bluuebunny/crossref_metadata_2025 huggingface dataset:
Raising awareness of Alzheimer’s clinical trials: Development of messages tailored to African American caregivers and individuals at risk
Authors: McGowan Melissa , Massett Holly A , Han Sae H , Watson Jennifer , Emmerson Karen , Burns Adam , Robinson Candice Watkins , Hummel Allyson , Silverberg Nina , Elliott Cerise L , Donley Grayson , Bernard Marie A
Published: December 2020

Background

Higher rates of Alzheimer’s Disease (AD) and related dementias (ADRD) among African Americans compared to non‐Hispanic whites are well‐documented, as is the underrepresentation of African Americans in AD/ADRD clinical research. Key documented impediments to enrollment of African Americans are too few researchers offering studies and limited materials that provide culturally relevant information. This abstract presents findings from focus groups conducted by the National Institute on Aging (NIA) to identify salient, culturally appropriate message concepts that raise awareness, address barriers and motivate African Americans to consider participation in AD/ADRD studies.

Method

Nine focus groups (N=65) were conducted among three African American audiences who: 1) have a family history of AD/ADRD; 2) have no family history of AD/ADRD; and, 3) are caregivers of persons with AD/ADRD. Sessions explored participants’ knowledge, attitudes, and beliefs about AD/ADRD and AD/ADRD clinical research unaided and in the context of testing multiple message concepts designed to increase interest and encourage individuals to seek information regarding AD/ADRD clinical trials.

Result

Message concepts were categorized into three reaction types: positive, negative, and mixed. Concepts that positively increased interest in trials were those that portrayed hope for future generations, connected research with the potential to prevent/treat AD/ADRD, and directly addressed the higher AD/ADRD incidence rates among African Americans. Highlighting the need to find treatments that work for all races was a top motivator to consider a trial. Concepts that decreased interest in trials were those viewed as: being overly emotional; making generalizations about participants’ motivations; downplaying the history of medical abuse; and, using conditional language (“one day”, “may”, “hopefully”). All groups were more receptive to messages that established a realistic, personal connection. Concept visuals will be presented.

Conclusion

This research conducted by the NIA improves our understanding of message concepts that are acceptable and motivating and which are unacceptable or inappropriate to African Americans around considering participating in AD/ADRD clinical research. The findings from this study will be used to develop, finalize and make available to the research community a suite of culturally appropriate, well‐tested materials to increase awareness of AD/ADRD and clinical research.
Comparison of cerebrospinal fluid phosphorylated tau 181 and 217 for cognitive progression
Authors: Mielke Michelle M. , Aakre Jeremiah A. , Algeciras‐Schimnic Alicia , Proctor Nicholas , Machulda Mary M. , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Dage Jeffrey L.
Published: December 2020

Background

A previous study demonstrated that cerebrospinal fluid (CSF) phosphorylated tau 217 (pTau217), compared to phosphorylated tau 181 (pTau181), correlated more strongly with Tau PET and was better able to distinguish between AD and non‐AD neurodegenerative diseases. The aim of this study was to compare these two CSF tau markers for cognitive progression.

Method

We included 666 cognitively unimpaired (CU) and 89 mild cognitive impairment (MCI) Mayo Clinic Study on Aging community‐based participants (mean age of 71.6 years) with CSF amyloid and tau measurements. CSF amyloid‐beta 42 (Aβ42) was measured with automated electrochemiluminescence Elecsys immunoassays (Roche Diagnostics); a cut‐off of <1026 pg/ml was considered amyloid positive (A+). CSF pTau181 and pTau217 were measured with the Mesoscale discovery platform (MSD). Cutoffs of pTau181≥217 pg/ml and pTau217≥288 pg/ml were considered tau positive (T+). Cox proportional hazards models with time as the time scale were used to examine the relationship between the CSF markers and progression from CU to MCI and MCI to dementia. Covariates included age, sex, education, and APOE.

Result

Tau positivity (T+) based on pTau217 (HR = 2.45, 95% CI: 1.45, 4.11) was a greater risk factor for incident MCI compared to pTau181 (HR = 2.07, 95% CI: 1.19, 3.61). Among individuals who were A+T+, T+ based on pTau217 (HR = 3.01, 95% CI: 1.66‐5.45) was a greater risk factor of incident MCI than pTau181 (2.80, 95% CI: 1.48, 5.31). Among the 89 MCI participants, T+ based on pTau217 was a much greater risk factor for dementia (HR = 4.92, 95% CI: 1.37, 17.61) than pTau181 (HR = 1.55, 95% CI: 0.43‐5.55).

Conclusion

CSF pTau217 is a better marker of cognitive progression, especially from MCI to dementia, compared to CSF pTau181.
“I understand a fury in your words, but not the words”: The association of dementia caregiving styles and salivary cortisol
Authors: Leggett Amanda N , Hodgson Nancy A , Connell Cathleen M , Gitlin Laura N , Kales Helen C
Published: December 2020

Background

Dysregulated cortisol patterns are indicators of physiological stress and may show evidence that caregiving for a person living with dementia (PLwD) can get under the skin. While the stress process of caregiving has been well observed, less attention has focused on the cognitive‐behavioral care management styles of dementia caregivers and how they may impact care outcomes such as physiological stress. Prior work by this team has identified five distinct caregiving styles through qualitative analysis of an interview regarding caregivers’ cognitive‐behavioral care management approach: “Externalizers” (superficial understanding, self‐focused, expressions of anger or frustration), “Individualists” (provide care by going it alone, emotionally removed), “Learners” (recognize need to change approach but are stuck, emotionally turbulent), “Nurturers” (positive affect and empathy, reflect natural mastery), and “Adapters” (arsenal of acquired management strategies, adapt to challenges). We hypothesize that more maladaptive care styles (e.g. Externalizers, Learners) will show evidence of dysregulated cortisol patterns.

Method

Participants included 100 primary family caregivers for PLwD who were 74% female, 18% non‐White, and on average 64 years old. Saliva was collected via passive drool method over two days. Two markers of salivary cortisol, area under the curve (AUC), and cortisol awakening response (CAR) were examined as separate outcomes in linear regressions, with caregiving styles as the key predictors (Nurturers as the reference group), and demographic characteristics, caregiver burden, depression, and sleep disturbance as covariates.

Result

Accounting for controls, having an Externalizer caregiving style was significantly associated with an elevated cortisol output (greater AUC), relative to having a Nurturer care style (β=0.33, p<.05). There was also a trend towards greater caregiver depression and larger AUCs (β=0.31, p=.059). Caregiving style was not significantly associated with the CAR.

Conclusion

Having an Externalizing care style characterized by expressions of anger, frustration, and lack of understanding of dementia is associated with an elevated cortisol pattern. This dysregulated pattern may put Externalizers at increased risk for a number of physical and mental health conditions relative to other caregiving styles. Assessing caregiving style in addition to care stressors may help identify caregivers in need of targeted intervention and help prevent negative health outcomes.
The influence of neighborhood factors on biological measures of stress in home‐dwelling multi‐ethnic older adults with dementia
Authors: Hodgson Nancy A
Published: December 2020

Background

Recently researchers have begun to examine the possible biological pathways through which neighborhood context may affect the health of vulnerable residents. Although stress is often hypothesized to contribute to the effects of neighborhoods on health, no studies have investigated associations of neighborhood characteristics and stress biomarkers in home dwelling persons living with dementia (PLwD). Identifying these biological pathways is fundamental to increasing our understanding of how neighborhoods can influence health and well being in vulnerable residents including those with dementia.

Methods

Guided by the National Institute on Minority Health and Health Disparities Framework, this pilot study examined pathways linking both micro (individual level) and macro (neighborhood) level factors in home dwelling PLwD. The model was used to determine what community level factors (density, total crime index, median home value, and noise index) were associated with measures of salivary cortisol controlling for sociodemographics, dementia stage, and comorbid illnesses. The sample included 100 participants: 30 Whites, 39 African Americans, and 31 Latinos with an average age of 73.6. Saliva samples were collected using Salivette collection tubes over two days and stored at −20 °C until analysis.

Results

Residents of neighborhoods with lower housing value and higher noise and density were disproportionately composed of racial/ethnic minorities (with the patterning for Hispanics more pronounced than for blacks.) Significantly lower levels of cortisol at wakeup and a less steep decline was associated with adverse neighborhood environments (higher noise, crime, density, and lower housing value). The strongest relationship between neighborhood characteristics and cortisol levels was found for neighborhood crime. Individuals with dementia residing in higher crime neighborhoods had significant lower levels of cortisol at wakeup and with less pronounced initial declines than those residing in low crime neighborhoods.

Conclusion

Given that lower cortisol at wakening and slower rate of decline in cortisol across the day are associated with adverse health outcomes, our analyses can inform the identification of risky communities that are most likely to benefit from health‐supportive community interventions to minimize the negative impacts of unsupportive community environment. These pilot results suggest that further investigation of the effects of neighborhood contexts on stress biomarkers and health outcomes in PLwD is warranted.
Proteomic, metabolomic, and transcriptomic examination of APOE transgenic mice
Authors: Mohler Eric G. , Ried Janina S. , Bahnassawy Lamiaa , Reinhardt Peter , Curado Marco Rocha , Bakker Margot H.M. , Nicolas Armel , Rao Francesco , Kohler Isabelle , Hankemeier Thomas , Ramaswamy Gayathri , Sáez María Eugenia
Published: December 2020

Background

ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) is an Innovative Medicines Initiative (IMI) project that focuses on apolipoprotein E (APOE) as it relates to Alzheimer’s disease. As part of this effort, the utility of APOE transgenic mice as a model of human apoE function was investigated. Specifically, proteomic, metabolomic, and transcriptomic analyses were conducted in aged APOE transgenic mice: ε2/2, ε3/3, ε4/4, knock‐out (KO).

Methods

Two studies were conducted. An initial proteomic and metabolomic study was conducted in brain tissue from male and female 22‐month old APOE ε3/3 and ε4/4 mice. A second proteomic, metabolomic, and transcriptomic study was conducted in brain tissue from 16‐month old APOE ε2/2, ε3/3, ε4/4, or KO mice receiving a low‐fat/low‐sucrose or high‐fat/high‐sucrose diet.

Results

Protein changes (upregulated and downregulated) in 22‐month old APOE ε4 males and females relative to age/sex matched ε3 mice were related to apoE function (LDL), immune function (IgGs) and cellular structure/function. Metabolomic differences in APOE ε4 female and/or male mice relative to ε3 mice were observed for lysophospholipid metabolites, sphinganine; and cholic acid. Enrichment analysis of top genes from the different comparisons involving the ε4 allele (ε 4vs ε3, ε4vs ε2 and ε4 vs KO) showed effects in mitochondrial/respiratory chain and immune‐related pathways.

Conclusion

Proteomic, metabolomic, and transcriptomic examination in APOE ε4 transgenic mice indicate genotype differences consistent with previously described effects of apoE on immune function and lipid signaling. Additional work in ADAPTED will characterize proteomic and metabolomic phenotypes in human‐derived inducible pluripotent stem cells and human patient samples. Comparison of the results across human cells, human samples, and the present findings will demonstrate the potential utility (or lack thereof) for APOE animal models. Disclosure: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This study was sponsored by AbbVie, Inc. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the abstract. Some authors are currently employed by AbbVie and may own AbbVie stock.
Teaching old drugs new tricks: Do cardiovascular medications effect cognitive decline?
Authors: Newby Danielle , Winchester Laura , Sproviero William , Fernandes Marco , Launer Lenore J. , Lovestone Simon , Nevado‐Holgado Alejo J
Published: December 2020

Background

Cardiovascular disease affects multiple organs beyond those of the cardiovascular system including the brain. However, the mechanisms linking cardiovascular disease and cognitive decline are still poorly understood. Studies suggest specific cardiovascular medications targeting different mechanisms may slow cognitive decline and reduce dementia risk in later life. We investigated the association of specific blood pressure (BP) lowering medications and cognitive decline over time in a nation‐wide study of aging.

Method

We utilised the English Longitudinal Study of Ageing cohort accessed via the Dementia’s platform UK. At baseline this cohort contained over 10,000 dementia‐free adults older than 50 years old [mean age 65 years, 54% female, 39% hypertension] followed up to 15 years. We included individuals with either a diagnosis of hypertension, taking any BP lowering medications or having systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg [mean 144 SBP and 79 DBP mmHg]. Cognition was assessed at multiple time points using memory and executive function tests. We examined the following drug classes: angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers, beta‐blockers, calcium channel blockers, diuretics and any other blood lowering medications. We applied inverse probability weighting to linear mixed effect models to assess treatment effects and to control for factors that may influence the propensity to be treated with a BP‐lowering medication.

Result

Participants taking any BP‐lowering medication, regardless of drug class, had slower cognitive decline compared to non‐drug users. For example, drug users had an increase of 0.032 per year for memory tests (p value 0.0016). Comparing specific drug classes with no drug users or between the other drug classes, the overall trend indicates most drug classes slowed cognitive decline, however the results lacked statistical significance.

Conclusion

We have established BP‐lowering medications effect cognitive decline. Further follow up is required to further understand the specific drug class effects using other real world datasets. This work provides an evidence base for further exploration into the management of cardiovascular health as a preventative strategy for maintaining brain health and slowing cognitive decline. In turn, this could inform health policy strategies for reducing dementia risk earlier in life.
Accounting for systematic spatiotemporal variation improves connectome‐based models of tau spreading in human Alzheimer’s disease
Authors: Vogel Jacob W. , Young Alexandra L. , Oxtoby Neil P. , Smith Ruben , Ossenkoppele Rik , Aksman Leon M , Strandberg Olof , La Joie Renaud , Grothe Michel J. , Rabinovici Gil D. , Alexander Daniel C. , Evans Alan C. , Hansson Oskar
Published: December 2020

Background

Studies in cells, animals and humans have each provided evidence that, in an Alzheimer’s disease (AD) context, tau may be spreading through the brain transneuronally. This information may be useful for modeling the spread of tau in humans. However, such models are confounded by the substantial heterogeneity in spreading patterns observed in AD. In this talk, I will discuss i) application of an epidemic spreading model (ESM) to tau‐PET data to model the spread of tau through the human connectome; ii) application of a spatiotemporal subtyping algorithm to identify separable tau‐spreading patterns; 3) how accounting for these heterogeneous patterns can improve connectome‐based models.

Method

The ESM simulates diffusion of an agent through a system of connected brain regions measured with diffusion tractography. We compare simulations across 312 individuals to observed tau‐PET data. We next use the Subtype and Staging Inference (SuStaIn), an algorithm combining disease progression models with clustering, to identify spatiotemporal subtypes of tau spreading across 1143 individuals. We describe demographic, cognitive and genetic associations with each subtype, and evaluate their stability over time and across different radiotracers. Finally, we apply the ESM separately to each AD subtype to assess whether overall model accuracy is improved by accounting for individual subtype.

Result

The best‐fitting ESM used the entorhinal cortex as the model epicenter, and explained 70% of the variance in the overall tau‐PET pattern across subjects. SuStaIn identified four spatiotemporal subtypes with differing tau‐PET patterns and phenotypic profiles: Limbic‐predominant, limbic‐sparing, posterior, and lateral‐temporal. These same four subtypes were observed in a separate cohort using a different radiotracer (similarity 0.7‐0.9). 86% of subjects exhibited the same subtype at follow‐up. The ESM selected a different epicenter for each subtype, and accounting for subtype‐specific variation resulted in a 17% improvement in model performance.

Conclusion

Connectome‐based models explain the majority of spatial variation in tau‐PET patterns. However, a one‐size‐fits‐all approach fails to account for heterogeneity of tau‐spreading patterns. Four stable phenotypes were observed, which may be characterized by vulnerability of different cortico‐limbic networks. Accounting for this heterogeneity will be necessary for any predictive modeling of tau spreading moving forward.
Understanding the effect of fatigue on the association between sleep disturbances and cognitive function ability among cognitively impaired older adults
Authors: Kerner Nancy , Cohen Hannah , Scodes Jennifer , Bell Sophie , Goldberg Terry E. , Westwood Andrew , Devanand Davangere P.
Published: December 2020

Background

Fatigue is associated with neuroinflammation of the brain, one of the signatures of neurodegenerative disorders across preclinical and clinical stages. Substantial research evidence demonstrates a bidirectional link between Alzheimer’s neuropathology and poor sleep. Whether neuroinflammation mediates the association between sleep disturbances and cognitive decline remains to be determined. In this pilot study, we examined whether fatigue impacts the relationship between sleep quality and cognitive function ability.

Method

We prospectively recruited adults aged 55‐90 years with mild cognitive impairment to evaluate their symptoms of Fatigue, Sleep, and Cognitive Function Abilities (CFA), using the NIH PROMIS Fatigue short form (v1.0), Sleep Disturbances (SD, v2.0) and Sleep‐related Impairment short form (SRI v2.0), as well as the NIH Neuro‐QOL Cognitive Function Abilities short form (v1.0). The Poor‐sleep group was defined as a T‐score of >50 on either SD or SRI scale. Depression was defined as a Geriatric Depression Scale score of 5 or greater and was a study exclusion criterion.

Result

Twenty‐seven patients enrolled in the study, including 14 women and 13 men. The mean age was 67.37+/‐ 9.00 years. The Poor‐sleep group had significantly lower CFA compared to the Good‐sleep group (b=‐6.28, p=0.019). Greater Fatigue scores were significantly associated with lower Cognitive Function Abilities scores (r=.49, p=0.010). These results remained significant after controlling for age. Further, total scale SRI score was significantly associated with total scale Fatigue score (r=.72, p<0.001).

Conclusion

Both fatigue and sleep disturbances were significantly associated with low CFA independently, along with a significant correlation between fatigue and poor sleep. The mechanisms by which fatigue and sleep disturbances contribute to cognitive test performance need to be elucidated in future research.
Efavirenz as a cholesterol‐targeting drug for AD
Authors: Pikuleva Irina A.
Published: December 2020

Background

Cytochrome P450 46A1 (CYP46A1) is the CNS‐specific cholesterol 24‐hydroxylase that controls cholesterol elimination and turnover in the brain. Efavirenz (EFV) is the FDA‐approved reverse transcriptase inhibitor given to HIV subjects at the 600 mg per day dose. We discovered that small doses of EFV allosterically activate CYP46A1 in mice and are evaluating whether CYP46A1 could be a pharmacologic target for Alzheimer’s disease (AD) and EFV as a disease‐modifying anti‐AD medication.

Method

Clinical and animal studies investigating EFV. Clinical studies include a proof‐of‐concept clinical trial in patients with AD. Animal studies include multiple in vivo and in vitro assessments of 5XFAD mice (an AD model) after the treatment with a small dose (0.1 mg/kg body weight) of EFV.

Result

A small dose of EFV activates CYP46A1 and improves behavioral performance of 5XFAD mice; the effect on the amyloid b burden is the treatment paradigm‐specific. The omics and other approaches suggest that the CYP46A1 activity modulation affects multiple signaling pathways and processes via the effects on the physicochemical properties of the plasma membranes. EFV analogs were found, which in vitro are even better CYP46A1 activators than EFV.

Conclusion

All our available data suggest that CYP46A1 is a viable therapeutic target for AD, and EFV could be the first generation medication that targets cholesterol metabolism and turnover in AD. Supported by the NIH AG067552 grant and the Alzheimer’s Drug Discovery Foundation grant GC‐2012681.
Onset of motor deficits, but not their severity, is augmented by TREM2 reduction in P301S tau transgenic mice
Authors: Feiten Astrid F. , van Hummel Annika , van der Hoven Julia , Przybyla Magdalena , Deng Yuanyuan , Delerue Fabien , Ke Yazi D. , Ittner Lars M.
Published: December 2020

Background

Alzheimer’s disease (AD) is characterised by extracellular amyloid‐β plaques and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule associated protein tau. These two pathological hallmarks have been explored for decades however it remains not fully understood how they interact with each other and how they trigger disease onset and progression. Recently, in genome wide association studies other genetic risk factors have been identified. One of them being polymorphisms of the triggering receptor expressed on myeloid cells 2 (TREM2). The effects of TREM2 on disease and especially in the context of tau pathology remain poorly understood and the current literature is conflicting.

Methods

Here, we have examined the effect of TREM2 on tau pathology in an P301S tau transgenic mouse model, TAU58/2. TAU58/2 mice are characterised by an early onset and progressive NFT pathology and behavioural, motor and memory deficits. TREM2 knockout (KO) mice were crossed with TAU58/2 transgenic mice and subjected to a variety of functional tests including RotaRod, elevated plus maze, open field and Morris water maze at different age time points. After behavioural assessment brains were collected and histological analysis performed.

Results

At 2 months of age TAU58/2 mice present with moderate motor deficits on the RotaRod, this phenotype was significantly aggravated upon TREM2 reduction and complete depletion. Further, we found that TREM2 KO induces a disinhibition like phenotype in older TAU58/2 non transgenic animals. Histological analysis revealed an increase in cells positive for tau phosphorylated at serine 422, a late stage pathology marker. Interestingly, knock out of TREM2 impacted on performance of transgenic and non‐transgenic mice differently.

Conclusion

Taken together, our results show that reducing TREM2 exacerbates the functional deficits of TAU58/2 transgenic mice. Furthermore, we found an accelerated progression of tau phosphorylation. Hence, our work suggests that reduction and loss of TREM2 function could contribute to functional deficits in AD via augmenting tau pathology.
Longer TOMM40 poly‐T variants associated with less regional gray matter in cognitively normal older APOE E3/E3 adults
Authors: Honea Robyn A , Vidoni Eric D , Morris Jill K , Michaelis Elias K , Burns Jeffrey M , Swerdlow Russell H
Published: December 2020

Background

The TOMM40 poly‐T is a polymorphism of the TOMM40 gene at rs10524523 (“523”), in linkage disequilibrium with APOE. The role of TOMM40 in Alzheimer’s disease risk is still controversial. We sought to use whole brain voxel‐based methods to investigate if older individuals with the absence of an APOE e4 allele with varying lengths of the TOMM40 Poly‐T allele had gray matter volume differences indicative of Alzheimer’s disease risk.

Method

We studied individuals without cognitive impairment (n = 69) from our KU Alzheimer’s Disease Center whose apolipoprotein (APOE) genotype was e3/e3, and who were Caucasian. The participants were grouped according to poly‐T length polymorphisms at “523” homozygous for S (S/S; n = 25), homozygous for VL (VL/VL; n = 19), and heterozygous (S/VL; n = 25). All individuals were scanned for T1‐weighted MPRAGE structural images using a 3T Skyra Siemens. Images were preprocessed and analyzed using CAT12, a Computational Anatomy Toolbox (http://www.neuro.uni‐jena.de/cat/) running under SPM12 and MATLAB (R2020a). To investigate associations between genotype and regional GM volume, we performed voxel‐based morphometry (VBM). In order to investigate associations between TOMM40 Poly‐T group and gray matter volume differences we included age, sex, and total intracranial volume (TIV), as variables of no interest in our full factorial model. The statistical threshold was set at Pheight < 0.05, corrected (FDR).

Result

All groups were similar and not significantly different in mean age, education, MMSE, and overall brain volume. Individuals with a VL/VL genotype had lower precuneus volumes (p = .023 FDR corrected, k = 213, ‐29, ‐84, 36) and temporal cortex volumes (p = .005 FDR corrected, k = 362, ‐45, ‐40, ‐32) compared to S/S individuals.

Conclusion

TOMM40 “523” VL variants are related to reduced gray matter volume in the precuneus and the temporal cortex in healthy individuals with an APOE e3/e3genotype. This is especially interesting as the precuneus has been identified in other studies, and it may be particularly sensitive to dysfunction in bioenergetic changes associated with faulty mitochondria. This adds to a growing literature implicating TOMM40 “523” and mitochondrial function in late‐onset Alzheimer’s disease progression.
Whole genome sequence association analyses of brain volumes in the TOPMed program
Authors: Sarnowski Chloé , Satizabal Claudia L. , Yanek Lisa R. , Bis Joshua C. , Smith Jennifer A , DeCarli Charles , Arnett Donna K. , Psaty Bruce M. , Nyquist Paul , Mathias Rasika A. , Destefano Anita L. , Seshadri Sudha ,   TOPMed Neurocognitive Working Group
Published: December 2020

Background

Genome‐wide association studies (GWAS) of brain volumes have identified common genetic variants with modest effect sizes that lie mainly in non‐coding regions. We sought to identify low frequency and rare variants influencing brain volumes by performing whole genome association analyses using sequence data from the Trans‐Omics for Precision Medicine (TOPMed) Program.

Methods

We analyzed up to 3,975 participants (58% women; 78% Europeans, 22% African‐Americans), mean age of 62.5 (13.9), from four TOPMed population‐ or family‐based studies (FHS, GENESTAR, CHS, and GENOA). We excluded participants with dementia, stroke, presence of large brain infarcts, tumor or any other finding affecting the scan. We tested the association of hippocampal (HV), total brain (TBV), lateral ventricular (LVV) and intracranial (ICV) volumes with individual genetic variants using mixed‐effect linear regression models adjusted for age, age2, sex, study and principal components. Models including HV, TBV and LVV were adjusted for ICV. We accounted for relatedness using a kinship matrix and trait variance variability using a random effects model. We retained variants with a minor allele count greater than 40.

Results

We detected new genome‐wide significant (P < 5 × 10−8) low frequency or rare variants in five regions associated with HV (5q31, P = 10−9) and TBV (2p22, P = 10−8; 17q25, P = 4 × 10−9; Xp11, P = 2 × 10−10; Xq21, P = 4 × 10−8). We also confirmed previously observed common variants in GWAS loci for HV (12q14 & 12q24), LVV (3q28, 12q23 & 16q24) and ICV (6q21, 6q22 & 17q21). The top 5q31 hit for HV (rs246587) lies at 19kb from the PCDHAC2 gene, encoding neural cadherin‐like cell adhesion proteins that most likely play a critical role in the establishment and maintenance of specific neuronal connections in the brain.

Conclusions

Our whole genome analysis revealed intriguing new loci associated with brain volumes. Future work will include ancestry‐specific and conditional analyses, gene‐based and burden tests as well as the inclusion of additional TOPMed cohorts. Supported by: U01s AG058589, AG052409, R01s AG054076, AG033040 AG049607, HL112064, NS062059, FHS contracts HHSN268201500001I and 75N92019D00031, R01HL131136 (Analysis Commons).
Associations between ambient air pollution and Alzheimer pathologic change in humans: A secondary analysis of IDEAS study data
Authors: Iaccarino Leonardo , La Joie Renaud , Lesman‐Segev Orit H. , Lee Eunice , Hanna Lucy , Gatsonis Constantine , Rabinovici Gil D.
Published: December 2020

Background

Amyloid accumulation is a defining feature of Alzheimer’s Disease (AD) and is a risk factor for cognitive decline and dementia. Previous cerebrospinal fluid and autopsy studies in humans have showed that brain β‐amyloid pathology may be promoted by exposure to air pollutants, possibly because of resulting chronic microglia activation and oxidative stress.

Methods

We tested the association between local concentrations of fine particulate matter (PM2.5) and ground‐level ozone (O3) and probability of amyloid‐PET positivity in 18,178 cognitively‐impaired participants from the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) study (age 75.8±6.3, N=10,991 Mild Cognitive Impairment (MCI) and N=7,187 Dementia, see Table 1 and Figure 1). The ambient concentration of airborne pollutants was estimated proximate to recorded patient residence zipcodes, using daily predictions from the Environmental Protection Agency (EPA) Downscaler model, which combines pollutant concentrations, photochemical properties and atmospheric data. Air quality data was collected considering two biennial time‐windows, i.e. 14‐years and 1‐year prior to amyloid‐PET (average quality in 2002‐2003 and 2015‐2016), to model early‐ and late exposure. Adjusted logistic models included demographic, lifestyle and socioeconomical factors as well as respiratory, cardiovascular, cerebrovascular, psychiatric and general health comorbidities.

Results

People residing in areas with higher predicted PM2.5 concentrations had a higher probability of being amyloid‐PET positive 14‐years later (odds ratio ‐ OR 1.10 [per 4 μg/m3 increase], 95%CI 1.05‐1.15, p<0.001). In sub‐group analyses, the association between PM2.5 and positive amyloid‐PET were significant in White/Caucasian, female and MCI participants. Exposure to higher predicted O3 concentrations was not associated with amyloid‐PET positivity overall (OR 1.03 [increase by 5 ppb], 95%CI 0.99‐1.06, p=0.11), but showed a significant association in females and in dementia patients. Similar relationships were observed with 2015‐2016 data. See Figure 2 for a complete summary of all logistic regression models.

Conclusions

Increasing air pollution, even within EPA standards, may directly impact brain health by promoting the accumulation of β‐amyloid plaques.
Towards a universal cortical tau sampling mask
Authors: Dore Vincent , Rowe Christopher C , Bourgeat Pierrick , Burnham Samantha C , Huang Kun , Krishnadas Natasha , Masters Colin L , Fripp Jurgen , Villemagne Victor LL
Published: December 2020

Background

The introduction of the A/T/(N) framework raised several issues regarding the definition of T+. In which region should tau scans be sampled? Based on which tracer? In this work, we developed a “universal” cortical tau mask derived from three major tau ligands for the AD continuum, over which several different global/regional sampling VOI or composites can be applied.

Method

221 healthy elderly controls (HC) and 67 Alzheimer’s disease (AD) patients underwent tau scans with either 18F‐AV1451 (HC=54/AD=24), 18F‐MK6240 (HC=157/AD=22) or 18F‐PI2620 (HC=10/AD=21). All HC were Ab‐ (<20CL) and all AD were Ab+(20CL). The tau scans were spatially normalized using CapAIBL and the cerebellum cortex was used as reference region. For each tracer, a difference image between the means of the Ab‐HC and Ab+AD patients was then generated. Difference images were subsequently thresholded at 1/3 of the difference between Ab‐HC and Ab+AD in the inferior temporal lobe.A MRI‐derived grey matter mask at PET resolution was applied to the composite mask to only sample cortical region. The mask was finally mirrored and fused to remove the hemispherical asymmetry due to the distribution of tau deposits in the assessed participants. Agreement between masks was assessed by dice‐scores.

Result

Visually, the three tracer‐specific masks appeared very similar (Fig 1, rows 1‐3). None of the known off‐target binding regions was discernible in the resulting masks. There was good agreement between all masks, with dice‐scores of 0.60 and 0.66 for cortical regions.

Conclusion

We constructed an “universal” tau mask for the AD continuum based on three commonly used tau tracers aiming at standardizing tau sampling (and quantification) across tracers and across centres. The “universal” tau mask can also be sub‐segmented into smaller regions to focus on specific areas or to construct a subset of composite masks that might better capture early tau deposition and spreading. Further refinement of the tau mask will require the addition of more tau tracers. (RO948, GTP1, PBB3, etc.).
Patterns of change in subjective cognitive complaints are associated with cognitive decline and dementia risk: Findings from the Sydney Memory and Ageing Study
Authors: Numbers Katya T. , Lam Ben C.P. , Crawford John D. , Kochan Nicole A. , Sachdev Perminder S. , Brodaty Henry
Published: December 2020

Background

Subjective cognitive complaints (SCCs) are now an established risk factor for dementia, however, little is known about whether changing patterns in SCCs over time are associated with cognitive decline and dementia risk. We examine the trajectory of SCCs over a 6‐year period to determine whether intraindividual patterns of reporting SCCs over time is related to cognitive decline and incident dementia.

Method

Participants were 1037 older adults without dementia (M
age = 78.65 years; 55% females) from the Sydney Memory and Ageing Study who were followed‐up biennially. Global cognition was measured using a comprehensive neuropsychological battery, and clinical diagnoses were made by an expert consensus panel. SCCs were obtained as participants’ response to a single question concerning their subjective report of memory decline. Patterns of SCCs over time were modelled by conducting categorical latent growth curve analysis using the logit transformation (Figure 1). We examined the associations between average level of SCC likelihood and change in SCC likelihood, with global cognition over six years using latent growth curve analysis, and with risk of incident dementia over 10 years using Cox regression.

Result

In this community‐dwelling older adult sample, there was an annual 10% increase in the odds of reporting SCCs (Figure 2). After controlling for demographics, depression, and personality, results revealed a negative longitudinal association between the slope of SCCs and the slope of global cognition scores, such that participants with an increasing propensity of reporting SCCs over time also showed a steeper rate of decline in global cognition (Figure 4). Cox regression revealed an association between increased SCCs and incident dementia risk (Table 1). That is, participants with an increasing propensity of reporting SCCs over time are also at greater risk for developing dementia (Figure 5).

Conclusion

This is the first study to use latent growth curve analysis to examine patterns of change in SCCs overtime. Traditionally, studies examining SCCs longitudinally categorise people as ‘stable’ versus ‘not stable’, however, important information may be lost this way. Understanding patterns of change in SCC reporting over time has significant potential to identify individuals at greater risk of cognitive decline and incident dementia.
Healthcare expenditures attributable to Alzheimer's disease in Japan: Life study
Authors: Fukuda Haruhisa , Maeda Megumi , Ono Rei
Published: December 2020

Background

The number of older adults with dementia in Japan is projected to exceed 7 million by 2025. This increase will place a heavy economic strain on Japan’s public insurance system as its population ages and workforce shrinks. Although the estimation of this economic burden is crucial to understanding the societal importance of dementia prevention, little is known about the additional healthcare expenditures attributable to dementia in Japan. This study aimed to quantify the healthcare expenditures attributable to Alzheimer's disease (AD).

Method

The analysis was conducted using the Longevity Improvement & Fair Evidence Study (LIFE Study) database, which comprises municipality‐level information centred on claims data. Claims data from April 2014 to March 2019 were obtained from one rural city. The study subjects were individuals who had received new diagnoses of AD in October 2014 or later. The healthcare expenditures for one year were estimated for subjects with adequate follow‐up data for the respective periods. Using the expenditures incurred during the six‐month period before AD diagnosis as a comparator, the additional expenditures incurred after AD diagnosis were estimated through fixed‐effects models.

Result

A total of 1,283 patients with new diagnoses of AD were identified from the LIFE Study database. Their mean age was 83.2 years, 67.1% were women, and the mean healthcare expenditure during the six months before AD diagnosis was US$1,038. For subjects with one‐year follow‐up data, the fixed‐effects model estimated that the first, second, and third months after AD diagnosis were associated with additional expenditures of US$1,787 (P < 0.001), US$1,388 (P < 0.001), and US$952 (P < 0.001), respectively, when compared with the pre‐AD period. The additional expenditures stabilized at approximately US$300 in the fourth month and later.

Conclusion

AD onset was associated with additional monthly healthcare expenditures of approximately US$300 per patient. The substantial economic burden of AD underscores the societal importance of implementing effective and efficient preventive measures.
Protocol of a clinical trial to implement physical activity for cognitive health in two aged persons' mental health services in Melbourne: The EXCEL study
Authors: Ellis Kathryn A , Curran Eleanor , Cox Kay L , Chong Terence WH , Palmer Victoria J , Anstey Kaarin J , Southam Jennifer , Coulson Brett , Moss Francine , Lautenschlager Nicola T
Published: December 2020

Background

Physical inactivity is a key contributor to chronic disease burden. Physical activity (PA) offers significant health benefits, including for brain health, and to groups with increased dementia risk such as older people with mental illness, Mild Cognitive Impairment or Subjective Cognitive Decline. There is a global call for dementia risk reduction interventions to be implemented into clinical practice. Older people with mental health problems experience significant barriers to PA and are a ‘hard to reach’ group for health promotion. Specific programs, integrated into mental health services, are needed. We will implement behaviour change theories to investigate the effectiveness, acceptability, feasibility and sustainability of an intervention to assist consumers of public Aged Persons Mental Health Services to follow PA clinical guidelines.

Method

This three‐phased study will involve consumers, mental health clinicians and General Practitioners (GPs). An optimisation phase includes initial theory‐based design, using a comprehensive intervention logic model that identifies key anticipated behavioural determinants and matched strategies to support change. The proposed intervention will be presented to consumers and clinicians for consideration. Their feedback will inform tailoring of the intervention prior to implementation. The implementation phase involves a trial of the intervention’s effectiveness compared to usual care for increasing consumer PA levels. Clinicians will be supported to incorporate PA guidelines into clinical practice using tailored behaviour change strategies over 12‐weeks. An individual PA prescription, relevant equipment and exercise demonstrations will be offered to consumers. We will measure PA levels using a validated questionnaire (the CHAMPS) to determine the number of participants meeting PA guidelines, along with measuring changes to quality of life, psychiatric symptom burden and dementia risk. An evaluation phase will use a mixed‐methods approach to evaluate change in the identified key behavioural determinants, as well as qualitative evaluation of the intervention across the three participant groups.

Results

This study will provide pragmatic evidence‐based information for clinical practice, supporting the design of implementation programs to enhance PA in older consumers with mental health problems.

Conclusion

This research addresses the need for integrated mental, cognitive and physical healthcare, facilitating holistic healthcare for groups at increased risk of cognitive decline.
Perspectives on dementia care amongst primary care providers
Authors: Macchi Zachary A , Pressman Peter S
Published: December 2020

Background

Persons with dementia require extensive medical and psychosocial support to delay progression and prolong functional independence. Early diagnosis improves quality of life, symptom management, and caregiver burden. Primary care providers (PCPs) are commonly the initial healthcare point of contact for individuals with dementia. However, there is a tendency towards under‐diagnosing dementia in the primary care setting and a majority of patients receive no formal diagnosis nor dementia type differentiation. Individuals with dementia also experience low rates of specialist referrals. Our aim is to describe the perspectives of PCPs regarding the management of dementia in order to identify areas for improving early dementia care delivery.

Method

We conducted a survey of 208 Internal Medicine PCPs practicing across three institutions in Denver, Colorado, including an academic hospital, Veterans Affairs system, and a local county hospital. A five‐point Likert scale was used to assess held views on clinical training, challenges of care compared to non‐neurologic illness (heart failure and diabetes), the PCP’s role in dementia care, screening and diagnosis, resources for referral, and barriers to care coordination.

Results

A total of 26 providers responded at a rate of 12.5%. Additional training in: triggers for referral, care plan formulation, and behavioral symptom management were identified as helpful to these providers. A number of responders strongly agreed that dementia care was challenging (37.5%, r2 =0.44, SD=0.66) compared to managing heart failure or diabetes (r2 =0.83, SD=0.91). PCPs reported a lack of referral resources (45.8%), difficulties in care coordination (41.7%) and minimally agreed with the statement that there “are effective ways to manage dementia” (79.1%). The biggest barriers to dementia care delivery were “inadequate time” (r2 =1.17, SD=1.08) and “inadequate resources for ongoing care” (r2 =0.80, SD=0.89).

Conclusion

PCP viewpoints on the challenges of dementia care, but perceived lack of effective management strategies, suggest a disconnect between clinical practice and evidence showing the benefits of comprehensive dementia care. Access to specialists (e.g. neurologists, geriatricians) might improve dementia care by improving allocation of dementia support resources. Our response rate is consistent with published, disincentivized surveys of PCPs.
Identifying mild cognitive impairment with older aboriginal Australians in community settings: Performance of the Clock Drawing Test relative to other cognitive screening tools
Authors: Nichols Madeleine , Lavrencic Louise , Radford Kylie
Published: December 2020

Background

The Clock Drawing Test (CDT) is commonly used in the detection of cognitive disorder. Easily administered in both clinical and non‐clinical settings and well accepted by patients, this test is a good candidate for use in early detection of dementia with older Aboriginal Australians. This study aimed to: (i) compare three CDT scoring methods and their reliability/validity in detecting mild cognitive impairment (MCI) and dementia in Aboriginal communities; (ii) determine the optimal CDT sensitivity, specificity and cut‐off scores; (iii) investigate the relative and combined performance of the CDT with other cognitive screening tools [Kimberly Indigenous Cognitive Assessment (KICA); Mini Mental State Examination (MMSE); Rowland Universal Dementia Assessment Scale (RUDAS)].

Method

A subset of participants (n=153; aged 60‐93) recruited for the Koori Growing Old Well Study completed neurocognitive evaluation as part of a comprehensive medical assessment and were diagnosed by expert consensus as intact, MCI or dementia. CDT responses originally scored as part of the Addenbrooke’s Cognitive Examination Revised (ACE‐R) were rescored using the Mendez and Sunderland methods by an assessor blind to diagnosis.

Result

There were strong positive correlations between all three CDT scoring methods (r
s
range=.895‐.924). All methods differentiated dementia from MCI and intact participants (p<.001), but not intact from MCI (Mendez p=.712; Sunderland p=.545; ACE‐R p=.094). There was no significant difference between scoring methods in diagnostic validity for dementia (AUC=.739‐.756); however, the simple ACE‐R method had the highest positive and negative predictive values (PPV=0.643; NPV=0.862), with optimal cut‐off score <3.

The MMSE outperformed all other screening tests in detecting cognitive impairment (MCI or dementia; AUC=.851) and was superior to both the KICA and CDT in distinguishing MCI from intact participants, but comparable to the RUDAS. Combining the CDT with other screening tools did not significantly improve their diagnostic performance for either cognitive impairment or MCI.

Conclusion

CDT alone is not an adequate screening tool for MCI; however, has potential for detecting moderate to severe cognitive impairment in older Aboriginal Australians. Relative to other screening tools, the MMSE performed well for detecting both cognitive impairment and MCI; the addition of the CDT did not significantly improve other tests’ performance.