bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing intra‐individual variability on executive functioning tasks in individuals with Mild Cognitive Impairment and Dementia of the Alzheimer Type: Results from the ARMADA Study
Authors: Ho Emily , Karpouzian‐Rogers Tatiana , Dworak Elizabeth , Weintraub Sandra , Gershon Richard C. 
Published: December 2023

AbstractBackgroundCognitive decline is most often assessed mean group differences on static measures of cognitive abilities (MacDonald et al., 2009). Another, perhaps more dynamic, method to understanding cognitive functioning is to evaluate variability in performance within an individual, termed intraindividual variability (IIV), which has been associated with reduction in gray matter and less efficient cognitive processing. Using results from a multi‐site, longitudinal ARMADA study that validated NIH Toolbox across the cognitive aging spectrum, we investigated whether IIV in reaction time processing can differentiate between older adults with normal cognition, mild cognitive impairment (MCI), or dementia of the Alzheimer type (DAT), as well as the relative magnitude of differences between groups.MethodAs part of the Advancing Reliable Measurement in Alzheimer’s Disease and cognitive Aging study (ARMADA; Weintraub et al 2020), participants completed the NIH Toolbox Cognition Battery, including two measures of executive functioning, Dimensional Change Card Sort and Flanker Inhibitory Control, which include granular reaction time data in milliseconds. We analyzed standard deviation and mean absolute deviation of item‐level data of all trials, correct trials only, and incorrect trials only for three groups: normal controls, those with amnestic MCI, and those with mild DAT.ResultsWe observe large effect sizes of reaction time by clinical group, with the mild DAT group demonstrating mean standard error across trials of approximately .5 seconds throughout, compared with .25 seconds for MCI and .10 seconds for the control group (Figure 1). This translates to an approximate 5‐fold increase in processing speed in the most severe clinical group. Examining time trends, we see that while the NC and MCI group were faster as the test progressed; there is no similar learning effect for the mild DAT group. Similar effect sizes were observed for the Flanker test.ConclusionThis study represents one of the first studies to examine clinical performance using process data from two executive functioning measures on the NIH Toolbox across the cognitive aging spectrum. Future work will explore more definitions of IIV to determine which measure will maximally differentiate between established clinical groups and examine longitudinal differences.
Development and assessment of a composite score for overall brain pathology in the Adult Changes in Thought (ACT) autopsy cohort
Authors: Sinha Sagnik , Gibbons Laura E , Latimer Caitlin S , Crane Paul K , Keene C Dirk , Mukherjee Shubhabrata 
Published: December 2023

AbstractBackgroundMany people with clinically diagnosed Alzheimer’s disease (AD) dementia during life show multiple comorbid neuropathologies at autopsy. We sought to develop and evaluate a composite brain pathology score (BPS) score in the Adult Changes in Thought (ACT) study.MethodWe chose nine standard neuropathological variables to derive the BPS: Thal phase, Braak stage, CERAD score, cerebral amyloid angiopathy (CAA) score, presence of Lewy Body disease, presence of hippocampal sclerosis, total microinfarcts, LATE stage, and presence of arteriolosclerosis. We used confirmatory factor analyses (CFA) to derive a composite score for BPS. We compared BPS to the AD Neuropathologic Change (ADNC) score.We performed non‐nested modeling to compare the association of each score (BPS vs ADNC) using the last cognitive score (memory, executive function, language, and visuospatial ability) prior to death, adjusting for age at death and sex. Non‐nested models were compared with the Adjusted‐R2, the Davidson‐MacKinnon J‐test, and the Cox–Pesaran test. We focused on people whose last cognitive data were≤2 years prior to death. We compared associations of ADNC and BPS with last known clinical diagnosis (no dementia vs. any dementia), adjusting for age at death and sex by considering area under receiver operator characteristic (ROC) curves.ResultSample size was 886 with mean age of death was 89 and 57% were female. A bifactor model fit the best (Figure 1) with residual correlations for Thal phase and CERAD score, and for LATE stage and presence of hippocampal sclerosis. The BPS explained more of the variance for each of the cognitive scores (Table 1) and was superior and statistically significant compared to the ADNC score in comparisons of non‐nested models (Table 2). The BPS was also more strongly associated (Odds Ratio = 3.2) with dementia diagnosis than the ADNC score (Odds Ratio = 2.0). The area under the ROC curve for ADNC score was 0.74, while it was 0.78 for BPS score. The difference between the areas under ROC curves was statistically significant (p‐value < 0.0001).ConclusionWe demonstrate an approach to developing a composite brain pathology score which incorporates multiple forms of pathology. Future efforts will be focused on co‐calibrating and harmonizing BPS in other autopsy cohorts.
Amyloid‐, tau‐, and FDG‐PET in amyloid‐negative patients clinically diagnosed with early‐onset Alzheimer’s disease in the LEADS study
Authors: Mundada Nidhi S. , soleimani‐Meigooni David N. , Zeltzer Ehud , Windon Charles , Tanner Jeremy A. , Heath Courtney Lawh , Iaccarino Leonardo , Shankar Ranjani , Amuiri Alinda , Aisen Paul S. S , Eloyan Ani , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. , Rabinovici Gil D. , La Joie Renaud 
Published: December 2023

AbstractBackgroundNegative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET.MethodsWe identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols.ResultsCompared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR>2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B).ConclusionsAmyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes.
Temporal associations between treated and untreated hearing loss and mild behavioral impairment in older adults without dementia
Authors: Gosselin Penny , Guan Dylan X. , Smith Eric E. , Ismail Zahinoor 
Published: December 2023

AbstractBackgroundHearing loss and mild behavioral impairment (MBI) are non‐cognitive markers of dementia that are cross‐sectionally linked to one another. Longitudinal approaches are necessary to further understand mechanisms underlying their association, which may inform interventions for hearing loss and MBI. This study investigated the relationship between hearing loss, with or without hearing aids (HAs), and MBI in dementia‐free older adults both cross‐sectionally and longitudinally.MethodData were analyzed from dementia‐free National Alzheimer’s Coordinating Center participants, aged ≥50, collected between 2005‐2022. Three self‐report questions were used to generate a three‐level categorical hearing status variable: No‐HL, Untreated‐HL (not wearing hearing aids), and Treated‐HL (regularly wearing hearing aids). MBI status was derived from the informant‐rated Neuropsychiatric Inventory Questionnaire using a published algorithm. At baseline (n = 7992), age‐, sex‐, education‐, and cognitive status‐adjusted logistic regression was used to examine the association between hearing status and presence of global and domain‐specific MBI. Cox proportional hazards models examined the effect of: 1) hearing status as exposure on rate of incident MBI (n = 6639); and 2) MBI status as exposure on rate of incident hearing loss (n = 7343).ResultCross‐sectionally, participants with Untreated‐HL (not wearing hearing aids) were more likely to exhibit global MBI (OR = 1.58) and individual MBI domains of social inappropriateness (OR = 2.08), affective dysregulation (OR = 1.64), and impulse dyscontrol (OR = 1.68), compared to those with No‐HL (Figure 1). Treated‐HL (regularly wearing hearing aids) did not differ from No‐HL for presence of global‐ or domain‐specific MBI. Longitudinally, older adults with Treated‐HL developed MBI at higher rates than No‐HL (HR = 1.42), and older adults with MBI at baseline developed Treated‐HL at higher rates than those without MBI (HR = 1.34) [Table 1].ConclusionOur cross‐sectional results indicate that HA use in dementia‐free hearing‐impaired older adults is associated with lower likelihood of having MBI. However, hearing loss requiring hearing aids was associated with incident MBI and vice versa. This bidirectional relationship may indicate a positive feedback loop between hearing loss and MBI, with Treated‐HL and MBI reflecting greater hearing loss severity and disease burden, increasing the rate of development of the complementary marker and of dementia.
Harmonization of amyloid and tau PET tracers in a multi‐center cohort from NIA Alzheimer’s disease research centers in the United States
Authors: Harrison Theresa M. , Landau Susan M. , Baker Suzanne L. , Lee JiaQie , Ward Tyler J. , Murphy Alice , Chadwick Trevor , Mormino Elizabeth C. , Johnson Sterling C , Rogalski Emily J , Koeppe Robert A. , Decarli Charles , Toga Arthur W. , Kukull Walter A. , Biber Sarah , Jack Clifford R. , Jagust William J. 
Published: December 2023

AbstractBackgroundThe Standardized Centralized Alzheimer’s & related dementias Neuroimaging (SCAN) project harmonizes processing of prospectively acquired PET and MRI scans from Alzheimer’s disease research centers (ADRCs) across the USA. SCAN data will be integrated with other ADRC data streams within the National Alzheimer’s Coordinating Center (NACC), including the Uniform Data Set which includes rich longitudinal demographic, cognitive, and neuropathological data, resulting in a large, potentially representative cohort. The project has sought to accommodate site‐to‐site variation in image acquisition while permitting harmonization of imaging data, necessitating new analytic approaches for different PET tracers and PET scans without MRIs.MethodPET scans underwent preprocessing for quality control and smoothing to a uniform resolution. MRI‐free processing pipelines and positivity thresholds were developed for each beta‐amyloid (Aβ)‐PET tracer: [11C]PiB, [18F]florbetaben (FBB), [18F]florbetapir (FBP) and [18F]flutafuranol (NAV). A generic Aβ‐PET template was used for spatial normalization and cortical summary SUVRs were calculated in template space. Aβ‐positivity thresholds were determined by examining both MRI‐dependent thresholds transformed into MRI‐free units and a young control mean+2SD. Centiloid (CL) conversions were completed for each Aβ‐PET tracer. Tau‐PET tracers ([18F]flortaucipir (FTP) and [18F]MK‐6240) required tracer‐specific warping templates for best performance relative to gold‐standard MRI‐dependent processing. Demographic and clinical data were obtained from NACC.Result15 ADRCs have contributed data to SCAN as of January 2023. 477 participants had preprocessed, SCAN‐compliant (https://scan.naccdata.org/) Aβ‐PET scans and NACC data; 219 of these participants (46%) also had tau‐PET scans (Table 1). This cohort included 18% of individuals from underrepresented groups. Clinical diagnostic groups ranged from cognitively unimpaired to MCI and dementia (74% of whom had AD dementia). Using pooled Aβ‐PET data across 4 tracers in CLs, there were expected differences in Aβ burden by diagnosis group (Fig. 1) and positive associations with tau (Fig. 2).ConclusionSCAN has successfully harmonized PET data from more than a dozen US ADRCs yielding a large, clinically heterogeneous cohort of deeply phenotyped research participants. SCAN data will be compatible with ADNI data allowing for further pooling of data and greater statistical power to drive critical questions in AD and related dementias research.
To split or not to split: data‐driven components along the PPAOS‐PAA spectrum
Authors: Illán‐Gala Ignacio , Lorca‐Puls Diego L. , Miller Zachary , Rubio‐Guerra Sara , Santos‐Santos Miguel A , Lleó Alberto , Grinberg Lea T. , Spina Salvatore , Rankin Katherine P , Kramer Joel H. , Rabinovici Gil D. , Boxer Adam L , Rosen Howard J. , Perry David C. , Miller Bruce L. , Seeley William W. , Mandelli Maria Luisa , Tempini Maria Luisa Gorno 
Published: December 2023

AbstractBackgroundIt is unclear whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) represent the two ends of a clinical continuum or exist as distinct syndromic entities with specific pathologic/prognostic correlates. We aimed to characterize the main clinical features along the spectrum of progressive non‐fluent speech‐language disorders (nf‐SLD) and explore the existence of data‐driven symptom clusters with etiological/prognostic value.MethodWe included 98 participants presenting with progressive motor speech impairment and/or agrammatism, of which 43 had an autopsy‐confirmed neuropathological diagnosis. Speech pathologists rated motor speech features indicative of dysarthria and AOS. Quantitative measures of expressive/receptive agrammatism were obtained and compared with healthy controls. Baseline and longitudinal disease severity was assessed with the Clinical Dementia Rating sum‐of‐boxes (CDR‐SB). We explored the clustering tendency of the data to form robust symptom clusters and used principal component analysis to extract data‐driven clinical components. The longitudinal CDR‐SB change was estimated with linear mixed‐effects models.ResultNinety‐one participants fitted previously reported clinical profiles (69 AOS+agrammatism, 18 PPAOS and 4 PAA), while 7 remained unclassifiable and were characterized by nonfluent speech and dysarthria in the absence of apraxia of speech or agrammatism. None of the baseline clinical features discriminated between FTLD subgroups. The Hopkins statistic ruled out the existence of syndromic clusters in the whole sample. Three data‐driven components explained 71% of the variance ([i]severity‐agrammatism, [ii]AOS, and [iii]dysarthria). The component characterized by prominent dysarthria was more specific to patients with Progressive Supranuclear Palsy while the component characterized by severity‐agrammatism predicted a faster CDR‐SB increase.ConclusionOur results suggest that nf‐SLD represents a clinical continuum. Splitting this continuum into different clinical phenotypes based on its major clinical features does not improve clinical‐pathological correlations, stressing the need for new clinical and biological markers. The term nf‐SLD could be used to group together these speech‐language phenotypes strongly associated with FTLD.
Investigating the impact of hypertension with and without diabetes on progression to Alzheimer’s disease: A clinic‐pathological study
Authors: Ruthirakuhan Myuri , Swardfager Walter , Xiong Lisa Y. , Ottoy Julie , MacIntosh Bradley J. , Rabin Jennifer S. , Ramirez Joel , Herrmann Nathan , Keith Julia , Lanctôt Krista L. , Black Sandra E. 
Published: December 2023

AbstractBackgroundHypertension and diabetes have each been associated with an increased risk of progression to Alzheimer’s disease (AD) dementia. Here, we investigated their combined impact on progression from cognitively normal to clinically‐diagnosed AD.MethodCognitively normal individuals from the National Alzheimer’s Coordinating Center were identified as having neither hypertension nor diabetes (HTN‐/DM‐), hypertension without diabetes (HTN+/DM‐), or hypertension with diabetes (HTN+/DM+). The presence of HTN and DM were based on their diagnosis from recent medical history or medication use. This study investigated whether HTN+/DM‐ or HTN+/DM+ were predictors of progression to clinically‐diagnosed AD compared to HTN‐/DM‐. In a subgroup analysis with post‐mortem data, we investigated whether HTN+/DM‐, and HTN+/DM+ were predictors of progression to clinically diagnosed AD due to underlying AD‐ and/or vascular neuropathology.ResultThis study included N = 11074 cognitively normal individuals (mean age: 71.7 (9.0), MMSE: 28.9 (1.4), male: N = 3818 (34%)). Approximately 7% (N = 830) progressed to clinically‐diagnosed AD, and the average duration of follow‐up was 5.2 (3.6) years. Forty‐two percent (N = 4608) were HTN‐/DM‐, 45% (N = 5034) were HTN+/DM‐, and 13% (N = 1432) were HTN+/DM+. Both HTN+/DM‐ (hazard ratio (HR): 1.24 (1.17‐1.32), p<.001), and HTN+/DM+ (HR: 1.31 (1.19‐1.44), p<.001) were significant predictors of progression to clinically‐diagnosed AD. Subgroup analyses with post‐mortem data (N = 919) demonstrated that compared to HTN‐/DM‐, those with HTN+/DM‐ had a higher risk of progressing to clinically‐diagnosed AD with underlying cerebrovascular disease (CVD) neuropathology (HR: 1.54 (1.17‐2.03), p = .002), whereas those with HTN+/DB+ had a higher risk of progression to clinically‐diagnosed AD with underlying AD (HR: 2.10 (1.16‐3.79), p = .01) and cerebral amyloid angiopathy (CAA) neuropathology (HR: 1.52 (1.09‐2.12), p = .01).ConclusionThese findings demonstrate that underlying CVD neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM‐, while both AD and CAA neuropathology contributes to the risk of clinically‐diagnosed AD in individuals with HTN+/DM+. This suggests that individuals with HTN+/DM‐ and HTN+/DM+ vary phenotypically and may warrant the need for different treatment strategies to reduce the future risk of AD.
Late‐life social activity and subsequent risk of dementia and mild cognitive impairment
Authors: Chen Yi , Grodstein Francine , Capuano Ana W. , Bennett David A. A , James Bryan D 
Published: December 2023

AbstractBackgroundPrevious research reported associations between more social engagement and better cognitive health. Social engagement is a multidimensional construct encompassing interrelated but distinct domains such as social activity, social network size, perceived social support, and loneliness. These domains are not equally amenable to interventions. We therefore focused on late‐life social activity, as a potentially modifiable facet of social engagement, and examined its relation to risks of dementia and MCI, independent of other aspects of social engagement, lifestyle, and health.MethodIn the Rush Memory and Aging Project (MAP), 1923 older adults without dementia at baseline were followed longitudinally, with annual clinical evaluation of dementia and MCI. The frequency of participation in six common social activities was assessed by a validated scale at baseline (mean = 2.6, range: 1‐4.3), as were size of social network, perceived social support, and perceived loneliness. A clinical diagnosis of MCI or dementia was rendered annually based on cognitive tests and diagnostic classification by a clinician. We used Cox proportional hazard models to quantify associations between social activity score and incident dementia or MCI. Primary models controlled for demographics; additional models included covariates for health, other social engagement indicators, and income. In secondary analyses, to consider reverse causality, we excluded participants who developed MCI or dementia within two years after baseline.ResultDuring a mean follow‐up of 6.7 (std = 4.7) years, 545 (28%) participants developed dementia, and 695 (49% of those without MCI at baseline) developed MCI. Each one‐unit increment in social activity score was associated with a 37% reduction in dementia risk [HR = 0.63, 95% CI: 0.53‐0.74] after adjusting for age, sex, education, race/ethnicity, and marital status (Figure 1A). Social activity was also related to a lower risk of MCI [HR = 0.77, 95% CI: 0.66‐0.89] (Figure 1B). Results were not meaningfully different after adjusting for vascular disease burden, BMI, ADL disability, physical activity, depressive symtoms, social network size, social support, social isolation, and income. Excluding participants who developed MCI or dementia soon after baseline did not change the patterns.ConclusionKeeping socially active at older age is related to lower dementia risk, possibly informing strategies for developing preventive interventions.