(AD) and all cause dementia. Considering the heterogeneous genetic and environmental factors that may contribute to development of dementia, co‐twin control analyses provide a level of control for confounding factors that is difficult to achieve with other case‐control designs.

Methods

A total of 8787 members of the NAS‐NRC Twin Registry of Male WWII Veterans born between 1917‐1927 were included in the study. Self or proxy‐reported history of TBI was collected from 1990–2005. In‐person dementia evaluations were conducted in participants’ homes and differential diagnoses and age of onset of dementia were assigned by an expert adjudication panel. Proportional hazard models, adjusting for education and twin strata, were used to estimate the risk of dementia associated with TBI in the full sample. In a subsample, the McNemar’s test was used to examine the association between TBI and dementia within twin pairs to control for shared genetic and environmental risk factors for dementia within the pairs.

Results

Of the 8787 men, 25% reported a history of TBI, while 3.8% had AD and 1.9% had other types of dementia. Median age of dementia onset was 75 years. The mean age of first TBI for those without dementia was 33 years (SD=23) and 38 (SD=24) for those with dementia. Hazard models show those with TBI had over twice the risk of being diagnosed with other cause dementia after a TBI (hazard ratio (HR) 2.29; 95%CI,1.2‐4.4), but not for risk of AD (HR 1.08; 95%CI,0.7‐1.6). A total of 108 twin pairs were discordant for presence of TBI and diagnosis of dementia or age of onset of dementia by at least 3 years. Within these twin pairs, TBI was associated with greater risk of other cause dementia (n=40 pairs), McNemar odds ratio (OR) 2.6, 95%CI 1.3‐5.3, but not for AD (n=68 pairs), OR 1.1, 95%CI 0.7‐1.8.

Conclusion

Our findings indicate that TBI may be associated with risk of types of dementia other than AD. This result held even after controlling for many unidentified shared genetic and early life environmental factors within twin pairs.
Untargeted metabolomics reveals sugar and homocysteine dysregulations in prodromal AD
Authors: Hajjar Ihab , Liu Chang , Jones Dean , Uppal Karan
Published: December 2020

Background

Altered metabolism may occur early in Alzheimer’s disease (AD). We used untargeted high‐resolution metabolomics in the cerebrospinal fluid (CSF) in mild cognitive impairment (MCI) to identify these alterations

Method

CSF from 92 normal controls and 93 MCI underwent untargeted metabolomics using high‐resolution mass spectrometry with liquid chromatography. Partial least squares discriminant analysis was used followed by metabolite annotation and pathway enrichment analysis (PES). Significant features were correlated with disease phenotypes using spearman correlation.

Result

We identified 294 features differentially expressed between the 2 groups and 94 were annotated. PES showed that pathways related to sugar regulation (N‐Glycan, p=0.0007; sialic acid, p=0.0014; Aminosugars, p=0.0042; galactose, p=0.0054) homocysteine regulation (p=0.0081) were differentially activated and significant features within these pathways correlated with disease phenotypes

Conclusion

We identified a metabolic signature characterized by impairments in sugar and homocysteine regulation in prodromal AD. Targeting these changes may offer new therapeutic approaches to AD.
Characterizing clinical misdiagnosis of dementia using Medicare claims records linked to Rush Alzheimer’s Disease Center (RADC) cohort study data
Authors: James Bryan D , Power Melinda C , Gianattasio Kan Z , Lamar Melissa , Oveisgharan Shahram , Shah Raj C , Marquez David X , Barnes Lisa L , Bennett David A
Published: December 2020

Background

Linkage of Medicare claims records to cohort studies of aging provides the opportunity to study misdiagnosis of dementia in clinical settings for older adults.

Methods

We linked 1991‐2016 fee‐for‐service Medicare Part A&B claims to data from 5 RADC cohorts (MAP, ROS, MARS, Clinical Core, and Latino Core). We assigned dementia status based on annual detailed cognitive evaluation and assigned clinical dementia diagnosis status using ICD‐9/ICD‐10 codes from Medicare claims (primary or secondary diagnoses) during participants’ study enrollment period. We classified persons as underdiagnosed if they did not have a clinical dementia diagnosis in 2 or more Medicare claims recorded up to 3 years leading to, and 1 year following the date of the first RADC assessment indicating dementia, and overdiagnosed if they did not have any RADC assessments indicating dementia but had a clinical dementia diagnosis in 2 or more claims recorded during the study period.

Results

Of the total 3,533 participants, 78% received the correct clinical diagnosis, 11% were underdiagnosed in Medicare claims, and 11% were overdiagnosed. Of the 703 persons who developed dementia, 381 (54%) were clinically underdiagnosed (i.e., sensitivity=46%), while 389 (14%) of 2,830 persons who did not develop dementia were overdiagnosed (specificity=86%).

Conclusions

This preliminary analysis corroborates previous findings from the Health and Retirement Study (HRS) and others that there is substantial misdiagnosis of dementia in clinical settings as recorded in fee‐for‐service Medicare claims when compared to comprehensive assessment for research, especially in regards to low sensitivity. Future work will examine predictors and consequences of clinical misdiagnosis.
Alternatives to MMRM for preclinical Alzheimer’s clinical trials
Authors: Donohue Michael C. , Sethuraman Gopalan , Langford Oliver , Lin Wenyi , Insel Philip , Thompson Wesley K. , Raman Rema , Sperling Reisa A. , Aisen Paul S.
Published: December 2020

Background

The Mixed Model for Repeated Measures (MMRM; Mallinckrodt, et al. 2001) is the most commonly used approach for assessing treatment effects in Alzheimer’s clinical trials. An alternative nonlinear Disease Progression Model (DPM) which assumes the ratio of group means is fixed over time has been proposed for DIAN‐TU (e.g. Wang, et al. 2018). We assess nonlinear models and alternative linear models for Preclinical Alzheimer’s clinical trials like the A4 Study (Sperling, et al. 2014).

Method

Tables 1 and 2 describe the mean and correlation structures that we considered. Models were fit to data from cognitively normal ADNI participants (amyloid positive vs negative). We compared mean PACC trajectories over time and Akaike Information Criterion (AIC; Sakamoto, et al 1986). All models were fit by maximum likelihood using the R package nlme. Simulations were used to assess power and Type I error for clinical trials in Preclinical Alzheimer’s (Figure 1).

Results

Figure 2 demonstrates the various mean structures fit to ADNI. Models with stronger shape assumptions are smoother than the unstructured mean of MMRM (dashed lines). The DPM‐like nonlinear model with fixed group mean ratio (“NL0”) provides a relative underestimate of the amyloid group difference at final visit. Comparing values of AIC (Figure 3), we find little evidence to support using alternatives to the unstructured mean and variance of the typical MMRM. Simulation studies (Table 3) suggest that power can be improved with simpler mean structures (Hybrid or Quadratic), while maintaining good Type I error control with an unstructured variance. It was difficult to fit the nonlinear models with the full suite of correlation structures. The NL0 could be reliably fit with random intercept and heterogeneous variance but showed no advantage over the simpler Hybrid or Quadratic mean structures.

Conclusion

ADNI data support the use of the MMRM with unstructured mean and variance, but simulations suggest simpler mean structures might provide a modest improvement in the power from 85%, with an unstructured mean, to 90%, with Hybrid or Quadratic mean. Nonlinear DPM‐like models demonstrated no advantage over linear model alternatives in ADNI and in simulations of Preclinical Alzheimer’s clinical trials.
Astrocyte glutamate uptake impacts [18F]FDG‐PET signal
Authors: da Rocha Andreia Silva , de Souza Débora Guerini , Bellaver Bruna , Fontana Igor C. , Machado Luiza Santos , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Souza Diogo O. , Zimmer Eduardo R.
Published: December 2020

Background

The role of astrocytes on brain functioning has become an important topic of debate. In this regard, an issue that still remains controversial is the astrocytes contribution to glucose brain metabolism and, therefore, to the uptake of 2‐Deoxy‐2‐[18F]Fluoroglucose([18F]FDG) detected by positron emission tomography(PET). For many years, it was widely assumed that the brain [18F]FDG‐PET signal directly reflects the neuronal use of glucose, overlooking the possible participation of other brain cells. Recently, rodent and human studies have demonstrated that astrocytes may contribute to [18F]FDG‐PET signal. To further explore these early findings, here, we used a pharmacological challenge on rodents. Clozapine was selected because it is known to decrease, on astrocytes, glutamate transport and the glutamate transporter 1 (GLT‐1) levels, an important trigger for glucose uptake in astrocytes.

Methods

Clozapine was administered for six weeks (25‐35mg/kg) to adult Wistar rats. Glucose brain metabolism was assessed using [18F]FDG‐microPET before and after the treatment. [3H]D‐Aspartate uptake was evaluated on brain slices. [3H]Glutamate release was analyzed on synaptosomal preparations. [3H]D‐Aspartate and [3H]2‐Deoxyglucose uptake were analyzed on primary cortical astrocytic and neuronal cultures treated with clozapine (50uM) for 48h. Immunocontent and expression of GLT‐1 and Glutamate‐Aspartate Transporter(GLAST) were assessed on the cortical tissue and cell cultures.

Results

Clozapine treatment significantly reduced [18F]FDG metabolism in the cerebral cortex, hippocampus, and striatum of adult rats. In addition, clozapine decreased cortical glutamate transport in brain slices – indexed by [3H]D‐Aspartate uptake – and reduced the cortical immunocontent and expression of GLT‐1. Astrocytic cultures treated with clozapine presented a decline on GLT‐1 density, [3H]D‐Aspartate uptake and [3H]2‐Deoxyglucose uptake, while the neuronal cultures presented no changes.

Conclusion

Here, we present microPET data showing that a challenge with clozapine causes a reduction on [18F]FDG signal in brain regions presenting high GLT‐1 density. Our cell culture findings indicate that astrocytes are, at least partially, the cells underlying the brain glucose metabolism response to clozapine. These results corroborate previous studies that highlight the need for a reevaluation in the way that brain [18F]FDG‐PET data is interpreted. Additionally, clozapine is a drug approved for clinical use, therefore, these findings could have high translational implications.
Cerebral amyloid and white matter hyperintensity volume are independently associated with rates of cerebral atrophy in Insight 46, a sub‐study of the 1946 British birth cohort
Authors: Keuss Sarah E , Poole Teresa , Cash David M , Lane Christopher A , Parker Thomas D , Buchanan Sarah M , Keshavan Ashvini , Coath William , Malone Ian B , Thomas David L , Sudre Carole H , Barnes Jo , Lu Kirsty , James Sarah‐Naomi , Wagen Aaron , Storey Mathew , Murray‐Smith Heidi , Wong Andrew , Richards Marcus , Fox Nick C , Schott Jonathan M
Published: December 2020

Background

Alzheimer’s (AD) and cerebrovascular disease are common causes of cognitive impairment in later life and often co‐exist. Understanding how AD and vascular pathologies act independently or together to influence neurodegeneration in later life is important for the development of effective treatments and clinical trial design.

Method

219 cognitively normal participants underwent cognitive testing, structural MRI and 18F‐florbetapir amyloid‐PET scans at two visits approximately two years apart. Changes in whole brain, ventricular and hippocampal volumes between time‐points were determined using the Boundary Shift Integral (BSI) (doi:10.1016/j.neuroimage.2009.12.059). Baseline white matter hyperintensity volume (WMHV) was generated using BaMoS (doi:10.1109/TMI.2015.2419072). Baseline amyloid SUVRs were derived with eroded subcortical white matter as the reference region and a composite grey matter target region. A cut‐point of 0.6104 was used to define amyloid positivity. Linear regression was used to investigate relationships of amyloid and WMHV with atrophy rates. Specifically, models were fitted with BSI as the outcome, scan interval as the explanatory variable, and interactions between scan interval and i) the explanatory variable of interest and ii) each of the covariates (age at baseline scan, sex and total intracranial volume). Amyloid and WMHV were assessed separately and then together within the same model. An interaction between amyloid, WMHV and scan interval was also tested in a further model.

Result

199 cognitively normal participants (mean baseline age 70.1±0.4 years; 47% female) had high‐quality imaging data (Table 1). Positive amyloid status was associated with greater rates of brain and hippocampal atrophy and ventricular expansion, with a positive relationship between SUVR and ventricular expansion and hippocampal atrophy (Table 2). Larger WMHV was associated with higher rates of brain and hippocampal atrophy and ventricular expansion (Table 2). None of these associations were meaningfully altered by including amyloid and WMHV within the same model (Table 3). There was no evidence of an interaction between amyloid and WMHV for any BSI measure (interaction p>0.13, all tests).

Conclusion

Markers of amyloid and presumed small‐vessel disease were independently associated with atrophy rates, and there was no evidence that either pathological process modified the effect of the other.
GAP rater certification program transforms the rater certification process
Authors: Mohs Richard , Smith Katy , Bork Jason , Bartolic Edward I. , Jenkins Cecily , Ward Rick , Rentz Dorene M.
Published: December 2020

Background

Rater certification is a key component in successful study startup and Alzheimer’s disease (AD) trial execution, but the current certification process is time consuming and redundant across trials. Existing rater training has not changed substantially in years, has become more complex, and offers raters limited opportunity to enhance cognitive assessment skills.

Method

The GAP Rater Certification Program is designed to transform rater certification. The GAP‐Net Rater Certification Matrix defines scale‐specific standards for proven, experienced, and developing raters (Figure 1). Standards are based on education, experience, previous certification, and demonstration of mastery. Rater training and certification follow defined processes and include the option to recertify after one year (Figure 2). Training is appropriately targeted to the rater’s level of experience and effectively tests the rater’s knowledge of each cognitive assessment. Rater qualifications maintained in a single database eliminate the need to complete Rater Experience Surveys (RES) on every trial.

Result

The GAP Rater Certification Program has been delivered to over 50 raters across 20 GAP‐Net sites. GAP is surveying participating raters and will share results of the Program’s implementation and impact. Initial results indicate the following: GAP’s Demonstration of Mastery provides effective ‘applied training’ by assessing rater’s knowledge of scales and administration competency and also providing a platform to share strategies that deliver meaningful outcomes. A rater certification process across AD trials is highly likely to save time during the qualification process and accelerate study startup. Expanding the Program to new / developing raters will increase the pool of raters at sites and eliminate potential startup bottlenecks. The applied training is appropriately targeted to rater’s level of experience. Redundant training will be minimized. One model predicts 84 hours would be saved using the Program over 6 trials for every site. GAP Rater Certification Database (InvestigatorSpace) facilitates information collection and sharing and increases efficiency during site selection and study startup.

Conclusion

The GAP Rater Certification Program removes redundancies in study startup and incorporates targeted training and Demonstration of Mastery designed to ensure quality raters and study data. Further enhancements will continue to focus on improving efficiencies and precision in rater qualification.