bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Approach to Open “Dead Space” and Modify Interfacial Features of Carbon Nanotube Assemblies by a Microwave Shock
Authors: Lin Dewu , Zhou Ying , Kobashi Kazufumi , Chen Guohai , Futaba Don N. , Hata Kenji
Published: December 2022

Despite 30‐year development of carbon nanotube (CNT) based materials, harnessing the outstanding nanoscale properties of individual CNT for macroscale applications remains challenging. High specific surface area, a crucial feature of CNTs, often suffers from the formation of tightly packed bundles with inaccessible “dead space”. Herein, a novel “microwave shock” approach to open the “dead space” trapped within bundles is reported. Employing N2 ambient during microwave irradiation, CNT bundles undergo an efficient structural alteration and interfacial modification simultaneously due to the strong radiative coupling, while the graphitic structure remains undamaged. In this way, a 15‐fold increase (from 42 to 648 m2 g−1) in the interstitial surface area as well as the lithiophilic functionalization (≈1 atom% nitrogen doping) are achieved without the degradation of other properties. Furthermore, to highlight the merits of this microwave shock process, the treated CNT films are applied as a host material for the anode in a lithium metal battery and demonstrate the suppression of dendritic lithium growth and improve cycling stability. This microwave shock approach provides an efficient avenue to modify nanocarbon‐based materials for further applications.
Many‐Body Correlations and Exciton Complexes in CsPbBr3 Quantum Dots
Authors: Zhu Chenglian , Nguyen Tan , Boehme Simon C. , Moskalenko Anastasiia , Dirin Dmitry N. , Bodnarchuk Maryna I. , Katan Claudine , Even Jacky , Rainò Gabriele , Kovalenko Maksym V.
Published: December 2022

All‐inorganic lead‐halide perovskite (LHP) (CsPbX3, X = Cl, Br, I) quantum dots (QDs) have emerged as a competitive platform for classical light‐emitting devices (in the weak light–matter interaction regime, e.g., LEDs and laser), as well as for devices exploiting strong light–matter interaction at room temperature. Many‐body interactions and quantum correlations among photogenerated exciton complexes play an essential role, for example, by determining the laser threshold, the overall brightness of LEDs, and the single‐photon purity in quantum light sources. Here, by combining cryogenic single‐QD photoluminescence spectroscopy with configuration‐interaction (CI) calculations, the size‐dependent trion and biexciton binding energies are addressed. Trion binding energies increase from 7 to 17 meV for QD sizes decreasing from 30 to 9 nm, while the biexciton binding energies increase from 15 to 30 meV, respectively. CI calculations quantitatively corroborate the experimental results and suggest that the effective dielectric constant for biexcitons slightly deviates from the one of the single excitons, potentially as a result of coupling to the lattice in the multiexciton regime. The findings here provide a deep insight into the multiexciton properties in all‐inorganic LHP QDs, essential for classical and quantum optoelectronic devices.
Synthesis of Complex Dihydroisoquinolin Derivatives via Cobalt‐Electrocatalyzed C−H Activation
Authors: Huang Yin‐Hui , Dong Lin
Published: December 2022

We developed a cost‐effective cobalt‐catalyzed electrochemical annulation to generate diversified novel complex dihydroisoquinolin derivatives from amides and alkenes in a simple and maneuverable undivided cell. The reaction proceeded C−H/N−H activation, and the catalyst was regenerated by anodic oxidation. Notably, the strategy of electrocatalysis avoided the consumption of stoichiometric chemical oxidants.

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Primary palliative care education in emergency medicine residency: A mixed‐methods analysis of a yearlong, multimodal intervention
Authors: Benesch Tara D. , Moore Justin E. , Breyre Amelia M. , DeWitt Raizel , Nattinger Caroline C. , Dellinger Elaine , Anderson Erik S. , Bulman Linda
Published: December 2022

Background

Emergency medicine (EM) physicians frequently care for seriously ill patients at the end of life. Palliative care initiated in the emergency department (ED) can improve symptom management and quality of life, align treatments with patient preferences, and reduce length of hospitalization. We evaluated an educational intervention with digital tools for palliative care discussions in an urban EM residency using the reach, effectiveness, adoption, implementation, and maintenance (RE‐AIM) framework.

Methods

Our intervention, conducted from July 2020 to August 2021, included education on palliative care techniques, digital tools, and incentives for participation. We tracked goals of care conversations and palliative care consults using electronic medical record data, conducted pre‐ and posttraining surveys, and used semistructured interviews to assess resident perspectives on palliative care conversations in the ED. Outcomes included number of goals of care conversations recorded by EM residents, consults to palliative care from the ED, and resident perspectives on palliative care in EM.

Results

The results were as follows: reach—45 residents participated in the intervention; effectiveness—89 goals of care conversations were documented by 23 ED residents, and palliative care consults increased from approximately four to 10 monthly; adoption—over half the residents who participated in the intervention documented goals of care discussions using an electronic dotphrase; implementation—by the completion of the intervention, residents reported increased comfort with goals of care conversations, saw palliative care as part of their responsibility as EM physicians, and effectively documented goals of care discussions; and maintenance—at 2‐month follow up, palliative care consults from the ED remained at approximately 10 monthly, and digital tools to prompt and track palliative care discussions remained in use.

Conclusions

An integrated palliative care training for EM residents with technological assists was successful in facilitating goals of care discussions and increasing palliative care consults from the ED.
Systemic barriers to reporting work injuries and illnesses in contexts of language barriers
Authors: Premji Stephanie , Begum Momtaz , Medley Alex
Published: December 2022

Background

Workers who experience language barriers are at increased risk of work‐related injuries and illnesses and face difficulties reporting these health problems to their employer and workers' compensation. In the existing occupational health and safety literature, however, such challenges are often framed in individual‐level terms. We identify systemic barriers to reporting among injured workers who experience language barriers within the varying contexts of Ontario and Quebec, Canada.

Methods

This study merges data from two qualitative studies that investigated experiences with workers' compensation and return‐to‐work, respectively, for injured workers who experience language barriers. We conducted semi‐structured interviews with 39 workers and 70 stakeholders in Ontario and Quebec. Audio recordings were transcribed and coded using NVivo software. The data was analysed thematically and iteratively.

Results

Almost all workers (34/39) had filed a claim, though most had initially delayed reporting their injuries or illnesses to their employer or to workers' compensation. Workers faced several obstacles to reporting, including confusion surrounding the cause and severity of injuries and illnesses; lack of information, misinformation, and disinformation about workers' compensation; difficulties accessing and interacting with care providers; fear and insecurity linked to precarity; claim suppression by employers; negative perceptions of, and experiences with, workers' compensation; and lack of supports. Language barriers amplified each of these difficulties, resulting in significant negative impacts in economic, health, and claim areas.

Conclusion

Improving the linguistic and cultural competence of organizations and their representatives is insufficient to address under‐reporting among workers who experience language barriers. Efforts to improve timely reporting must tackle the policies and practices that motivate and enable under‐reporting for workers, physicians, and employers.
Two‐stage cost‐sensitive clinical decision support system for detecting Alzheimer’s disease
Authors: Kleiman Michael J
Published: December 2022

Background

A two‐stage clinical decision support pipeline was developed to first recommend individuals for further testing based on easily administered screening tests, followed by a more robust identification of impairment based on additional cognitive testing and neuroimaging. The ultimate goal of the pipeline is to recommend further in‐depth diagnostic assessment for those identified as “likely impaired” and reduce the incidence of healthy controls needing to undergo costly diagnostic assessments.

Method

The first stage of the paradigm used easily‐collected demographic and questionnaire data with simple trail‐making and word recall, while the second stage introduced volumetric MRI and full cognitive testing from the MoCA and both the verbal learning and verbal fluency tasks. Both stages of the paradigm utilized gradient‐boosted ensemble classifiers trained on 1181 participants from the ADNI dataset (517 controls and 522 MCI, 142 AD) and evaluated on our cohort of 105 participants (23 controls, 59 MCI, 23 AD).

Result

In the first selection stage, all dementia patients (23/23), 93.2% of MCI patients (55/59), and 43.5% of controls (10/23) were selected for further testing. After the second stage, 73.9% of controls (17/23) were ruled out, and “likely impairment” was identified in all dementia patients (23/23) and 83.1% MCI patients (49/59) with overall 87.8% sensitivity after 50 repeats of a stochastic cross‐validation procedure.

Conclusion

The ability of this two‐stage paradigm to rule out controls prior to costly in‐depth diagnostic assessment can be useful to reduce the staffing and time costs associated with appropriately identifying dementia. Overall detection was similar between a dual‐stage and single‐stage paradigm, suggesting that the dual‐stage paradigm is effective at reducing screening costs without compromising efficacy.
Towards emotionally aligned social robots for dementia: perspectives of care partners and persons with dementia
Authors: Dosso Jill A , Bandari Ela , Malhotra Aarti , Hoey Jesse , Michaud Francois , Prescott Tony J , Robillard Julie M.
Published: December 2022

Background

Persons living with dementia and their care partners place a high value on aging in place and maintaining independence. Socially assistive robots – embodied characters or pets that provide companionship and aid through social interaction – are a promising tool to support these goals. There is a growing commercial market for these devices, with functions including medication reminders, conversation, pet‐like behaviours, and even the collection of health data. While potential users generally report positive feelings towards social robots, persons with dementia have been under‐included in design and development, leading to a disconnect between robot functions and the real‐world needs and desires of end‐users. Furthermore, a key element of social and emotional connectedness in human relationships is emotional alignment – a state where all partners have congruent emotional understandings of a situation. Strong emotional alignment between users and robots will be necessary for social robots to provide meaningful companionship, but a computational model of how to achieve this has been absent from the field. To this end, we propose and test Affect Control Theory (ACT) as a framework to improve emotional alignment between older adults and social robotics.

Method

Using a Canadian online survey, we introduced respondents to three exemplar social robots with older adult‐specific functionalities and evaluated their responses around features, emotions, and ethics using standardized and novel measures (n=171 older adults, n=28 care partners, and n=7 persons living with dementia).

Result

Overall, participants responded positively to the robots. High priority uses included companionship, interaction, and safety. Reasoning around robot use was pragmatic; curiosity and entertainment were motivators to use, while a perceived lack of need and the mechanical appearance of the robots were detractors. Realistic, cute, and cuddly robots were preferred while artificial‐looking, creepy, and toy‐like robots were disliked. Most importantly, our evidence supported ACT as a viable model of human‐robot emotional alignment.

Conclusion

This work supports the development of emotionally sophisticated, evidence‐based, and user‐centered social robotics with older adult‐ and dementia‐specific functionality.
Premature Cardiovascular Disease and Brain Health in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Jiang Xiaqing , Allen Norrina , Lewis Cora , Sidney Stephen , Yaffe Kristine
Published: December 2022

Background

Cardiovascular disease (CVD) is associated with cognitive impairment and dementia risk in late life, yet little is known about the role of premature (defined younger than 60 years) CVD events with cognition and brain health earlier in the life course, including in midlife. As part of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, we investigated the association of premature CVD events in young and middle adulthood with cognition and white‐matter health in midlife.

Methods

We studied 3,146 Black and White participants (57% women, 48% Black) aged 18‐30 years at baseline (1985‐86) who were followed up to Year 30 (mean age 55.1±3.6 years) when 5 cognitive tests measuring different domains were administered. A subset (656 participants) had brain MRI with measures of white matter hyperintensity (WMH) burden and white matter integrity. Premature CVD events were adjudicated based on participants' history and medical records of coronary heart disease, stroke/TIA, cardiac revascularization, congestive heart failure, carotid artery disease, and peripheral artery disease. We conducted linear regression to determine the association of premature CVD with cognitive and structural brain measures.

Results

Five percent (n = 147) of participants had premature CVD events over the 30 years. Having premature CVD events was associated with lower cognitive function in all domains. After adjustment for demographics, education, depressive symptoms, physical activity, diet, APOE ε4, and cardiovascular risk factors (CVRFs), premature CVD was associated with lower cognition (z‐standardized) except for verbal fluency: global cognition (‐0.19, 95% CI ‐0.35 to ‐0.03), verbal memory (‐0.24, 95% CI ‐0.41 to ‐0.07), processing speed (‐0.46, 95% CI ‐0.63 to ‐0.30), and executive function (‐0.38, 95% CI ‐0.56 to ‐0.20). Premature CVD was also associated with greater WMH volumes (total, frontal, temporal, and parietal lobes) and alternations of white matter integrity (higher total and temporal lobe mean diffusivity and lower parietal lobe fractional anisotropy) after adjusting for demographics, total intracranial volume, and CVRFs.

Conclusion

Premature CVD is associated with worse midlife cognition and white‐matter health independent of CVRFs. Young and middle adulthood is a critical time for CVD prevention, the efforts of which may delay the onset of cognitive decline and dementia later in life.
Brain energy rescue with ketones improves cognitive outcomes in MCI
Authors: Cunnane Stephen
Published: December 2022

Background

An emerging strategy to delay the onset of Alzheimer disease (AD) is to use ketones to overcome the progressive brain energy deficit caused by deteriorating brain glucose metabolism in mild cognitive impairment (MCI). Ketones (acetoacetate and beta‐hydroxybutyrate) are the brain’s main alternative fuel to glucose; in contrast to glucose, ketone metabolism by the brain is now known to be unaffected in MCI and AD. Successful brain energy rescue with ketones in MCI was recently reported.

Methods

In the 6‐month, randomized, placebo‐controlled Benefic Trial (NCT02551419), the active arm was a ketogenic medium chain triglyceride (kMCT) supplement in a lactose‐free skim milk emulsion (15 g kMCT twice/day; n = 39 completers). The placebo arm was a non‐ketogenic iso‐energetic vegetable oil (n = 44 completers). Brain ketone and glucose metabolism were assessed by PET.

Results

Performance on all five cognitive domains improved significantly over 6 months in the kMCT group: (i) Episodic memory (trial 1, Free and Cued Recall Test) increased by 1 word (+0.5 Δ Z‐score); (ii) Executive function (Verbal Fluency Test) correct answers increased by 2 words (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), time taken on the Stroop Colour Naming Test decreased by 1 sec (p = 0.09), and errors on the Trail Making Test increased by 0.8 on placebo (p = 0.02); (iii) Language (Boston naming test) correct answers increased by 1.3 words. (iv) Processing speed increased directly with higher brain ketone uptake in several white matter tracts. (v) Improved attention was directly associated with increased ketone uptake and functional connectivity in the dorsal attention network.

Conclusions

Improved cognition correlating positively with improved brain energy supply by ketones suggests a direct link to brain energy status. The moderate effect size of this kMCT intervention indicates a clinically meaningful benefit on certain cognitive outcomes, some of which relate directly to risk of MCI progressing to AD. Other potential ketogenic interventions that have been less well studied in MCI or AD include a ketogenic diet and ketone salts or esters. Whether brain energy rescue with ketones can delay the onset or progression of AD should now be assessed.
Brain endothelial dysfunction in AD
Authors: de Vries Helga E
Published: December 2022

Increasing evidence suggests that neurovascular dysfunction and neuro‐inflammation is associated with early stages of Alzheimer’s disease (AD). The neuroprotective blood‐brain barrier (BBB) is indispensable for the maintenance of brain homeostasis and proper neuronal functioning. Dysfunction of the BBB and inflammation thereof significantly contributes to the pathogenesis of AD. Amyloid‐β deposition in the microvasculature of the brain, a process referred to as capillary cerebral amyloid angiopathy (capillary CAA), propagates vascular remodeling, which results in impaired function of the blood‐brain barrier and inflammation thereof. While improving vascular function and dampening neuro‐inflammation may be an attractive new way to fight capillary CAA, the underlying factors that mediate vascular alterations in Alzheimer’s disease and capillary CAA pathogenesis remain largely unknown.

Our earlier work indicated that hypoxia is a key mediator of vascular dysfunction, which resulted in the induction of angiopoietin like‐4 (ANGPTL4), a hypoxia‐induced factor, in reactive astrocytes in well characterized post‐mortem tissues of patients with capillary CAA. In vitro studies indicated that ANGPTL4 stimulate endothelial cell migration and sprouting in a 3D spheroid model of human brain endothelial cells. Our more recent work now indicates that bioactive lipids and receptors thereof, like the liver‐X‐receptors, may also affect vascular function. In particular, sphingolipids and ceramides play a crucial role in the neuro‐inflammatory process and was associated with vascular dysfunction. The work on how bioactive lipids affect BBB dysfunction in AD will be discussed during this presentation.
Translational profiling identifies sex‐specific metabolic and epigenetic reprogramming of microglia in cerebral amyloidosis models with an antibiotic‐altered gut microbiome
Authors: Shaik Shabana M , Cao Yajun , Dodiya Hemraj B. , Zhang Xulun , Boutej Hejer , Han Weinong , Kriz Jasna , Sisodia Sangram S.
Published: December 2022

Background

Microglia, the brain‐resident macrophages perform immune surveillance and engage in pathological processes by changing their phenotype and maintain homeostasis. Previously, we showed that antibiotic‐mediated changes in the gut microbiome of APPPS1‐21 transgenic mice resulted in significant decrease in amyloidosis and altered microglial phenotype that are specific to male mice. The molecular events underlying microglial phenotypic transition remain unclear due to lack of models that allow reliable in vivo proteomics. Here, we generated ‘APPPS1‐21‐CD11br’ microglia reporter mice and assessed their protein networks during their phenotypic transition in a sex‐specific manner.

Method

Six groups of mice that included WT‐CD11br, antibiotic (ABX) or vehicle‐treated APPPS1‐21‐CD11br male and female were sacrificed at 7‐weeks of age (n=15/group) and used for immunoprecipitation of microglial polysomes from cortical homogenates using anti‐FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry (LC‐MSMS) and label‐free quantification was used to identify newly synthesized peptides extracted from polysomes

Result

We showed ABX‐treatment led to reduced Ab levels in male APPPS1‐21‐CD11br mice with no significant changes in the females. We first identified sex‐specific oxidative stress induced by Ab peptides leading to mitochondrial dysfunction and altered calcium signaling. Notably, the female mice also showed dysregulation of ribosomal machinery. Further, microglial polypeptides were associated with FcgR‐mediated phagocytosis in male mice and actin organization in female mice. Interestingly, ABX‐treatment resulted in substantial remodeling of epigenetic landscape for metabolic shift to accommodate increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex‐specific manner. The male mice showed glycolytic shift for neuroprotective phenotype to promote Aβ clearance. However, the female mice showed loss of energy homeostasis due to persistent mitochondrial dysfunction associated with impaired lysosomal clearance and inflammatory phenotype.

Conclusion

Our studies provide first snapshot of the dynamic translational state of microglial cells in a sex‐specific manner. We identified that antibiotic‐mediated changes in gut microbiome results in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance. This microglial plasticity to support neuro‐energetic homeostasis for its function based on sex, paves the path for therapeutic modulation of immunometabolism for neurodegeneration.
Dementia Care Coordination: Evaluating a Program to Support Caregivers through Collaboration with the Alzheimer’s Association and Health Care Partners
Authors: McGurin Nicole E , McCarthy Liz , Arsenault Lisa , Showalter Elizabeth , Patterson Brooke
Published: December 2022

Background

A dementia diagnosis presents a myriad of non‐medical needs that are burdensome to caregivers and critical for disease management. Most medical professionals lack the time and training to meet these needs for support, education, and resources. The Alzheimer’s Association MA/NH Chapter has developed the Dementia Care Coordination program that partners health care providers and payors with dementia care consultants to improve outcomes for caregivers. Dementia Care Coordination is a telehealth‐based program that has provided invaluable support and tools for caregivers to manage the increased challenges and isolation of the COVID‐19 pandemic. This caregiver support and efficacy are vital to the health and well‐being of a person living with dementia.

Methods

A mixed‐methods approach was used to evaluate Dementia Care Coordination. Program data were analyzed. A survey measuring self‐efficacy, unmet needs, and satisfaction was distributed to caregivers at baseline and three months and six months post‐referral. Key informant interviews with caregivers supplemented survey results. A survey measuring provider confidence in dementia management and program impact and satisfaction was distributed to referring partners. Case studies with several referring partners provided additional descriptions.

Results

Total Referrals for Dementia Care Coordination have increased 91% since the pandemic. Surveys for both caregivers and referring partners found high satisfaction with the program. Key informant interviews with caregivers and case studies with referring partners described the positive impact of the program. Ongoing analyses of the quantitative data from the surveys indicate improvement in unmet needs and self‐efficacy among caregivers and improved provider confidence to manage dementia.

Conclusions

Dementia Care Coordination is a successful program to meet the needs of and improve outcomes for caregivers. The support, education, and resources were pivotal in managing the additional stresses of the COVID‐19 pandemic for dementia caregivers. The Alzheimer’s Association New England Chapters will use the evaluation data to further improve the program, expand healthcare partners, serve more families, and develop a tool kit for replication in other chapters.
Effects of Alzheimer’s Disease Risk Factors on Cerebrovascular Dynamics in Gray Matter
Authors: Kim Donghoon , Hughes Tim M. , Kim Jeongchul , Harvey Danielle J. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D. , Whitlow Christopher T. , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina E , Bobinski Matthew , Jung Youngkyoo
Published: December 2022

Background

Cerebrovascular functional parameters such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT) may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated the relationships between cerebrovascular functional parameters and AD risk factors, including APOE genotype, hypertension, and diabetes.

Method

Sixty‐five subjects (Table 1) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including pseudo‐continuous ASL (PCASL). CVR maps were obtained under a hypercapnic challenge using a computer‐controlled gas blender. A multi‐TI PCASL sequence was also employed to obtain resting CBF and ATT. Separate linear regression models were tested with response variables of quantitative CBF, CVR and ATT in whole brain gray matter (GM) and AD‐prone GM regions including hippocampus, parahippocampal, entorhinal, inferior parietal lobule, precuneus, and cuneus, adjusted for covariates: age, sex, and years of education. To investigate the effects of a risk factor on the interrelated vascular dynamic parameters, a cerebrovascular composite was created with the implementation of the weighting factors, obtained from covariates adjusted logistic regression, for each AD risk group and mild cognitive impairment (MCI). The factor score p‐values were calculated from two‐sample t‐tests with the cerebrovascular composite.

Result

In both whole brain GM and AD‐prone GM regions, subjects with the risk factors generally had lower resting CBF, but differential relationship with CVR. Subjects with hypertension had significantly higher CVR, while APOE e4 carriers showed significantly lower CVR (Figure 1 and 2). From the cerebrovascular composite analysis, CVR showed higher weights in hypertension and APOE e4 carrier groups in both whole brain GM and AD‐prone GM regions (Table 2) although there still were fractions of linear weights of CBF or ATT, which were not negligible.

Conclusion

Hypertension and APOE e4 carrier showed group differences of CVR in both whole brain GM and AD‐prone GM regions and the directions were opposite, implying their pathophysiological mechanisms may differ. As resting CBF and ATT showed lower weights in the composite than CVR, CVR may be a more sensitive brain perfusion parameter relating VCID.
Effects of blood pressure lowering for the prevention of dementia: meta‐analysis of individual patient data from five seminal randomised controlled trials involving 28008 participants
Authors: Peters Ruth , Xu Ying , Fitzgerald Oisin , Aung Htein Linn , Beckett Nigel S. , Bulpitt Christopher J. , Chalmers John , Forette Françoise , Gong Jessica , Harris Katie , Humburg Peter , Matthews Fiona E , Staessen Jan , Thijs Lutgarde , Tzourio Christophe , Warwick Jane , Woodward Mark , Anderson Craig S.
Published: December 2022

Background

Observational studies indicate U‐shaped associations of blood pressure (BP) and incident dementia in older age, but randomised controlled trials of BP lowering treatment show mixed results on this outcome in hypertensive patients. We undertook a pooled individual participant data analysis of five seminal double‐blind placebo‐controlled randomised trials to better define the effects of BP lowering treatment for the prevention of dementia and cognitive decline.

Methods

Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia.

Results

The total sample included 28,008 individuals recruited from 20 countries. After a median follow‐up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk.

Conclusion

Using data from double‐blind placebo‐controlled clinical trials, we provide evidence in the first single‐stage individual participant meta‐analysis to support benefits of antihypertensive treatment in late‐mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well‐controlled hypertension and of antihypertensive treatment commenced earlier in the life‐course to reduce the long‐term risk of dementia.
Live‐cell imaging of internalised oligomeric tau reveals differences between neuronal cell types
Authors: Lyu Chen
Published: December 2022

Background

It has recently been established that pathological forms of aggregated tau spread from affected to recipient cells in the brain, facilitating disease progression. Here we have applied live‐cell imaging to visualise internalised tau in recipient neuronal cells.

Method

Recombinant human 2N4R tau was aggregated using heparin and dithiothreitol, sonicated, and labelled with the fluorescent dye, Cy5. Differentiated SH‐SY5Y human neuroblastoma cells (dSH‐SY5Y), mouse primary cortical neurons (PCNs) and human induced pluripotent stem cell‐derived neurons (iPSCs) were exposed to Cy5‐tau for up to 7 days. Confocal microscopy was used to visualise internalised Cy5‐tau in live‐cells and paraformaldehyde‐fixed cells. BODIPY 493/503 and Lysotracker dyes were used to label neutral lipids and lysosomes, respectively.

Result

Live‐cell imaging showed rapid (within five minutes) internalisation of Cy5‐tau by all cell types, appearing as small speckles (<0.1µm diameter), with larger masses (>0.5 µm diameter) forming over time. In contrast, only small speckles of Cy5‐tau were detectable inside fixed cells. The size of Cy5‐tau accumulations in PCNs, but not in dSH‐SY5Y or iPSCs, increased further over time, reaching up to 6 µm diameter after 7 days. Lysotracker labelling of live cells indicated significant colocalisation with Cy5‐tau in all three cell types. BODIPY also partially colocalised with both Lysotracker and Cy5‐tau in PCN and iPSCs, but not in dSH. Furthermore, some large (>5 µm diameter) Cy5‐tau spheres in PCNs were Lysotracker‐negative, indicating that incorporation of Cy5‐tau may deacidify lysosomes.

Conclusion

Live‐cell imaging of neuronal cells has revealed previously unreported internalised tau structures that are not detectable in fixed cells. The sizes of tau spheres that form inside cells exposed to oligomeric tau differ between neuronal cell types, which is a consideration for selecting the most appropriate disease model. The colocalisation between Cy5‐tau and specific organelle labelling indicated tau intracellular trafficking pathway.
Plasma neurofilament light chain in cognitively unimpaired late middle‐aged & older adult APOE ε4 homozygotes, heterozygotes, & non‐carriers from the Arizona APOE Cohort
Authors: Ghisays Valentina , Su Yi , Malek‐Ahmadi Michael H. , Jansen Willemijn J. , Protas Hillary D. , Chen Yinghua , Lee Wendy , Luo Ji , III Robert J. Bauer , Chen Kewei , Caselli Richard J. , Zetterberg Henrik , Blennow Kaj , Reiman Eric M.
Published: December 2022

Background

APOE4 gene dose, the number of apolipoprotein E ‐ɛ4 (APOE4) ɛ4 alleles in a person’s genotype, is associated with higher Alzheimer’s disease (AD) risk and younger median age at dementia onset. We previously found relationships between PET, plasma, and measurements of core AD CSF biomarkers in APOE4 gene dose. Here, we characterize longitudinal neurofilament light chain (NfL) changes in the Arizona APOE cohort, including cognitively unimpaired participants, with longitudinal plasma NfL measurements in APOE4 homozygotes (HMs), heterozygotes (HTs) and non‐carriers (NCs).

Method

Plasma NfL measurements were performed at the University of Gothenburg using a Single molecule array (Simoa) immunoassay. Annual log‐transformed plasma NfL changes were compared with linear‐tend and univariate ANOVA adjusted for age, sex, and education in 45 HMs, 107 HTs, and 201 NCs who were cognitively unimpaired, 47‐85 years old and did not differ significantly in their age, sex, or educational level. Pearson r correlations with age and annual log‐transformed NfL changes were assessed in 353 participants with at least 2 visits (range 2‐6 visits with an average of ∼3) and an average follow‐up of ∼7 years (range 1‐12 years).

Result

Annual log‐transformed NfL changes were linearly associated with APOE4 gene dose (linear trend HM>HT>NC, P=0.01) and positively associated with age (r = 0.31, P<0.0001). Pairwise comparisons from the univariate ANOVA adjusted for age, sex, and education (P=0.001) showed significantly higher annual NfL changes in HM and HT groups versus NC controls (P=0.01).

Conclusion

Age and APOE4 gene dose are associated with greater annual plasma NfL changes in CU subjects close to their estimated ages at clinical onset. Studies are needed to better elucidate relationships between different Aβ, tau, inflammatory, and other CSF, or blood‐based biomarkers, and APOE4 gene dose at other ages and in larger subject groups.
Association between late‐life air pollution exposure and medial temporal lobe atrophy in older women
Authors: Wang Xinhui , Salminen Lauren , Petkus Andrew J. , Driscoll Ira , Millstein Joshua , Beavers Daniel P. , Espeland Mark A. , Braskie Meredith N , Thompson Paul M , Gatz Margaret , Chui Helena C , Resnick Susan M. , Kaufman Joel D. , Rapp Stephen R. , Shumaker Sally A. , Younan Diana , Chen Jiu‐Chiuan
Published: December 2022

Background

Ambient air pollution exposures increase the risk of Alzheimer’s disease (AD) and related dementias, which may be driven by structural brain alterations in the medial temporal lobe (MTL). The MTL consists of subregions critical for memory and vulnerable to AD neuropathology, including the hippocampus, parahippocampal gyrus (PHG), entorhinal cortex (ERC), and amygdala. However, previous structural MRI studies examining the hypothesized adverse effects of exposure on MTL were cross‐sectional and largely focused on hippocampus which yielded mixed results, failing to provide insights on the underlying neuropathological processes affected by air pollution exposures.

Method

We conducted a longitudinal study including 653 cognitively‐normal community‐dwelling women from the Women’s Health Initiative Memory Study with two MRI brain scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11; Meanage at MRI‐1 = 77.3±3.5). Using regionalized universal kriging models, exposures at residential locations were estimated as 3‐year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2; traffic‐related pollution) prior to MRI‐1. Volumes of the total MTL and MTL subregions were derived using multi‐atlas region segmentation with ensembled registration. We used linear regressions to estimate exposure effects on 5‐year standardized volume changes, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. We also examined if associations differed between APOE4 carriers (n = 123) and non‐carriers (n = 463).

Result

MTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI = [‐0.43,‐0.21]) and 0.12cm3 (95%CI = [‐0.23,‐0.01]) over 5 years, equivalent to respectively 17% (95%CI = [11%, 24%]) and 6% (95%CI = [0.6%, 12%]) increased dementia risk. For PHG, we found loss of 0.24cm3 (95%CI = [‐0.30,‐0.19]) and 0.09cm3 (95%CI = [‐0.14,‐0.04]) associated with PM2.5 and NO2 respectively. There was loss of 0.06cm3 (95%CI = [‐0.10,‐0.01]) in ERC associated with PM2.5, but not with NO2. No associations were found with amygdala or hippocampal atrophy. The observed adverse exposure effects on MTL atrophy did not differ by APOE4 genotype.

Conclusion

MTL atrophy in older women was associated with late‐life exposures to PM2.5 and NO2, and the putative adverse effects varied across brain subregions. The PHG and ERC—the MTL subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.
Functional Neurophysiological Biomarkers of Early‐Stage Alzheimer’s Disease: An Experimental Perspective of Network Hyperexcitability in Disease Progression and Pharmacological Interventions
Authors: Drinkenburg Wilhelmus (Pim) , Tok Sean , Ahnaou Abdel
Published: December 2022

Background

Neuronal network hyperexcitability and related alterations in the excitation‐inhibition balance hold promise as early functional biomarkers of network dysfunction and as prodromal indicators of Alzheimer’s disease (AD) pathogenesis. However, the translational validity of hyperexcitability as found in some AD pathology animal models seems restricted by their limited capacity to encompass the complexity of clinical AD.

Method

A comparison was made between different AD pathology mouse models with respect to the development of neuronal network hyperexcitability (LFPs) and epileptiform EEG. To this end, amyloid APP‐KI and APP/PS1 mice were assessed with and without hippocampal seeding of (human‐derived) pathological tau conformers at different ages (3‐6 months) and post‐seeding periods (1‐5 months) concerning alterations in amyloid and tau pathology in relation to hyperexcitability‐related, vigilance‐controlled neurophysiological changes.

Results

Animals from both AD models progressively developed AT8‐tau pathology that is amplified by the presence of amyloid pathology, but that only in APP/PS1 is further intensified by the starting amount of amyloid pathology. Alterations in EEG gamma oscillations appears to be associated with the development of amyloid and tau pathology, and may be an indicator of neuropathology, of neuronal network dysfunction, and of a potential disposition to future deposition of pathogenic amyloids. Immediate localized alterations in hippocampal EEG power spectra associated with tau seeding were found, while a lack of longitudinal changes in neuronal hypersynchrony was noted: hyperexcitability as indicated by increased broadband power spectra was noted in APP/PS1 but not APP‐KI animals at baseline. These differential findings between AD models exemplify the difficulty and complexity associated with identifying physiologically relevant and translatable early biomarkers of AD dysfunction.

Conclusion

Functional neurophysiological biomarkers based on early alterations in neuronal circuits, including hyperexcitability, in combination with dysfunctional (GABA‐ergic) inhibitory control of cortical pyramidal neurons should be assessed and validated in the complex context of neurodegeneration, specific amyloid/tau pathology, as well as neuroinflammation and disturbed sleep‐related processes like glymphatic clearance. This complexity constitutes both an additional challenge and a novel opportunity to AD pathology rodent models, in which such an integrative approach is feasible, but whose translational validity is still to be determined in the development of neuroprotective and neurorestorative therapeutic strategies.
A changing diagnostic paradigm of Alzheimer’s disease; an introduction to IWG and NIA‐AA criteria
Authors: van der Flier Wiesje M. , Scheltens Philip
Published: December 2022

Background

With the introduction of the NINCDS‐ADRDA criteria in 1984, Alzheimer’s disease (AD) could for the first time be diagnosed with high probability during life. The pathological characteristics of AD were not mentioned at all however, since they could not yet be measured in living individuals.

Method

In the following decades, advances in MRI measures, markers in Cerebrospinal Fluid (CSF), and amyloid‐imaging using PET can be counted among the largest successes of AD research. As a result, the AD disease process can now be demonstrated during life. In addition, these novel diagnostic tests allow the measurement of Alzheimer’s pathology before the stage of dementia. Nonetheless, until well into the 21st century, the 1984 criteria remained common standard.

Result

The publication of the IWG‐criteria in 2007 was a first attempt to integrate biomarker knowledge into diagnostic criteria. These criteria allowed a diagnosis of AD before dementia. In 2011 a roundtable under auspices of NIA‐AA published separate sets of criteria for dementia and MCI due to AD, and even for preclinical AD –the latter reading more like a research agenda than a set of criteria. The 2018 NIA‐AA research framework defines AD as a biological construct, independently of clinical staging. A diagnosis of AD can hence entirely be based on biomarkers. The most recent publication of the IWG in 2021 however proposes that a diagnosis of AD should be reserved to those with symptoms only, otherwise individuals should be considered ‘at risk’ of progression to AD.

Conclusion

Questions remain with respect to operationalization, e.g. choices and cut‐offs, for the biomarkers of use. Among the most fundamental questions is the question whether you can have disease but no symptoms, and when disease is symptomatic. Ultimately, truly longitudinal studies are needed to answer the question whether everybody with abnormal amyloid and tau will develop dementia, given enough time of life. This is particularly important now disease modifying treatment are at the horizon. In this presentation, I provide an overview of the different sets of criteria, outlining a number of open questions to be addressed before these criteria can be fully used in clinical practice.
Associations between Low‐value Medication in Dementia and Healthcare Costs
Authors: Platen Moritz , Hoffmann Wolfgang , Michalowsky Bernhard
Published: December 2022

Background

Low‐value medication (Lvm) provides little or no benefit to patients may be harmful and wastes healthcare resources. However, there is evidence from the literature that Lvm is highly prevalent in age‐associated mental illnesses, such as dementia. Evidence about the financial consequences of Lvm among people living with dementia (PwD) is limited. This study analyzed the association between receiving Lvm and healthcare costs from a payers’ perspective.

Method

This analysis is based on data of 516 community‐dwelling PwD. In total, 14 Lvm were extracted from 1) dementia‐specific guidelines, 2) the German equivalent of the Choosing Wisely campaign, and 3) the PRISCUS list. Healthcare utilization was retrospectively assessed via face‐to‐face interviews with PwD, caregivers, and professional care staff and monetarized by standardized unit costs to calculate costs from a payer perspective. Associations between Lvm and healthcare costs were analyzed using multiple linear regression models.

Result

Every third person living with dementia (n = 159, 31%) received Lvm. PwD who received Lvm were less cognitively impaired (Mini Mental State 23.0 vs. 21.7, p = 0.013). To receive Lvm was associated with higher medical care costs (b = 2,520€; CI95% 1,252€ – 3,788€, p< 0.001), particularly due to higher prevalence of in‐hospital treatment (b = 1,576€; CI95% 424€ – 2,728€, p = 0.007) and higher cost for medication (b = 784€; CI95% 466€ – 1,101€, p< 0.001).

Conclusion

Lvm was very prevalent, more likely to occur in the early stages of dementia and can cause financial harm for payers due to higher costs for in‐hospital care and medications. Further research is required to derive measures to prevent cost‐driving Lvm in primary care and move health expenditures towards higher‐value resource use.
Prediction of cognitive decline for enrichment of Alzheimer’s disease clinical trials with machine learning
Authors: Tam Angela , Laurent César , Dansereau Christian
Published: December 2022

Background

Many participants do not experience cognitive decline during clinical trials, which reduces the power of trials to detect treatment effects. As an enrichment strategy, we use machine learning to identify individuals who will likely decline throughout the typical duration of a clinical trial.

Method

Baseline MRI, cognitive tests, demographics, and APOE genotype were used to classify decliners, i.e. individuals whose CDR‐Sum of Boxes increased during a predefined time window, and stable individuals. A model to predict decline at 24 months was trained on a discovery dataset of patients with early AD (clinical diagnosis of mild cognitive impairment or AD dementia) from ADNI1 and NACC2 (n = 1151). This model was then validated on a Phase 3 trial placebo arm (n = 115) and the PharmaCog3 initiative (n = 76). A second model to predict decline at 48 months in presymptomatic populations was trained on a discovery dataset of 628 individuals from ADNI and NACC who were cognitively unimpaired at baseline and then validated on OASIS‐34 (n = 128).

Result

The models achieved up to 79% AUC (cross‐validated and out‐of‐sample). We estimated the required sample sizes per arm to detect a 30% treatment effect at 80% power. An early AD clinical trial with an unenriched cohort would require 422 participants, while using the enriched cohort of likely decliners identified by our model can reduce the necessary sample size to 206 individuals. Similarly, a presymptomatic AD trail would require 2577 individuals, while using the enriched cohort of likely decliners identified by our model can reduce the necessary sample size to 1412 individuals. In both early AD and presymptomatic populations, the predicted decliners experienced a cognitive worsening that was at least three times as severe as the predicted stable group (Figure 1).

Conclusion

Our prognostic tool to enrich trials with participants likely to decline can reduce sample sizes by as much as 51%. Such a tool can improve trial quality, reduce trial costs, and increase the likelihood of a trial’s success.

[1] adni.loni.usc.edu

[2] naccdata.org

[3] www.imi.europa.eu/projects‐results/project‐factsheets/pharma‐cog

[4] oasis‐brains.org