Mini-Forum: Communicating and Using Dementia Risk Evidence (Guest Editor: Allyson Rosen)
Pages 933-944
Introduction
Allyson C. Rosen
Communicating and Using Dementia Risk Evidence
Abstract: Advances in biomarkers, genetics, and other data used as dementia risk evidence (DRE) are increasingly informing clinical diagnosis and management. The purpose of this Mini-Forum is to provide a solutions-based discussion of the ethical and legal gaps and practical questions about how to use and communicate these data. Investigators often use DRE in research. When participants ask for their personal results, investigators have concerns. Will data that was intended to study groups be valid for individuals? Will sharing data cause distress? Debates around sharing DRE became heated when blood-based amyloid tests and amyloid reducing drugs appeared poised to enable clinicians easily to identify people with elevated brain amyloid and reduce it with a drug. Such an approach would transform the traditional role of DRE from investigational to foundational; however, then the high costs, uncertain clinical benefits and risks of the therapy led to an urgent need for education to support clinical decision making. Further complicating DRE use are direct to consumer genetic testing and increasingly available biomarker testing. Withholding DRE becomes less feasible and public education around responsible use and understanding become vital. A critical answer to these legal and ethical issues is supporting education that clearly delineates known risks, benefits, and gaps in knowledge, and communication to promote understanding among researchers, clinicians, patients, and all stakeholders. This paper provides an overview and identifies general concepts and resource documents that support more informed discussions for individuals and interdisciplinary groups.
Pages 945-952
Editorial
Sarah Walter*, Angela Taylor*, Jamie Tyrone, Sara Langer, John-Richard Pagan, Cynthia Huling Hummel, Bonnie M. Wheaton, Doris T. Zallen, Allyson C. Rosen *These authors contributed equally to this work.
Disclosing Individual Results in Dementia Research: A Proposed Study Participant’s Bill of Rights
Abstract: This Study Participant’s Bill of Rights is a call to action for researchers in Alzheimer’s disease and related dementias (ADRD) to proactively design clinical studies that provide the option for research participants to learn their individual research results if they choose, and in a manner that ensures study integrity. This Bill of Rights was crafted by a committee of study participants, care partners, representatives of dementia advocacy organizations, and other stakeholders in dementia research for the Advisory Group on Risk Education for Dementia (AGREEDementia). The framework developed by the Multi-Regional Clinical Trials (MRCT) Return of Individual Research Results provides a useful context for researchers to plan their studies and disclosure.
Pages 953-962
Editorial
Allyson C. Rosen, Jalayne J. Arias, J. Wesson Ashford, Deborah Blacker, Jasmeer P. Chhatwal, Nathan A. Chin, Lindsay Clark, Sharon S. Denny, Jill S. Goldman, Carey E. Gleason, Joshua D. Grill, Judith L. Heidebrink, Victor W. Henderson, James A. Lavacot, Jennifer H. Lingler, Malavika Menon, Rachel L. Nosheny, Fabricio F. Oliveira, Monica W. Parker, Annalise Rahman-Filipiak, Anwita Revoori, Malia C . Rumbaugh, Danurys L. Sanchez, Suzanne E. Schindler, Christopher G. Schwarz, Leslie Toy, Jamie Tyrone, Sarah Walter, Li-san Wang, Ellen M. Wijsman, Doris T. Zallen, Neelum T. Aggarwal and members of AGREEDementia
The Advisory Group on Risk Evidence Education for Dementia: Multidisciplinary and Open to All
Abstract: The brain changes of Alzheimer’s disease and other degenerative dementias begin long before cognitive dysfunction develops, and in people with subtle cognitive complaints, clinicians often struggle to predict who will develop dementia. The public increasingly sees benefits to accessing dementia risk evidence (DRE) such as biomarkers, predictive algorithms, and genetic information, particularly as this information moves from research to demonstrated usefulness in guiding diagnosis and clinical management. For example, the knowledge that one has high levels of amyloid in the brain may lead one to seek amyloid reducing medications, plan for disability, or engage in health promoting behaviors to fight cognitive decline. Researchers often hesitate to share DRE data, either because they are insufficiently validated or reliable for use in individuals, or there are concerns about assuring responsible use and ensuring adequate understanding of potential problems when one's biomarker status is known. Concerns include warning people receiving DRE about situations in which they might be compelled to disclose their risk status potentially leading to discrimination or stigma. The Advisory Group on Risk Evidence Education for Dementia (AGREEDementia) welcomes all concerned with how best to share and use DRE. Supporting understanding in clinicians, stakeholders, and people with or at risk for dementia and clearly delineating risks, benefits, and gaps in knowledge is vital. This brief overview describes elements that made this group effective as a model for other health conditions where there is interest in unfettered collaboration to discuss diagnostic uncertainty and the appropriate use and communication of health-related risk information.
Pages 963-966
Commentary
Douglas R. Galasko, Joshua D. Grill, Jennifer H. Lingler, Judith L. Heidebrink for the symptomatic subcommittee of the Advisory Group on Risk Evidence Education for Dementia (AGREEDementia)
A Blood Test for Alzheimer’s Disease: It’s about Time or Not Ready for Prime Time?
Abstract: A blood test for Alzheimer’s disease is now available for clinical use in persons with cognitive impairment. This is an extraordinary milestone, though the amyloid-based PrecivityAD™ test is not without limitations. Pre and post-test counseling are essential. Phosphorylated tau blood tests are likely to follow soon. When used in conjunction with an appropriate clinical evaluation, blood tests provide the opportunity for an early, accurate, and accessible diagnosis of Alzheimer’s disease. Standalone use, however, carries a significant risk of misinterpretation and is strongly discouraged. Now is the time to develop appropriate use criteria to guide the use of these promising assays.
Pages 967-974
Ethics Response
Thomas K. Karikari
Blood Tests for Alzheimer’s Disease: Increasing Efforts to Expand and Diversify Research Participation Is Critical for Widespread Validation and Acceptance
Abstract: The recent academic and commercial development, and regulatory approvals, of blood-based Alzheimer’s disease (AD) biomarkers are breakthrough developments of immense potential. However, clinical validation studies and therapeutic trial applications are limited almost exclusively to non-Hispanic White cohorts often including highly-educated, high-earning participants. This commentary argues that the true benefits of blood tests for AD will be realized by active inclusion of diverse groups including minoritized populations, people of socioeconomic status different from those included in existing cohorts, and residents of low- and middle-income countries. The article discusses key factors that are critical for a successful implementation of diversity programs.
Pages 975-979
Commentary
Suzanne E. Schindler
Predicting Symptom Onset in Sporadic Alzheimer’s Disease: “How Long Do I Have?”
Abstract: Predicting not just if but when cognitively normal individuals will develop the onset of Alzheimer’s disease (AD) dementia seems increasingly feasible, as evidenced by converging findings from several approaches and cohorts. These estimates may improve the efficiency of clinical trials by better identifying cognitively normal individuals at high risk of developing AD symptoms. As models are refined, the implications of disclosing estimates of the age of AD symptom onset must be examined, since telling a cognitively normal individual the age they are expected to develop AD symptoms may have different implications than disclosing increased risk for AD dementia.
Pages 981-988
Commentary
Mario A. Parra ( Handling Associate Editor: David Libon)
Barriers to Effective Memory Assessments for Alzheimer’s Disease
Abstract: Recently, Alzheimer’s Disease International (ADI) stressed that around 75% of people living with dementia globally are still not receiving a diagnosis. In this commentary, I reflect on how efforts towards better cognitive assessments, particularly of memory, can be aligned and harmonized to contribute to such needs. I highlight some barriers that ongoing collaborations and trials are facing and their potential drivers. I suggest some strategies that can help overcome them and in so doing, integrate research agendas. We need to ignite the debate towards strategies that can help level the playfield to tackle Alzheimer’s disease with true global solutions.
Pages 989-992
Commentary
Timothy Daly, Ignacio Mastroleo, Raffaella Migliaccio
Avoiding Over-Reliance on Multi-Domain Interventions for Dementia Prevention
Abstract: Given the unknown therapeutic value of targeting Alzheimer’s disease pathology and the discovery of robust risk factors for dementia, non-pharmacological risk reduction (RR) is increasingly offered as an alternative to targeting Alzheimer’s disease pathology. While RR will surely be a useful tool to make public health gains, we propose solutions to three possible issues with over-reliance on multi-domain interventions to achieve RR: limited individual impact, an exclusive focus on later life, and overlooking social determinants of dementia. We argue in favor of a broader debate within the research community and greater society about how different therapeutic avenues should be explored.
Pages 993-996
Ethics Response
Alan J. Lerner
Biomarkers and Mindfulness: A Way Forward
Abstract: After years of anticipation, non-invasive tests for detecting cerebral amyloidosis and Alzheimer’s disease (AD) are entering clinical care. The PrecivityAD™ test from C2N is a plasma-based test yielding an Amyloid Probability score with high sensitivity and specificity for brain amyloid accumulation, but some samples may have inconclusive results. The AGREEDementia consortium raised concerns that the field needs study of how best to use and communicate results of PrecivityAD™. Continued attention and mindfulness should be applied to the whole class of dementia biomarker tests and directed in light of FDA biomarker context of use framework. Unintended uses of biomarkers tests may have unintended consequences, such as mislabeling patients. AD biomarker tests may efficiently stratify AD risk but will inevitably be included in electronic medical records and be subject to interpretation by medical personnel lacking proper knowledge or context to interpret results appropriately. Another way forward is mindful discussion and consensus among all stakeholders about the uses and limits of each specific test.
Pages 997-999
Commentary
Doris T. Zallen
Alzheimer’s Disease: Risk Tests and the Medical Record
Abstract: Although the medical record is the centerpiece of modern medical care, its usefulness is diminished by the reluctance of people to disclose important health information, such as a higher risk for Alzheimer’s disease, to their doctors. Steps should be taken now to ensure that the medical record, the repository of one’s health information, can continue to serve the needs of the medical community and of patients.
Pages 1001-1009
Sarah Walter, Anne B. Kim, Melissa Flores, Jaimie Ziolkowski, Elizabeth Shaffer, Neelum T. Aggarwal
Including General Audiences in a Virtual Scientific Dementia Conference: Will They Get Anything From It?
Abstract: Background: Study participants, patients, and care partners are key stakeholders in research and have asked for greater inclusion in the dissemination of scientific learning. However, the participation of general audiences in scientific conferences dedicated to Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) is not widely supported or studied. Objective: Our objectives were to evaluate the interest, level of engagement, and impact of including general audiences in a virtual dementia conference. Methods: A diverse group of lay participants, identified via community-based health advocacy groups and research centers, were invited to attend the 2021 Alzheimer’s Association International Conference (AAIC), with optional small-group discussions. Participants received complimentary access to all scientific sessions and were supported via navigation tips, recommended sessions, and a glossary of frequently used terms and acronyms. Results: Lay participants demonstrated a high level of engagement, even among those that were research-naïve, attending virtual sessions for an average of 11.7 hours across the five days and recommending a variety of sessions to each other on topics extending from prevention of dementia to new therapies and care. Most participants said they would attend the conference again and rated the quality of interaction as high, while requesting more opportunities to engage directly with researchers. Conclusion: General audiences, in particular research participants, are advocating for greater participation in scientific conferences. This program can serve as a model to accomplish inclusion; thereby acknowledging their invaluable contribution to science.
Pages 1011-1019
Jalayne J. Arias, Grace A. Lin, Ana M. Tyler, Michael P. Douglas, Kathryn A. Phillips
Geriatricians’ Perspectives on the Multiple Dimensions of Utility of Genetic Testing for Alzheimer’s Disease: A Qualitative Study
Abstract: Background: Research advancements in Alzheimer’s disease (AD) raise opportunities for genetic testing to improve diagnostic and risk assessment. Despite emerging developments, it is unclear how geriatricians perceive the potential clinical and personal utility of genetic testing for their patients. Geriatricians’ perspectives are essential to understanding potential ethical, policy, and clinical challenges. Objective: In this paper, we report on geriatricians’ perspectives on the utility of genetic testing for AD. Methods: Semi-structured interviews with California geriatricians within different practices settings to collect and characterize their perspectives on genetic testing for AD. We used an adapted grounded theory approach to analyze recorded and transcribed interviews. Results: We identified geriatricians’ (n=10) perspectives on the clinical and personal utility of testing, alongside their views on clinical care approaches for older adults. Geriatricians perceived minimal clinical utility of genetic testing for AD, though that may change with the availability of disease-modifying therapies. Yet, they recognized the potential personal utility of testing (e.g., assisting with future financial planning). Finally, geriatricians expressed concerns regarding patients’ anxiety from learning about genetic status, particularly through direct-to-consumer (DTC) testing. Conclusion: Our data highlight that the decision to order genetic testing requires clinical and ethical considerations, including balancing limited clinical utility with the potential personal utility. Although DTC testing is available, geriatricians perceive that they have an important role in managing the decision to test and interpreting the results. Further research is needed to inform policy and ethical guidelines to support geriatricians’ critical role to counsel patients considering clinical and DTC genetic testing.
Pages 1021-1033
Emily A. Largent, Twisha Bhardwaj, Justin T. Clapp, Olivia Saúl Sykes, Kristin Harkins, Joshua D. Grill
You’ve Got a Friend in Me: How Cognitively Unimpaired Older Adults Select a Study Partner to Participate with Them in Alzheimer’s Disease Research
Abstract: Background: Participants in Alzheimer’s disease (AD) prevention studies are generally required to enroll with a study partner; this requirement constitutes a barrier to enrollment for some otherwise interested individuals. Analysis of dyads enrolled in actual AD trials suggests that the study partner requirement shapes the population under study. Objective: To understand if individuals can identify someone to serve as their study partner and whether they would be willing to ask that individual. Methods: We conducted semi-structured interviews with cognitively unimpaired, English-speaking older adults who had previously expressed interest in AD research by signing up for a research registry. We also interviewed their likely study partners. Audio-recorded interviews were transcribed and coded in an iterative, team-based process guided by a content analysis approach. Results: We interviewed 60 potential research participants and 17 likely study partners. Most potential participants identified one or two individuals they would be willing to ask to serve as their study partner. Interviewees saw value in the study partner role but also understood it to entail burdens that could make participation as a study partner difficult. The role was seen as relatively more burdensome for individuals still in the workforce or with family responsibilities. Calls from the researcher to discuss the importance of the role and the possibility of virtual visits were identified as potential strategies for increasing study partner availability. Conclusion: Efforts to increase recruitment, particularly representative recruitment, of participants for AD prevention studies should reduce barriers to participation by thoughtfully designing the study partner role.
Pages 1035-1043
Ethics Review
Jessica Mozersky, J. Scott Roberts , Malia Rumbaugh, Jasmeer Chhatwal, Ellen Wijsman, Douglas Galasko, Deborah Blacker, on behalf of AGREED
Spillover: The Approval of New Medications for Alzheimer’s Disease Dementia Will Impact Biomarker Disclosure Among Asymptomatic Research Participants
Abstract: In this article we address how the recent, and anticipated upcoming, FDA approvals of novel anti-amyloid medications to treat individuals with mild Alzheimer’s disease (AD) dementia could impact disclosure of biomarker results among asymptomatic research participants. Currently, research is typically the context where an asymptomatic individual may have the option to learn their amyloid biomarker status. Asymptomatic research participants who learn their amyloid status may have questions regarding the meaning of this result and the implications for accessing a potential intervention. After outlining our rationale, we provide examples of how current educational materials used in research convey messages regarding amyloid positivity and the availability of treatments, or lack thereof. We suggest language to improve messaging, as well as strengths of current materials, in addressing these issues for research participants. Although novel medications are currently only approved for use among symptomatic individuals, their availability may have implications for disclosure among asymptomatic research participants with evidence of amyloid deposition, who may be especially interested in information on these interventions for potential prevention, or future treatment, of mild cognitive impairment or dementia due to AD.
Regular Section
Pages 1045-1055
Review
Audrey Valverde, John Mitrofanis
Photobiomodulation for Hypertension and Alzheimer’s Disease
Abstract: Although the cause(s) of Alzheimer's disease in the majority of cases remains elusive, it has long been associated with hypertension. In animal models of the disease, hypertension has been shown to exacerbate Alzheimer-like pathology and behavior, while in humans, hypertension during mid-life increases the risk of developing the disease later in life. Unfortunately, once individuals are diagnosed with the disease, there are few therapeutic options available. There is neither an effective symptomatic treatment, one that treats the debilitating cognitive and memory deficits, nor, more importantly, a neuroprotective treatment, one that stops the relentless progression of the pathology. Further, there is no specific preventative treatment that offsets the onset of the disease. A key factor or clue in this quest for an effective preventative and therapeutic treatment may lie in the contribution of hypertension to the disease. In this review, we explore the idea that photobiomodulation, the application of specific wavelengths of light onto body tissues, can reduce the neuropathology and behavioral deficits in Alzheimer's disease by controlling hypertension. We suggest that treatment with photobiomodulation can be an effective preventative and therapeutic option for this neurodegenerative disease.
Pages 1057-1072
Yiyao Huang, Tom A.P. Driedonks, Lesley Cheng, Harinda Rajapaksha, David A. Routenberg, Rajini Nagaraj, Javier Redding, Tanina Arab, Bonita H. Powell, Olga Pletniková, Juan C. Troncoso, Lei Zheng, Andrew F. Hill, Vasiliki Mahairaki, Kenneth W. Witwer
Brain Tissue-Derived Extracellular Vesicles in Alzheimer’s Disease Display Altered Key Protein Levels Including Cell Type-Specific Markers
Abstract: Background: Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer’s disease (AD). Extracellular vesicles (EVs) may also leave the brain to betray the state of the CNS in the periphery. Only a few studies have profiled the proteome of bdEVs and source brain tissue. Additionally, studies focusing on bdEV cell type-specific surface markers are rare. Objective: We aimed to reveal the pathological mechanisms inside the brain by profiling the tissue and bdEV proteomes in AD patients. In addition, to indicate targets for capturing and molecular profiling of bdEVs in the periphery, CNS cell-specific markers were profiled on the intact bdEV surface. Methods: bdEVs were separated and followed by EV counting and sizing. Brain tissue and bdEVs from age-matched AD patients and controls were then proteomically profiled. Total tau (t-tau), phosphorylated tau (p-tau), and antioxidant peroxiredoxins (PRDX) 1 and 6 were measured by immunoassay in an independent bdEV separation. Neuron, microglia, astrocyte, and endothelia markers were detected on intact EVs by multiplexed ELISA. Results: Overall, concentration of recovered bdEVs was not affected by AD. Proteome differences between AD and control were more pronounced for bdEVs than for brain tissue. Levels of t-tau, p-tau, PRDX1, and PRDX6 were significantly elevated in AD bdEVs compared with controls. Release of certain cell-specific bdEV markers was increased in AD. Conclusion: Several bdEV proteins are involved in AD mechanisms and may be used for disease monitoring. The identified CNS cell markers may be useful tools for peripheral bdEV capture.
Pages 1073-1083
Stefan Frenzel, Josh C. Bis, Elias F. Gudmundsson, Adrienne O’Donnell, Jeannette Simino, Amber Yaqub, Traci M. Bartz, Guy G.O. Brusselle, Robin Bülow, Charles S. DeCarli, Ralf Ewert, Sina A. Gharib, Saptaparni Ghosh, Monica Gireud-Goss, Rebecca F. Gottesman, M. Arfan Ikram, David S. Knopman, Lenore J. Launer, Stephanie J. London, W. T. Longstreth, Oscar L. Lopez, Debora Melo van Lent, George O’Connor, Claudia L. Satizabal, Srishti Shrestha, Sigurdur Sigurdsson, Beate Stubbe, Rajesh Talluri, Ramachandran S. Vasan, Meike W. Vernooij, Henry Völzke, Kerri L. Wiggins, Bing Yu, Alexa S. Beiser, Vilmundur Gudnason, Thomas Mosley, Bruce M. Psaty, Frank J. Wolters, Hans J. Grabe, Sudha Seshadri
Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis
Abstract: Background: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. Objective: To study the cross-sectional associations of pulmonary function with structural brain variables. Methods: Data from six large community-based samples (N=11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. Results: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. Conclusion: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.
Pages 1085-1101
Ryo Shikimoto, Shoko Nozaki, Norie Sawada, Yoko Shimizu, Thomas Svensson, Atsuo Nakagawa, Masaru Mimura, Shoichiro Tsugane (Handling Associate Editor: Allyson Rosen)
Coping in Mid- to Late Life and Risk of Mild Cognitive Impairment Subtypes and Dementia: A JPHC Saku Mental Health Study
Abstract: Background: The relationship between coping in mid- to late life and cognitive functions remains unclear. Objective: To investigate the relationship between habitual coping behaviors of a large Japanese population in their mid- to late-lives and their risk of cognitive decline 15 years later. Methods: Overall 1,299 participants were assessed for coping behaviors (in 2000) and cognition (2014–2015). We used the Stress and Coping Inventory to assess the frequency of six coping behaviors (i.e., consulting, planning, positive reappraisal, avoidance, fantasizing, and self-blame). Logistic regression analyses were conducted to examine odds ratios (ORs) for the diagnosis of mild cognitive impairment (MCI), MCI subtypes (single- and multiple-domain MCI), and dementia for coping behaviors. Results: Among the eligible 1,015 participants (72.6 [SD = 5.5] years old in 2014–2015), the numbers for cognitively normal, single-domain MCI, multiple-domain MCI, and dementia were 650 (64.0%), 116 (11.4%), 213 (21.0%), and 36 (3.5%), respectively. Among the six coping behaviors, avoidant coping was significantly associated with noticeable cognitive decline (multiple-domain MCI and dementia). This association remained significant after adjusting for sex, age, education, diagnosis of current major depressive disorder, past history of ischemic heart disease, diabetes, regular alcohol consumption, and smoking (OR = 2.52, 95% CI = 1.23 to 5.15). No significant association with other coping behaviors was found. Conclusion: Avoidant coping in mid- and late life is associated with cognitive decline among older people.
Pages 1103-1122
Alice Bittar*, Rabab Al-Lahham*, Nemil Bhatt, Kenya Moore, Mauro Montalbano, Cynthia Jerez, Leiana Fung, Salome McAllen, Anna Ellsworth, Rakez Kayed *These authors contributed equally to this work.
Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner
Abstract: Background: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies. Objective: We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy. Methods: Aged mice received a single intravenous injection of 120 µg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays. Results: TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo. Conclusion: This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains.
Pages 1123-1138
Tao-Ran Li, Di-Yang Lyu, Feng-Qi Liu, for the Alzheimer’s Disease Neuroimaging Initiative
Cerebrospinal Fluid sTREM2 in Alzheimer’s Disease Is Associated with Both Amyloid and Tau Pathologies but not with Cognitive Status
Abstract: Background: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is considered a biomarker of microglial activation. The relationships between CSF sTREM2 levels and Alzheimer’s disease (AD) CSF core biomarkers, cognitive status, and neurodegeneration remain unclear. Objective: To assess the association between CSF sTREM2 levels and AD progression and other AD hallmarks. Methods: Using the Alzheimer’s Disease Neuroimaging Initiative database, we investigated 1,035 participants, including 310 cognitively normal controls, 527 patients with mild cognitive impairment, and 198 patients with dementia. They were grouped according to CSF pathology (A/T profile) severity. CSF sTREM2 levels were compared between the groups, and linear regression analysis was performed to evaluate the factors affecting sTREM2 levels. The predictive effectiveness of sTREM2 levels was tested, and the correlation with other indicators was explored. The increase rate was assessed using linear mixed-effects models. Results: Higher CSF sTREM2 levels were associated with older age as well as higher CSF p-tau or t-tau and amyloid-β levels (all p < 0.001), but not with cognitive status. sTREM2 levels were not correlated with the baseline or longitudinal scale and neuroimaging result changes, and could not predict clinical conversion, but were correlated with multiple non-amyloid-β and non-tau CSF cytokines related to inflammation and neurodegeneration (p < 0.0001). The increased sTREM2 expression rate did not change among groups. Conclusion: CSF sTREM2 levels were jointly determined by age, amyloid-β, and tau pathologies, leading to complex AD cognitive continuum changes. Although sTREM2 levels could not predict cognitive deterioration and neurodegeneration, they could reflect the microglial state as a non-specific biomarker.
Pages 1139-1151
Min Chu, Li Liu, Haitian Nan, Deming Jiang, Yihao Wang, Pedro Rosa-Neto, Yueshan Piao, Liyong Wu
Extremely Early-Onset Frontotemporal Dementia: A Case Report and Literature Review
Abstract: Background: In most cases, the onset of frontotemporal dementia (FTD) occurs between the ages of 45 and 65 years. However, some patients experience an extremely early disease onset. Objective: To investigate the clinical, genetic, and pathological features of extremely early-onset FTD. Methods: We conducted a comprehensive clinical, genetic, and neuropathological analysis of a 25-year-old patient experiencing the onset of behavioral variant frontotemporal dementia (bvFTD). In addition, we conducted a literature review and summarized the clinical, genetic, and pathological features of patients with FTD with onset age ≤25 years. Results: The patient was diagnosed with bvFTD; however, there was no family history of FTD, no positive genetic test results and no deposition of TDP43, tau, ubiquitin, and synuclein in the brain. Literature screening identified 18 patients with onset age ≤25 years with FTD. The youngest patient was 14-years-of-age. Most patients (8/14) had a positive family history. The most common clinical phenotype was the behavioral variant (12/14). Genetic results were reported for 11 patients; the most common pathogenic gene was MAPT (10/12), with four cases of G389R, two cases of P301S, one case of G335S, one case of G335A, one case of G335V, and one case of L315R. Pathological results were reported for 13 patients; the most common pathological subtype was tau (8/13). Conclusion: FTD can start at an extremely early age. The most common phenotype of extremely early onset FTD was the behavioral variant, the most common pathogenic gene was MAPT, and the most common neuropathological type was tau.
Pages 1153-1162
Shijing Wu*, Li Hu*, Jiajing Lin*, Kanglan Li, Shicai Ye, Shaoping Zhu, Zhou Liu *These authors contributed equally to this work.
Excretion of Amyloid-β in the Gastrointestinal Tract and Regulation by the Gut Microbiota
Abstract: Background: Amyloid-β (Aβ) is important in the etiology of Alzheimer’s disease (AD). Removal of Aβ from the brain is a major strategy for the prevention and treatment of AD. Objective: To clarify whether Aβ42 can be cleared by intestinal excretion and whether the gut microbiota (GM) can affect the excretory clearance of Aβ42 in the peripheral blood and intestines. Methods: Male 8-month-old C57BL6 mice were maintained on either normal chow or received broad-spectrum antibiotics in their drinking water for one week. Sterile saline, fluorescein isothiocyanate (FITC), or FITC-Aβ42 (fluorescein isothiocyanate-labeled amyloid-β42 peptides) was injected 1 h before sampling. Related changes of Aβ42 before and after injection were evaluated. Results: FITC-Aβ42 was injected into mice through the tail vein and could later be detected in feces. Furthermore, the fecal concentrations of FITC-Aβ42 were higher in mice that had been fed antibiotics to alter their GM than in normal mice. However, the FITC-Aβ42 concentrations in blood showed the opposite pattern. Conclusion: Aβ42 can be excreted into the intestinal lumen and is regulated by the GM.
Pages 1163-1175
Yizhu Tian, Deyu Li, Daifa Wang, Ting Zhu, Meiyun Xia, Wenyu Jiang
Decreased Hemodynamic Responses in Left Parietal Lobule and Left Inferior Parietal Lobule in Older Adults with Mild Cognitive Impairment: A Near-Infrared Spectroscopy Study
Abstract: Background: The brain activation patterns of mild cognitive impairment (MCI) are still unclear and they involve multiple brain regions. Most previous studies have focused on abnormal activation in the frontal and temporal lobes, with few investigating the entire brain. Objective: To identify and compare the changes in cerebral hemodynamics and abnormal activation patterns in the entire brain of MCI patients and healthy older adults. Methods: Patients with MCI (n=22) and healthy controls (HC, n=34) matched by age, education levels, sex, and mental state were enrolled. They performed the same letter and category verbal fluency test (VFT) tasks while their behavioral performance and global cerebral hemodynamics were analyzed. Results: The performance during the category VFT task was significantly better than that during the letter VFT task across all participants (HC: correct: p<0.001; intrusions: p<0.001; MCI: correct: p<0.001; intrusions: p<0.001). The number of correct words during the letter and category VFT tasks was significantly higher in the HC group than in the MCI group (p<0.001). The deoxygenated-hemoglobin (HbR) concentrations in the left parietal lobule (p=0.0352) and left inferior parietal lobule (p=0.0314) were significantly different during the category VFT task. Conclusion: The differences between HC and MCI groups were greater in the category task. The HbR concentration was more sensitive for the category VFT task and concentration changes in the left parietal lobule and left inferior parietal lobule may be useful for clinical screening and application; thus, they deserve more attention.
Pages 1177-1186
Haruhisa Fukuda, Megumi Maeda, Fumiko Murata, Yutaka Murata
Anti-Dementia Drug Persistence Following Donepezil Initiation Among Alzheimer's Disease Patients in Japan: LIFE Study
Abstract: Background: Donepezil is frequently used to treat Alzheimer's disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia drug use after donepezil initiation may inform the development and improvement of treatment strategies, but there is little evidence from Japan. Objective: To determine anti-dementia drug persistence following donepezil initiation among AD patients in Japan using insurance claims data. Methods: Insurance claims data for AD patients with newly prescribed donepezil were obtained from 17 municipalities between April 2014 and October 2021. Anti-dementia drug persistence was defined as a gap of ≤60 days between the last donepezil prescription and a subsequent prescription of donepezil, another cholinesterase inhibitor, or memantine. Cox proportional hazards models were used to analyze the association between care needs levels and discontinuation. Results: We analyzed 20,474 AD patients (mean age±standard deviation: 82.2±6.3 years, women: 65.7%). The persistence rates were 89.1% at 30 days, 79.4% at 90 days, 72.6% at 180 days, 64.5% at 360 days, and 58.3% at 540 days after initiation. Among the care needs levels, the hazard ratio (95% confidence interval) for discontinuation was 1.01 (0.94-1.07) for patients with support needs, 1.12 (1.06-1.18) for patients with low long-term care needs, and 1.31 (1.21-1.40) for patients with moderate-to-high long-term care needs relative to independent patients. Conclusion: Japanese AD patients demonstrated low anti-dementia drug persistence rates that were similar to those of other countries. Higher long-term care needs were associated with discontinuation. Further measures are needed to improve drug persistence in AD patients.
Pages 1187-1201
Christopher R. Beam*, Susan E. Luczak*, Matthew S. Panizzon, Chandra A. Reynolds, Kaare Christensen, Anna K. Dahl Aslan, Jeremy A. Elman, Carol E. Franz, William S. Kremen, Teresa Lee, Marianne Nygaard, Perminder S. Sachdev, Keith E. Whitfield, Nancy L. Pedersen, Margaret Gatz, for the IGEMS Consortium (Handling Associate Editor: Andrea Zammit) *These authors contributed equally to this work.
Estimating Likelihood of Dementia in the Absence of Diagnostic Data: A Latent Dementia Index in 10 Genetically Informed Studies
Abstract: Background: Epidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available. Objective: We apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the twin design of the sample to validate the results. Methods: Using 10 twin studies, we implement a latent variable approach that aligns different tests available in each study to assess cognitive, memory, and functional ability. The model separates general cognitive ability from components indicative of dementia. We examine the validity of this continuous latent dementia index (LDI). We then identify cut-off points along the LDI distributions in each study and align them across studies to distinguish individuals with and without probable dementia. Finally, we validate the LDI by determining its heritability and estimating genetic and environmental correlations between the LDI and clinically diagnosed dementia where available. Results: Results indicate that coordinated estimation of LDI across 10 studies has validity against clinically diagnosed dementia. The LDI can be fit to heterogeneous sets of memory, other cognitive, and functional ability variables to extract a score reflective of likelihood of dementia that can be interpreted similarly across studies despite diverse study designs and sampling characteristics. Finally, the same genetic sources of variance strongly contribute to both the LDI and clinical diagnosis. Conclusion: This latent dementia indicator approach may serve as a model for other research consortia confronted with similar data integration challenges.
Pages 1203-1213
Ting-Hsiang Chen, Yi-Chun Yeh, Mei-Feng Huang, Hui-Mei Chen, Jia-In Lee, Cheng-Sheng Chen (Handling Associate Editor: Zahinoor Ismail)
Validation and Comparison of the Informant-Rated and Self-Rated Versions of the Mild Behavioral Impairment Checklist
Abstract: Background: The Mild Behavioral Impairment Checklist (MBI-C) has been developed to assess mild behavioral impairment (MBI). However, no study has validated the use of MBI-C using a promising translation method in Taiwan. Thus, consistency and discrepancy between informant-rated and self-rated scores have not been extensively researched. Objective: This study validated and compared the informant- and self-rated versions of the MBI-C among community-dwelling people in Taiwan. Method: We recruited 202 pairs of individuals without dementia aged ≥50 years and their cohabitating informants. The participants completed the MBI-C (MBI-C-self), and the informants completed the MBI-C (MBI-C-informant) and the Neuropsychiatric Inventory Questionnaire (NPI-Q) independently. Internal consistency, inter-rater reliability, and convergent validity were examined. Results: Both MBI-C-self and MBI-C-informant exhibited satisfactory Cronbach’s α values (0.92 and 0.88, respectively). The MBI-C-informant total score was correlated with the NPI-Q total score (r = 0.83, p < 0.001). Inter-rater reliability between the two versions, as represented by the inter-rater correlation coefficient, was 0.57 (p < 0.001). The prevalence of MBI based on the MBI-C-informant scores was 1.5% higher than that based on the MBI-C-self scores according to the suggested cut-off score of 8.5. The affective dysregulation domain score of MBI-C-informant was significantly lower than that of MBI-C-self. Conclusion: MBI-C-informant exhibited both high reliability and validity. Discrepancies between MBI-C-informant and MBI-C-self related to the detection rates and affective dysregulation domain scores were noted. The level of consistency and discrepancy between these two versions provide implications for the use of MBI-C in clinical practice and future research.
Pages 1215-1231
Yumiao Guo*, Meimei Kang*, Xinjie Hui*, Xiaojun Fan, Lianguo Zhang, Yejun Wang, Rong Wang, Xiuhong Nie *These authors contributed equally to this work.
The Association Between Cognition of Obstructive Sleep Apnea Patients and Urinary AD7c-NTP Level: Investigation and Application
Abstract: Background: Obstructive sleep apnea (OSA) is a multi-component disorder, which has many comorbidities, including cognitive impairment. Although its potential risk factors were unknown, they could affect the patient's quality of life and long-term prognosis. Objective: The purpose of this study was to investigate the application of urinary Alzheimer's disease-associated neurofilament protein (AD7c-NTP) levels in the assessment of cognitive impairment in OSA patients, and to analyze the predictive value of potential high-risk factors on cognitive impairment in OSA patients. Methods: 138 young and middle-aged adults were recruited and underwent overnight polysomnographic recording, Montreal Cognitive Assessment (MoCA), and urinary AD7c-NTP test. AD7c-NTP and other factors were further applied as biomarkers to develop a cognition risk prediction model. Results: Compared with the control, OSA patients showed significantly lower MoCA scores and higher urinary AD7c-NTP concentrations, while the severe OSA group appeared more significant. The urinary AD7c-NTP level of the OSA cognitive impairment group was higher than that of the non-cognitive impairment group. The results of regression analysis showed that urinary AD7c-NTP level was an independent predictor of cognitive impairment in OSA patients. Based on urinary AD7c-NTP levels and other selected factors, a multimodal prediction model for assessing the risk of cognitive impairment in OSA patients was initially established. Conclusion: The increased urinary AD7c-NTP level could be used as a relevant peripheral biomarker of cognitive impairment in OSA patients. A model using urinary AD7c-NTP combined with other factors was developed and could accurately assess the cognition risk of OSA patients.
Pages 1233-1247
Andrew E. Weller, Thomas N. Ferraro, Glenn A. Doyle, Benjamin C. Reiner, Richard C. Crist, Wade H. Berrettini (Handling Associate Editor: Karissa Barthelson)
Single Nucleus Transcriptome Data from Alzheimer’s Disease Mouse Models Yield New Insight into Pathophysiology
Abstract: Background: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer’s disease (AD)-related pathology. Objective: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice. Methods: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA). Results: We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr, Fth1, Pcsk1n, Malat1, Rpl37, Rtn1, Sepw1, Uba52, Mbp, Arl6ip5, Gm26917, Vwa1, and Pgrmc1. We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp, Rbm4b, Pnisr, Opcml, Cpne7, Adgrb1, Gabarapl2, Ubb, Ndfip1, Car11, and Stmn4. IPA identified 3 statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including ‘FXR/RXR Activation’, ‘LXR/RXR Activation’, and ‘Acute Phase Response Signaling’. Conclusion: DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings.
Pages 1249-1261
Xin-Rui Wu*, Kai-Min Wu*, Yue-Ting Deng, Shu-Yi Huang, Liu Yang, Qiang Dong, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu (Handling Associate Editor: Yong Liu) *These authors contributed equally to this work.
Association of Kidney Function with Risk of Incident Dementia: A Prospective Cohort Study of 275,167 UK Biobank Participants
Abstract: Background: Previous studies have reported inconsistent associations between chronic kidney disease (CKD) and dementia. Objective: To evaluate whether CKD is a risk factor for dementia and compare the performance of different measures of calculating estimated glomerular filtration rate (eGFR). Methods: 275,167 participants from UK Biobank were included and eGFR at baseline was calculated using serum creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C equations (eGFRcr-cys). Restricted cubic splines and Cox regression models were performed to assess the relationship of eGFR with all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD). Results: We observed a U-shaped relationship between each eGFR and risk of all-cause dementia and VaD, with eGFRcys and eGFRcr-cys showing a closer linkage (peGFRcys < 0.0001, peGFRcr-cys < 0.0001 and peGFRcr = 0.0001). Lower and supranormal eGFR were related to increased risk of all-cause dementia. Compared to the reference category of 90-104 ml/min/1.73 m2, adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause dementia for eGFRcr-cys 30-59, <30, and ≥105 ml/min/1.73 m2 were 1.26 (95%CI [1.05-1.50], p = 0.012), 2.62 (95%CI [1.54-4.47], p < 0.001), and 1.41 (95%CI [1.17-1.70], p < 0.001). No statistically significant association was observed between eGFR with risk of AD. Conclusion: This prospective study identified impaired kidney function as a critical risk factor for dementia and noted the application of cystatin C strengthened the relationship between CKD and dementia, underlining the significant value of preserving kidney function to reduce the risk of dementia and considering cystatin C measurement as part of clinical practice.
Pages 1263-1275
Jinghuan Gan*, Zhichao Chen*, Zhihong Shi, Xudong Li, Shuai Liu, Yiming Liu, Hongcan Zhu, Lu Shen, Guili Zhang, Yong You, Qihao Guo, Nan Zhang, Yang Lv, Baozhi Gang, Junliang Yuan, Yong Ji *These authors contributed equally to this work.
Temporal Variation in Disease Onset and Clinical Features of Lewy Body Disease in China
Abstract: Background: Lewy body dementia is the second most common neurodegenerative dementia, but data concerning the onset age and clinical features in the prodromal stage remain limited in China. Objective: To investigate the associations between onset age and clinical manifestations of cognitive impairment with Lewy bodies in a large-sample cohort. Methods: We included 74 patients with mild cognitive impairment with Lewy bodies (MCI-LB), 533 patients with dementia with Lewy bodies (DLB), 118 patients with Parkinson’s disease with MCI (PD-MCI), and 313 patients with Parkinson’s disease dementia (PDD) in this multicenter cohort from 22 memory clinics of China from 1 January 2018 to 31 March 2022. The onset age, clinical manifestations, and neuropsychological assessments were recorded and analyzed after reviewing the medical records. Results: The average onset age of memory loss was 68.28 (± 7.00) years, and parkinsonism happened 2.00 (± 1.24) years later for patients with MCI-LB. The average onset age of parkinsonism was 60.56 (± 8.96) years, and the memory loss happened 3.49 (± 3.02) years later for patients with PD-MCI. Rapid eye movement sleep behavior disorder and visual hallucinations were frequently reported in MCI-LB, DLB, and PDD, while visual hallucinations were least frequently reported in PD-MCI. Lower scores of MMSE and depression, and higher scores of activities of daily living and delusions, were independently associated with older onset age in DLB. Conclusion: The onset of PD-MCI precedes MCI-LB, and memory loss occurs 3 years after parkinsonism. The onset age is associated with cognition and neuropsychiatric symptoms in process.
Pages 1277-1289
Jialun Shen, Meng Li, Cheng Long, Li Yang, Jinxiang Jiang (Handling Associate Editor: Ling-Qiang Zhu)
Altered Odor-Evoked Electrophysiological Responses in the Anterior Piriform Cortex of Conscious APP/PS1 Mice
Abstract: Background: Olfactory decline is an indicator of early-stage Alzheimer’s disease (AD). Although the anterior piriform cortex (aPC) is an important brain area involved in processing olfactory input, little is known about how its neuronal activity is affected in early-stage AD. Objective: To elucidate whether odor-induced electrophysiological responses are altered in the aPC of 3-5-month-old APP/PS1 mice. Methods: Using head-fixed multi-channel recording techniques in APP/PS1 AD mouse model to uncover potential aberrance of the aPC neuronal firing and local field potential (LFP) in response to vanillin. Results: We show that the firing rate of aPC neurons evoked by vanillin is significantly reduced in conscious APP/PS1 mice. LFP analysis demonstrates reduced low- and high-gamma (γlow, γhigh) oscillations during both the baseline and odor stimulation periods in APP/PS1 mice. Moreover, according to spike-field coherence (SFC) analysis, APP/PS1 mice show decreased coherence between odor-evoked spikes and γlow rhythms, while the coherence with γhigh rhythms and the ΔSFC of the oscillations is unaffected. Furthermore, APP/PS1 mice show reduced phase-locking strength in the baseline period, such that there is no difference between baseline and odor-stimulation conditions. This contrasts markedly with wild type mice, where phase-locking strength decreases on stimulation. Conclusion: The abnormalities in both the neuronal and oscillatory activities of the aPC may serve as electrophysiological indicators of underlying olfactory decline in early AD.
Pages 1291-1300
Marina Ritchie, Megan Witbracht, Michelle M. Nuño, Dan Hoang, Daniel L. Gillen, Joshua D. Grill
Effect of Aducanumab Approval on Willingness to Participate in Preclinical Alzheimer’s Disease Trials
Abstract: Background: Clinical trials now test promising therapies in the preclinical stages of Alzheimer’s disease (AD). Participant willingness to enroll in different types of preclinical AD trials is understudied and whether the FDA approval of aducanumab affected these attitudes is unknown. Objective: To evaluate preferences toward three preclinical AD trial scenarios and whether the FDA approval of aducanumab changed willingness to participate among potential trial participants. Methods: Through an electronic survey, we asked enrollees in a recruitment registry age 50-79 to rate their willingness (using a 6-point Likert scale) to enroll in three hypothetical preclinical AD trial scenarios: an in-clinic infused monoclonal antibody intervention, a home-infused monoclonal antibody intervention, and an oral BACE inhibitor intervention. We administered the survey before and after the FDA approval of aducanumab. We used a generalized estimating equation model to assess group differences in preference for the trial scenarios. We used a paired t-test to determine if willingness to participate (using total willingness across three scenarios as the outcome) changed after the FDA decision. Results: At baseline, the mean participant willingness was highest in the in-clinic infusion scenario. There was no significant change in willingness to participate, overall, after the FDA decision. Participants who were independently aware of the FDA’s decision (prior to the second survey) demonstrated reduced willingness to participate; participants unaware of the FDA decision demonstrated no change. Conclusion: Willingness to participate in preclinical AD trials may have been negatively affected by the FDA’s decision to approve aducanumab among those aware of the decision.
Pages 1301-1320
Krista L. Harrison, Sarah B. Garrett, Madina Halim, Alissa Bernstein Sideman, Theresa A. Allison, Daniel Dohan, Georges Naasan, Bruce L. Miller, Alexander K. Smith, Christine S. Ritchie
“I Didn't Sign Up for This”: Perspectives from Persons Living with Dementia and Care Partners on Challenges, Supports, and Opportunities to Add Geriatric Neuropalliative Care to Dementia Specialty Care
Abstract: Background: In the United States, dementia specialty centers affiliated with centers of excellence for research hold promise as locations to develop innovative, holistic care in care systems otherwise siloed by discipline or payer. Objective: We conducted foundational research to inform development of patient-and family-centered palliative care interventions for dementia specialty centers. Methods: We interviewed persons living with dementia (PLWD), current, and former care partners (CP) recruited from a specialty dementia clinic and purposively selected for variation across disease syndrome and stage. A framework method of thematic analysis included coding, analytic matrices, and pattern mapping. Results: 40 participants included 9 PLWD, 16 current CPs, and 15 former CPs of decedents; 48% impacted by Alzheimer’s disease dementia. While help from family, support groups and adult day centers, paid caregiving, and sensitive clinical care were invaluable to PLWD, CPs, or both, these supports were insufficient to navigate the extensive challenges. Disease-oriented sources of distress included symptoms, functional impairment and falls, uncertainty and loss, and inaccessible care. Social and relational challenges included constrained personal and professional opportunities. The obligation and toll of giving or receiving caregiving were challenging. Clinical care challenges for PLWD and/or CPs included care fragmentation, insufficient guidance to inform planning and need for expert interdisciplinary clinical care at home. Conclusion: Findings highlight the breadth and gravity of gaps, which surpass the disciplinary focus of either behavioral neurology or palliative care alone. Results can inform the development of novel interventions to add principles of geriatrics and neuropalliative care to dementia care.
Pages 1321-1327
Lochanie Fonseka, David Wang, Brigid Ryan, Gary Cheung, Etuini Ma’u
Incidence of Young Onset Dementia in Waikato, New Zealand: A Population-Based Study
Abstract: Background: There is limited epidemiological research on the incidence of young onset dementia (YOD). Estimates of YOD incidence in New Zealand are extrapolated from international studies that do not reflect New Zealand’s population and ethnic diversity. Objective: To determine the incidence of YOD in the geographical area served by the Waikato District Health Board. Methods: All new inpatient and outpatient in the age range 30-64 years with a documented diagnosis of dementia at Waikato Hospital between 1 January 2014 – 31 December 2016 were identified. Incidence rates were calculated by 5-year age-band, sex, and ethnicity. Results: 64 incident cases of YOD were included. Incidence rates for all cause YOD were 13.3 (95% CI 10.3-17.0) and 22.7 (95% CI 17.5-29.1) per 100,000 person-years in the age range 30-64 years and 45-64 years respectively. The incidence rate in Māori (20.0, 95%CI 11.4-32.4) was higher compared to non-Māori (12.0, 95%CI 8.9-15.9), but this difference was not statistically significant (p=0.09). Conclusion: The incidence of YOD in this study is similar to global estimates. Incidence may be higher in Māori compared to non-Māori, highlighting the need for culturally appropriate approaches to dementia prevention, intervention, and care.
Pages 1329-1337
Xiaolei Shi, Nan Zhou, Bin Sun, Yongshun Wu, Yachun Hu, Yuping Ning, for the Alzheimer’s Disease Neuroimaging Initiative
Perivascular Space Predicts Brain Hypometabolism of Individuals with Underlying Amyloid Pathology
Abstract: Background: Reduced signal on fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valid proxy for neurodegeneration in Alzheimer’s disease (AD). Perivascular space (PVS) is believed to be associated with AD pathology and cognitive decline. Objective: This study aimed to investigate the associations of PVS with FDG-PET and cognitive performance based on the burden of amyloid pathology. Methods: We used magnetic resonance imaging (MRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). MRI-visible PVS in basal ganglia (BG) and centrum semi-oval (CSO) were visually classified as: none/mild, moderate or frequent/severe. The association of PVS with brain FDG-PET was explored based on the burden of amyloid pathology, where a cerebrospinal fluid (CSF) t-tau/Aβ42 with the ratio ≥0.27 was defined as high amyloid pathology. Moreover, the relationships between PVS and cognitive performance variables (ADNI-MEM and ADNI-EF) were studied. Results: For participants with higher tau/Aβ42 ratio, CSO-PVS severity was independently associated with lower FDG-PET. There were significant interaction effects between moderate or frequent/severe CSO-PVS and time on FDG decline in people with high amyloid pathology. The interaction between CSO-PVS and time (follow-up) was consistently associated with ADNI-MEM and ADNI-EF decline in individuals with high amyloid pathology. Conclusion: The study established the differential utility of PVS in BG and CSO for predicting brain metabolism. These findings suggest that CSO-PVS serves as a contributing factor to brain metabolism and cognitive decline associated with amyloid pathology.
