bluuebunny/crossref_metadata_2025_split huggingface dataset:
The M4 muscarinic acetylcholine receptor positive allosteric modulator VU0467154 normalizes non‐rapid eye movement sleep deficits in non‐pathologically aged mice.
Authors: Russell Jason K , Wan Laura , Ingram Shalonda , Bubser Michael , Lindsley Craig W , Jones Carrie K 
Published: December 2023

AbstractBackgroundThe central cholinergic system plays an important role in normal arousal and sleep/wake architecture, and is known to decline in non‐pathological aging and Alzheimer’s disease (AD). The M4 muscarinic acetylcholine receptor (mAChR) is expressed in cortical, limbic, and thalamic brain regions, crucial for the control of arousal and sleep/wake architecture. While previous clinical studies have identified M4 as an exciting target for the potential treatment of behavioral disturbances and other symptoms associated with AD, there remains limited data on its role in the control of sleep/wake architecture and arousal in non‐pathological aging and AD. In the current studies, we evaluated the effects of the selective M4 positive allosteric modulator (PAM) VU0467154 on sleep disruptions observed in non‐pathologically aged mice across the circadian rhythm.MethodHD‐X02 telemetry devices (DSI) were implanted in young (4‐5‐year‐old) and aged (20‐21‐month‐old) C57/BL6 mice, followed by administration of vehicle or a dose of the M4 PAM VU0467154 during either the inactive and active phase. Time in wake, non‐rapid eye movement (NREM), and rapid eye movement sleep (REM) sleep were assessed across 24‐hours post‐ dosing. NREM sleep fragmentation was also assessed for the 8‐hours post‐dosing. Arousal, as measured by gamma power during wake, and sleep quality, as measured by delta power during NREM sleep, were expressed relative to a 1‐hour predose baseline. In addition, young mice were concurrently dosed with a maximally efficacious dose of VU0467154 (30 mg/kg) in combination with the M4 antagonist VU6028418 to confirm that the observed effects were mediated through an M4‐dependent mechanism.ResultVU0467154 increased NREM sleep and decreased arousal following dosing during either phase; and reduced NREM sleep fragmentation and REM sleep following dosing during the inactive phase in young mice. These effects are attenuated by the M4 antagonist VU6028418. In aged mice, similar effects of VU0467154 are observed, with NREM sleep quality also enhanced during the inactive phase.ConclusionWhen evaluated across the circadian rhythm, the M4 PAM VU0467154 normalized deficits in NREM sleep fragmentation and increased NREM sleep duration and quality in non‐pathological aged mice in the inactive phase.
Distinct neuroinflammatory mechanisms in Alzheimer’s disease and Frontotemporal Lobar Degeneration
Authors: Thapa Simrika , Anastassiadis Chloe , Vasilevskaya Anna , Multani Namita , Taghdiri Foad , Salvo Cristina , Mora‐Fisher Daniela , Anor Cassandra Jessica , Varriano Brenda Maricela , Misquitta Karen , Tang‐Wai David F. , Kovacs Gabor G. , Fox Susan , Lang Anthony E , Tartaglia Carmela 
Published: December 2023

AbstractBackgroundNeuroinflammation is an important pathophysiological process in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Frontotemporal Lobar Degeneration (FTLD). Limited studies have revealed distinct inflammatory markers between proteinopathies. Whether AD and FTLD have distinct neuroinflammatory profiles that relate to different clinical manifestations remains unclear. We assayed a large number of inflammatory proteins to delineate neuroinflammatory signatures across different proteinopathies.MethodUsing Olink Inflammation panels, we measured 737 inflammatory proteins in CSF from 22 AD [11 early‐onset (EOAD); 11 late‐onset (LOAD)], 45 FTLD patients and 5 healthy controls (HC). Multiple linear regression analyses were performed and comparison of expression between the groups was done by ANOVA F‐tests, adjusted for age, sex and age of onset, with FDR correction for multiple comparisons. The relationship between inflammatory markers and neurofilament light chain (NfL) was examined by Pearson correlation as well as linear regression analysis incorporating the interaction effect of NfL and disease groups.ResultOut of 442 proteins that passed quality control, five neuroinflammatory proteins (PKLR, CAT, CXCL9, MMP1, MEPE) involved in extracellular matrix regulation, neuroprotection and chemoattractant activity were significantly downregulated in AD compared to HC (q<0.05, FDR‐corrected). Comparing AD and FTLD, 40 were significantly upregulated in AD (q<0.05, FDR‐corrected). C3, a pro‐inflammatory complement protein was significantly downregulated in AD compared to FTLD. Interestingly, seven inflammatory proteins were significantly correlated with NfL in AD following FDR correction: C7 (r = 0.79, q<0.05), LGALS9 (r = 0.72, q<0.05), LYVE1 ((r = 0.72, q<0.05), ADAMTS1 (r = 0.71, q<0.05), MRC1 (r = 0.69, q<0.05), SEMA3G (r = 0.69, q<0.05), and CCN2 (r = 0.68, q<0.05). No inflammatory proteins were correlated with NfL in FTLD. Comparing EOAD and LOAD, anti‐inflammatory cytokine TGF‐β, was upregulated in EOAD compared to LOAD (q<0.05, FDR‐corrected). A significant interaction effect of NfL and AD sub‐groups (EOAD and LOAD) was found with TNFRSF13B, CCL21, IL5RA, IL7, and MZB1 (q<0.05, FDR‐corrected), where except for IL7, all proteins were positively correlated with NfL in LOAD but not in EOAD.ConclusionAD and FTLD patients display distinct inflammatory profiles with varying relationships between inflammatory and neurodegenerative markers. EOAD and LOAD also showed distinct inflammatory patterns. Our results underscore that proteinopathy‐specific neuroinflammatory mechanisms are involved in disease pathogenesis.
Analyses of Quality of Life in Frontotemporal Lobar Degeneration: Findings from the ALLFTD Consortium
Authors: Nelson Kevin M , Forsberg Leah K. , Brushaber Danielle , Syrjanen Jeremy A. , Lapid Maria I. , Heuer Hilary W. , Boxer Adam L. , Rosen Howard J. , Boeve Brad F. , Consortium ALLFTD 
Published: December 2023

AbstractBackgroundThe DEMQOL (Dementia Quality of Life) scale is a patient reported questionnaire and proxy form that captures subjective life quality. Participants in ALLFTD and their Study Partners (SP) complete these questionnaires at each study visit.MethodWe analyzed the DEMQOL in participants and their SPs when the SP was reported to be a spouse or equivalent. Analyses focused on the final overall quality of life (QoL) rating for the participant (poor, fair, good, or very good).ResultDEMQOL responses from 907 dyads (participant: mean age 58.3±13.4 years, 44% female, and mean education 15.9±2.5 years) were analyzed. Participants rated their overall QoL as very good (45.8%), good (36.5%), fair (14%), and poor (3.5%). SPs rated their participant’s overall QoL as very good (33.6%), good (41%), fair (19.4%), and poor (6%). There was a discordance in ratings between participants and SPs (p<0.0001); in almost 50% of cases, participants rated their QoL better (33.2%) or worse (15.2%) than their SP rated their QoL. When considering disease severity (CDR®+NACC‐FTLD global score), participants rated their QoL better than their SP rated their QoL (CDR®+NACC‐FTLD = 0: 19.4%, CDR®+NACC‐FTLD = 0.5: 42%, and CDR®+NACC‐FTLD = 1+: 33.2%), worse than (CDR®+NACC‐FTLD = 0: 15.1%, CDR®+NACC‐FTLD = 0.5: 13.3%, and CDR®+NACC‐FTLD = 1+: 15.2%), or the same (CDR®+NACC‐FTLD = 0: 65.6%, CDR®+NACC‐FTLD = 0.5: 44.8%, and CDR®+NACC‐FTLD = 1+: 51.6%).ConclusionAmong participants and SPs, similarities and differences in QoL ratings are fairly consistent regardless of global CDR®+NACC‐FTLD rating. Generally, participants are equally or more optimistic about QoL than their SPs. Longitudinal analyses are forthcoming.
In‐vivo and post‐mortem retinal and brain pathological findings in a homozygote for the A431E PSEN1 mutation
Authors: Guzman Samuel , Koronyo‐Hamaoui Maya , Koronyo Yosef , Shi Haoshen , Hiniker Annie , Hawes Debra , Kashani Amir H , Ringman John M 
Published: December 2023

AbstractBackgroundThe neuropathology associated with PSEN1 mutations shares many features with late‐onset Alzheimer’s disease although atypical features are also seen. An important question is whether the manifestations of PSEN1 mutations are dose‐dependent. We present the neuropathological findings of a homozygote for the pathogenic A431E mutation in PSEN1 relative to heterozygotes and the finding of retinal Aβ lesions consistent with those that were topographically detected in vivo by retinal fluorescence imaging.MethodsA homozygote for the A431E PSEN1 mutation began having symptoms at age 33 and underwent a comprehensive ophthalmic and neurologic evaluation at age 37 before passing away at age 39. Brain and eyes were collected and brain sections and retinal flatmounts and cross‐sections were processed and immunostained with 4G8 or 12F4 (anti‐Aβ), AT8 or pS396 (anti‐phosphoTau) antibodies. Retinal vascular and astrocytic markers were also assessed.ResultsBrain weight of the homozygote was 1180 grams relative to 840 and 860 grams in two heterozygotes with only mild to moderate gross atrophy appreciable relative to moderate to severe atrophy in the heterozygotes. More abundant 4G8 (Aβ) staining was appreciable in widespread brain areas in the homozygote relative to the heterozygotes with some having a “cotton wool” morphology. Conversely, neurofibrillary tangle density was markedly lower in the homozygote relative to heterozygotes in all areas assessed. Retinal in vivo imaging revealed very small, yellow deposits in the macula in both eyes that were atypical for a 37‐year‐old. These lesions correlated topographically with areas of Aβ deposits stained in post‐mortem flatmounts. In retinal cross‐section, Aβ accumulation, including vascular Aβ40 and Aβ42 deposits, pS396‐positive staining and NFTs are clearly detected, along with enhanced GFAP‐positive gliosis.ConclusionThe neuropathological changes seen in a person homozygous for the A431E PSEN1 mutation showed an increased degree of Aβ pathology and evidence of a lesser degree of downstream pathology, possibly representing a more rapidly evolving disease with progressive disability despite a relative lack of neurodegeneration. We also demonstrated that Aβ and tau pathology occurs in the retina in this form of AD and that it can be visualized on clinical examination during life.Funded by: P30AG066530, U01AG051218, R01AG062007
Differences in the association between midlife hypertension status and late‐life cognition and cognitive change: results from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: Gilsanz Paola , Soh Yenee , George Kristen M , Peterson Rachel , Hirst Andrew K , Mayeda Elizabeth Rose , Glymour M. Maria , Mungas Dan M. , Whitmer Rachel A. 
Published: December 2023

AbstractBackgroundThis study evaluates the association of midlife hypertension status and domain‐specific late‐life cognitive change allowing for possible differences by sex.MethodThe Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort is a multi‐ethnic study of 1,712 Kaiser Permanente Northern California members age 65+ at enrollment in 2017. For 1,696 participants, we categorized the last examined clinical blood pressure measures from 1964‐1985 (mean age = 37.5) as hypotensive, normotensive, prehypertensive, or hypertensive. Verbal episodic memory and executive function were assessed using Spanish and English Neuropsychological Assessment Scales across three interview waves over 4 years and scores were z‐standardized to the baseline. Sex‐stratified linear mixed models with random intercepts estimated the associations of midlife hypertension status with domain‐specific baseline cognition and cognitive change using years since baseline as timescale. Models adjusted for age at blood pressure measurement, KHANDLE baseline age, race, ethnicity, education, practice effects, and interview mode (phone vs in‐person).ResultA greater proportion of men than women had midlife pre‐hypertension (44% vs 31%) or hypertension (21% vs 11%) (Table 1). Among men and women, midlife hypertension status was not associated with baseline executive function or verbal episodic memory (Table 2). Compared to men with normal midlife blood pressure, those with midlife hypotension (b = ‐0.10, 95% CI: ‐0.17, ‐0.04) or midlife hypertension experienced steeper declines in executive functioning (b = ‐0.05, 95% CI: ‐0.10, ‐0.004). Among women, only midlife hypertension was associated with decline in executive function (b = ‐0.04 95% CI: ‐0.09, 0.003), though not significantly different from normotensive women. Compared to normotensive men, those with midlife hypotension (b = ‐0.17, 95%CI: ‐0.27, ‐0.07) and those with pre‐hypertension (b = ‐0.06, 95% CI: ‐0.12, ‐0.004) experienced steeper decline in verbal episodic memory. Among women, only midlife hypertension was associated with steeper declines executive function (b = ‐0.04, 95% CI: ‐0.09, 0.003), though not significantly different from normotensive women. Though effect estimates of midlife hypertension status on cognitive outcomes differed by sex, these differences were not statistically significant.ConclusionBoth hypotension and hypertension 30‐50 years prior to cognitive assessments predicted accelerated cognitive decline in older men. Patterns were less consistent for women but not statistically distinguishable from associations among men.
The Effect of the COVID‐19 Pandemic on Subjective Cognitive Decline and Mood
Authors: Loor Angelique , Chapman Silvia , Joyce Jillian L. , Waltrip Leah H. , Rizer Sandra , Shagalow Shaina , Cosentino Stephanie 
Published: December 2023

AbstractBackgroundSubjective Cognitive Decline (SCD) is being recognized as one of the earliest clinical signs of Alzheimer’s disease (AD). However, SCD is susceptible to a range of task factors (e.g., how SCD is measured) and person factors (e.g., mood). Currently, there is rising concern about the COVID‐19 pandemic’s impact on memory and mood. The purpose of this study was to investigate the effects of the pandemic on various types of SCD ratings and aspects of mood in older adults.Methods83 cognitively healthy older adults completed three counterbalanced 20‐item SCD questionnaires to examine SCD in general, SCD compared to 5 years ago (retrospective), and SCD compared to same‐aged peers (age‐anchored). Individuals also completed mood questionnaires that assess depression, anxiety, and apathy. After completing each SCD and mood questionnaire, participants rated the extent to which the pandemic affected their ratings using a Likert scale (range: much worse [‐2], a little worse [‐1] not changed [0], a little better [1], much better [2]). One‐sample and paired‐sample t‐tests examined pandemic effect ratings for each measure. Bivariate correlations examined pandemic effect ratings in relation to age and lifestyle features (sleep, loneliness, exercise, and social contact).ResultsOne sample t‐tests revealed that age‐anchored SCD ratings were not affected by the pandemic; that is, pandemic effect ratings (mean = ‐0.11) were not significantly different from zero (p = .118). In contrast, retrospective SCD (mean = ‐0.25, p = .001) and general SCD ratings (mean = ‐0.26, p<.001) were negatively affected. Additionally, depression (p = .007), anxiety (p = .002), and apathy (p = .05) ratings were all negatively affected by the pandemic. Pandemic effect ratings for depression (r = .45; p< .001) and general SCD (r = .26; p = .018) were associated with the current quality of sleep as compared to pre‐pandemic sleep quality.ConclusionAge‐anchored SCD ratings are relatively resilient to the effects of the COVID‐19 pandemic. These results add to the growing evidence for using age‐anchored SCD ratings in studies of cognitive aging. Overall, these findings point to sleep quality as a potential mechanism by which older adults’ subjective cognitive experiences and mood may have been, and continue to be, affected by the pandemic.
Recruitment of Underrepresented Groups into the AHEAD Study: Strategic plan of Action
Authors: James Taryn T. , Gleason Carey E. , Gee Alexander , Gooding Diane C. , Lofton Brenda Caroll , Carter Fabu P. , Green‐Harris Gina , Norris Nia , Lawrence Sacheen L. , King Margaret F , Salazar Hector , Cardenas Cecilia , Cole Aleshia , Cronin Katherine , Carlsson Cynthia M , Bouges Shenikqua 
Published: December 2023

AbstractBackgroundTo ensure that therapies are applicable for all groups, ethnic/racial diversity in Alzheimer’s disease (AD) clinical trials is an ethical imperative. Toward this goal, we developed a recruitment model founded on 1) building trust by providing accurate and transparent information, and 2) using culturally sensitive approaches to address legitimate concerns. Our ultimate goal is to empower individuals from under‐represented groups (URG) to participate in AD research.MethodOur group focuses on recruitment of racialized groups. Using a multistep approach (figure1), we established partnerships and created community advisory boards (CABs) comprised of leaders who effectively advocate for community needs. Research projects are presented to the CABs to determine alignment with community needs. Assessments with community leaders and advisory networks help identify opportunities to fulfill community needs. Recruitment of African Americans (AA) into the AHEAD study, a study assessing the recently approved monoclonal antibody, lecanemab in participants with preclinical AD, began by presenting the project to the Black Leaders of Brain Health (BLBH) CAB. Incorporating their input into our approach, we will structure community talks and events in a culturally appropriate manner in discussions with the larger AA community. Example, we utilized a questionnaire at an event to introduce AA participants in a biomarker study to the AHEAD study (figures 2 & 3).ResultFeedback received from BLBH includes advocating to funders, including the NIH to fund research that reflects inclusivity and diversity. BLBH recommended building URG voices into study design by having a diverse scientific team and hiring community members to collect data. Additionally, rather than excessive compensation, researchers should speak to the study benefits both for the individual’s and the community’s health. Finally, BLBH members emphasized the need to include hopeful messages and advice to improve health, rather than merely pointing out that AA are most likely among racial groups to have the disease.ConclusionRecruitment models involving trust building and partnerships with groups consisting of community members of URG will be mutually beneficial for both the health researcher and the communities that they serve. This may serve as a means to tip the scale toward increased participation by URG in biomedical research.
Association of race/ethnicity with renewal to the Consent‐to‐Contact (C2C) local recruitment registry
Authors: Salazar Christian R. , Xu Yiren , Morgan Olivia M. Bernstein , Hoang Dan , Witbracht Megan G. , Gillen Daniel L , Grill Joshua D. 
Published: December 2023

AbstractBackgroundOnline recruitment registries may serve as tools for accelerating the enrollment of historically underrepresented participants in Alzheimer’s disease (AD) trials. A potential challenge, however, is retaining registry participants until they can be recruited into prospective studies. We sought to examine the association of race/ethnicity with renewal among adults over age 50 who enrolled in a local online recruitment registry.MethodStudy participants enrolled in the University of California, Irvine Consent‐to‐Contract (C2C) registry, a local online registry designed to improve recruitment into AD studies. At enrollment, participants completed an online structured questionnaire to assess sociodemographic characteristics, source of recruitment and self‐reported medical history. Research attitudes were assessed with the 7‐item Research Attitude Questionnaire (RAQ). We examined the frequency of participant completion of annual renewal within 15 months from initial enrollment to the registry. To evaluate the association of race/ethnicity with first‐year renewal, we used ordinal logistic regression models that were adjusted for age, sex, educational attainment, number of chronic conditions and research attitudes.ResultAmong 3,065 included C2C participants, the average age at enrollment was 66 years, 87% (n = 2,658) were Non‐Hispanic (NH) White, 6% (n = 191) were Hispanic/Latino, 6% (n = 180) were NH) Asian, and 1% (n = 36) were NH Black. Compared to NH Whites, Hispanics/Latinos exhibited a 40% lower odds of renewal (adjusted Odds Ratio [aOR] = 0.60, 95% Confidence Interval [CI]: 0.44 ‐ 0.82), 32% lower odds of renewal for NH Asians (aOR = 0.68, 95% CI: 0.50 ‐ 0.93) and 16% lower odds for NH Blacks (aOR = 0.84, 95% CI: 0.43‐1.66). Higher age, more years of education, and better research attitudes was associated with higher odds of first‐year renewal in the fully adjusted model.ConclusionUnderrepresented populations may be at greater risk for loss to follow‐up in online recruitment registries. Future research addressing potential barriers to continued participation and interventions to improve retention will be critical to maximize the impact of registries.
Atrophy in brainstem nuclei with early Alzheimer’s Disease pathology, a biomarker for identification of at risk individuals?
Authors: Mueller Susanne G 
Published: December 2023

AbstractBackgroundAutopsy studies suggest that AD‐related tau pathology may affect the brainstem already in adolescence/young adulthood suggesting that it could be a biomarker for the identification of at risk individuals in the preclinical stage. The overall goal was to investigate a. if a newly developed method for the segmentation of internal brainstem structures from T1 and T2 weighted MRIs can be used to identify subjects with volume losses in brainstem nuclei known to be affected by tau pathology, and b. if these brainstem volume losses affect cognition.MethodThe age‐adjusted Total Cognition Composite Score (CCS) and T1 and T2 weighted images were obtained from 675 participants in the Human Connectome Project of typical Aging. The T1 and T2 image intensities were recalibrated and a T1/T2 image calculated. The brainstem was extracted from these 3 images, and k‐means clustering used to identify five brainstem tissue types (Figure 1). The five tissue maps were warped onto a brainstem tissue template on which 48 structures were labeled. Jacobian determinant (JD) maps were calculated and the mean JD from these rois extracted. Linear regression with the mean roi JD as dependent and age as independent variable were used to generate a 675×48 matrix where residuals >2 SD above the fit line were set to 1 (larger than age‐average), those >2 SD below to ‐1 (smaller than age‐average) and all others to 0. Hierarchical clustering analysis with the 675×48 matrix as input was used to identify different brainstem atrophy patterns.ResultThe cluster analysis identified 11 clusters. 31 individuals (mean(SD) age: 56.2(16.2), range:36‐100) were assigned to Cluster 8. This cluster had the most rois (n = 17) with significant volume loss (Figure 2 for detailed results) and the 31 individuals the lowest CCS score compared to those assigned to other clusters (98.2(19.5) vs.109.6(15.2), p = 0.003).ConclusionThe new brainstem segmentation identified a subgroup with lower cognitive performance and widespread volume loss exceeding that in their age cohort in brainstem nuclei known to be affected by AD. Additional studies will be necessary to determine if individuals showing this specific brainstem atrophy pattern are indeed at risk to develop AD in their later life.