bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neocortical‐type Lewy bodies and limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change in community‐dwelling older persons
Authors: Agrawal Sonal , Yu Lei , Nag Sukriti , Arfanakis Konstantinos , Barnes Lisa L , Bennett David A , Schneider Julie A 
Published: December 2020

AbstractBackgroundLewy bodies are common in aging and often co‐occur with Alzheimer's disease (AD). There is recent and expanding recognition of another common proteinopathy, limbic predominant age‐related TDP‐43 neuropathologic change (LATE‐NC), in the aging brain and all 3 proteinopathies are associated with the APOEε4 genotype. Most studies have focused on the association of LATE‐NC and AD, but there are few studies that specifically focus on LATE‐NC and Lewy body disease. The objective of this study was to test the hypothesis that neocortical Lewy bodies are independently associated with LATE‐NC.MethodParticipants without dementia from three longitudinal clinical‐pathologic studies, the Rush Memory and Aging Project, the Religious Orders Study, and the Minority Aging Research Study were included. Uniform neuropathologic examinations provided measures of LATE‐NC, neocortical Lewy bodies, and AD. LATE‐NC pathology was defined as the distribution of TDP‐43 in the brain by using a staging system: stage 0, no TDP‐43 deposition; stage 1, TDP‐43 deposition localized to the amygdala; stage 2, extension to the hippocampus and/or entorhinal cortex; stage 3, further extension to the neocortex. Lewy bodies were assessed in the neocortical regions by immunohistochemistry. Ordinal logistic regression models were used to examine the association of neocortical Lewy bodies with the odds of having more severe LATE‐NC after controlling for demographics, global AD pathology score, and APOEε4.Result1564 participants [mean age‐at‐death= 89.5 years (SD= 6.7); mean education=16.2 years (SD= 3.6); 68% women; 26% APOEε4] were included in the analyses. Neocortical Lewy bodies were present in 214 (13.7%) of descendants. 136 (63.5%) subjects with neocortical Lewy bodies had LATE‐NC pathology [stage 1 (n=40), stage 2 (n=32), and stage 3 (n=64)]. Neocortical Lewy bodies were associated with a higher odds of more advanced LATE‐NC stages (Odds Ratio = 1.55; 95% Confidence Interval = 1.17–2.04) after controlling for demographics and AD pathology. These results persisted after adjusting for presence of APOEε4.ConclusionThese findings suggest that neocortical Lewy bodies are independently associated with LATE‐NC in the older brain. Future research is needed on the diagnosis, prognosis, and pathogenesis of mixed neocortical Lewy body disease and LATE‐NC and related neurodegeneration in aging brain.
Individual electromagnetic profiles for the prediction of episodic memory change in early stages of dementia
Authors: Colomo Alejandra García , Sanz David López , Nebreda Alberto , de Frutos Jaisalmer , Fernández Ricardo Bruña , Losada María Luisa Delgado , Higes Ramón López , Maestú Fernando 
Published: December 2020

AbstractBackgroundRecent literature defines Alzheimer’s disease (AD) as a continuum consisting of three differentiated stages, preclinical, prodromal and dementia, in which the progressive neurological deterioration gives rise to a growing cognitive decline. According to this idea, presenting subjective cognitive decline (SCD), on its own or in association with a diagnosable mild cognitive impairment (MCI), increases the risk of developing AD‐related dementia in the following years. AD is usually described as a disconnection syndrome. Studies performed with magnetoencephalography (MEG) and diffusion weighted imaging (DWI) have shown alterations in patterns of functional connectivity, power spectrum, fractional anisotropy, and mean diffusivity even in the initial stages of the disease. These patterns could constitute an early biomarker, and thus allow for an early diagnosis and, hopefully, treatment. The main purpose of this study is to determine which, if any, MEG and DWI variables allow for an early differentiation of subjects with SCD or MCI who will show a worse cognitive evolution.MethodWe studied 64 Spanish individuals (age 71,44 ± 4,74), fourteen of which were diagnosed with MCI. The remaining 50 participants did not exhibit any objective neuropsychological impairment, but presented subjective cognitive complaints and were thus categorised as SCD. Participants were followed longitudinally and evaluated at two points in time approximately 3 years apart. All participants underwent a neuropsychological evaluation, a MEG scan, and a magnetic resonance imaging scan. From these scans, we calculated: functional connectivity, power spectrums, fractional anisotropy, and mean diffusivity values. The resulting values were used as predictors of the cognitive change experienced in episodic memory by means of a stepwise general linear model.ResultWe found an optimal predictive model (R2 = 0,500; p < 0,01) consisting of variables such as the alpha power in the left inferior parietal lobe (β = 15,387) and the mean diffusivity of the left cingulate part of the cingulum bundle (β = 149,720).ConclusionThis region and tract have been previously reported to play a role in episodic memory, supporting the evidence that their functional or structural affectation could be an early marker of neuronal deterioration and disease progression.
Sex differences in associations between brain microstructure and cognitive aging
Authors: Reas Emilie T , Hagler Donald J , Lee Ronald R , Dale Anders M , McEvoy Linda K 
Published: December 2020

AbstractBackgroundCytoarchitectural brain changes during normal aging remain poorly characterized, with further uncertainty whether patterns of brain aging underlying cognitive dysfunction differ by sex. Prior studies have demonstrated that the diffusion MRI technique restriction spectrum imaging (RSI) predicts cognitive decline and pathology in Alzheimer’s disease (Reas et al., 2017,2018,2019), but sensitivity of RSI to typical brain aging has not been assessed.MethodThis study used RSI to examine sex differences in associations of brain microstructure with age and cognition in community‐dwelling participants of the Rancho Bernardo Study. Ninety women and 57 men aged 56‐99 completed RSI and cognitive assessment (global cognitive function, executive function, verbal memory, visual memory, logical memory). RSI metrics of restricted, hindered, and free water diffusion were computed in cortical gray matter, hippocampus, and white matter fibers. Sex‐specific correlations assessed associations of RSI with age and with cognitive function. Mediation analyses examined whether RSI measures mediated effects of age on cognitive performance.ResultAge‐related increases in free water, and decreases in measures thought to reflect intraneurite (restricted) and extraneurite (hindered) diffusion, and neurite complexity, were observed throughout gray matter and fibers. Associations remained after adjusting for cortical thinning, and regional associations emerged after adjustment for global microstructure. Associations of microstructure with age and with cognitive function were stronger and more widespread for women than men. Adjustment for age attenuated RSI‐cognition correlations for both sexes, as well as sex differences in these associations. Microstructure partially mediated effects of age on cognitive performance for men and women. Whereas age more strongly correlated with RSI and cognitive measures for women, RSI measures more strongly mediated age effects on cognitive function for men.ConclusionMicrostructural brain changes, which may reflect cell shrinkage, demyelination, axonal and dendritic loss, or reduced neurite complexity, occur with typical aging and correlate with performance in multiple cognitive domains. Age‐related microstructural injury is more pronounced for women, and patterns by which microstructure mediates cognitive aging differ by sex. Normal aging may be accompanied by cytoarchitectural damage that underlies cognitive decline, and the mechanisms by which age‐related neural injury impairs cognitive function may differ between men and women.
Demographics and brain models variably predict cognition in an ethnoracially diverse sample by cohort
Authors: Gannon Bethany Kaye Amele , Fletcher Evan M 
Published: December 2020

AbstractBackgroundConsiderable heterogeneity in cognitive trajectories has been well documented in studies of older individuals from diverse samples, including minority communities. Such studies often have not included brain factors in their models. Modeling demographic factors and neuroimaging brain data as predictors of cognition in a diverse sample set is crucial to further delineate differences in associations to cognitive outcomes by ethnoracial cohort.MethodFour ethnoracial cohorts of older participants with variable baseline cognitive statuses were sampled from the UC Davis Aging and Diversity Cohort (Table 1). We modeled cognitive baseline and change outcomes for episodic verbal memory and executive function, using predictors consisting of demographic and brain variables in an ethnoracially diverse sample. Brain measures were brain gray and white matter signatures of cognition (Fig. 1a, b) and white matter hyperintensity burden (WMH) at baseline. For longitudinal, we retained the WM measures but used signature atrophy regions of cognitive change. We hypothesized that distinct profiles of predictor variables might emerge by ethnoracial group.ResultTable 2 presents an overview of our model fit by R2 metric across all four ethnoracial groups. Baseline fits were higher for non‐white ethnoracial groups than for Whites. Longitudinal fits were similarly high for all cohorts having sufficient data. Table 3a, b reveals varying explanatory profiles for baseline predictors. For non‐brain variables, education was most consistently significant, with others also significant in several models. Brain GM was consistently significant except in Asians; meanwhile WM signatures were significant only in Asians. In longitudinal models (Table 4a, b) brain tissue atrophy was most consistently significant, along with WM measures among Whites. No non‐brain variables were significant.ConclusionOur findings support baseline ethnoracial variability expressed in our initial hypothesis, while also suggesting that brain GM and tissue atrophy measures may be strong predictors regardless of cohort. Education is frequently significant across cohorts at baseline, consistent with existing research. GM baseline and tissue atrophy are consistent predictors except in Asians, contrasting our hypothesis. WM factors vary by cohortgrouping, exhibiting significance in Asians and Whites, suggesting ethnoracial profile differences in support of our hypothesis and requiring further research.
Structural MRI changes in a two‐year follow‐up in subjective cognitive decline
Authors: Bubbico Giovanna , Lauriola Mariella , Minerva Michele , Iorio Angelo DI , Esposito Roberto , Perrucci Mauro Gianni , Tartaro Armando 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) is a state in which a subjectively perceived decline in cognition appears in the absence of an objective decline detected by neuropsychological tests. It tends to occur at the late phase of preclinical AD and has been proposed as a pre‐MCI stage (Rabin et al., 2017). Hippocampal atrophy is a well‐known feature of AD (Halliday, 2017).MethodBrain morphometry was observed in a 2‐years follow‐up. Participants were assigned to the SCD or non‐SCD group according to the SCD research criteria: SCD‐Q score ≥7 was classified as SCD (Rami et al., 2014). Among seventy community‐ dwelling individuals who had been enrolled at baseline (Lauriola et al., 2017), thirty‐five (64.6 ±5.6 y, 15M/20F) took‐part in the follow‐up phase. All participants underwent complete neuropsychological battery and a 3T Structural Magnetic Resonance Imaging (MRI) examination (Philips Achieva X Series). High‐resolution structural images were acquired through a 3D magnetization‐prepared rapid acquisition gradient echo sequence: matrix 256 × 256, field of view 240 × 240 × 170 mm, slice thickness 1 mm, no gaps, in‐plane voxel size 1 mm × 1 mm, flip angle 12°, repetition time = 8.2 ms, echo time = 3.8 ms. Structural T1‐weighted images were processed using FSL software (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki, version 6.0). Gray matter differences were assessed with VBM (voxel‐based morphometry), as implemented in FSL (FMRIB Software Library v6.0).ResultSignificant differences (p=0.03, corrected for multiple comparison) were observed between SCD and non‐SCD partecipants in the hippocampus global total intracranial normalized volume (TIV). Atrophy maps on hippocampal areas showed major involvement of the para‐hippocampal region, of the left mesial temporal lobe (Fig. 1).ConclusionSCD hippocampal volumetry reduction might be considered a negative prognostic finding as a potential prelude to an evolution in early dementia.
Plasma microRNA vary in association with the progression of Alzheimer’s disease
Authors: Guévremont Diane , Tsui Helen , Knight Robert , Fowler Christopher J , Masters Colin L , Martins Ralph N , Abraham Wickliffe C , Tate Warren P , Cutfield Nick , Williams Joanna M ,   Australian Imaging, Biomarkers and Lifestyle (AIBL) Research Group
Published: December 2020

AbstractBackgroundEarly intervention in Alzheimer’s disease (AD) requires development of an easily administered test able to identify those at risk. Focusing on microRNA robustly detected in plasma and standardizing the analysis, we sought to identify disease‐stage specific biomarkers.MethodUsing TaqMan microfluidics arrays and a statistical consensus approach, we assessed plasma levels of 182 neurodegeneration‐related microRNA, in cohorts of amyloid‐positive, mild cognitive impairment and AD participants, relative to their respective controls.ResultPlasma microRNA were shown to be dynamically altered with AD progression. Distinct disease stage microRNA biomarkers were identified, and these were shown to predict membership of the groups (AUC >0.8). Bioinformatics demonstrated that these microRNA target known AD‐related pathways. Furthermore, a significant correlation was found between three microRNA and amyloid‐ß load.ConclusionOur results show that microRNA signatures alter during the progression of AD, relate to the underlying disease pathology and may prove to be useful diagnostic markers.
What’s in a name? Semantic, as well as episodic, memory plays an important role in the diagnostic sensitivity of the free and cued selective reminding test in MCI
Authors: Colvin Mary K. , Daly Maureen , Laffer Alexandra , Sherman Janet C. 
Published: December 2020

AbstractBackgroundThe Free and Cued Selective Reminding Test (FCSRT) is highly sensitive in the detection of AD, even at early stages (Grober, et al., 2008; Papp et al., 2015; Slachevsky et al., 2018). By controlling encoding and retrieval, the task is especially sensitive to memory consolidation deficits that characterize AD. During the learning phase, patients name items that are paired with semantic cues aimed to boost encoding and retrieval. However, benefit from the semantic cues requires intact semantic memory and access. As the “cognitive signature” of AD includes reduced semantic processing (Henry and Crawford, 2004.), we asked whether this reduction impacts FCRST performance.Method170 patients (M
age=74.1±6.2, M
edu=16±3.0; 57% male) clinically referred for neuropsychological evaluation to address cognitive decline completed the FCSRT and semantic access measures, the Boston Naming Test (BNT) and semantic (animal) fluency. Neuropsychologists independently and blindly assigned diagnosis specifying NCD severity (Mild v. Major) and type (amnestic v. non‐amnestic). To determine the impact of semantic processing on FCRST performance we examined whether naming accuracy (NA): (1) differed between patient groups on first FCSRT learning trial; (2) was impacted by item prototypicality, 3) was predicted by BNT and semantic fluency performances, and (4) predicted subsequent FCSRT performance (total free, and total cued recall accuracy).ResultSs included 50 Mild NCD, amnestic; 59 Mild NCD, non‐amnestic; 23 Major NCD, amnestic; and 38 Major NCD, non‐amnestic. NA on the first FCSRT learning trial was higher for Mild than Major NCD and non‐amnestic than amnestic patients without severity x type interaction. Across all groups: NA was predicted by BNT (p < .05) and semantic fluency (p < .05), and was better for high than for low prototypicality items. Also across all groups, NA predicted subsequent memory for the items, including total free recall accuracy (p < .001) and total cued recall accuracy (p < .001).ConclusionThe diagnostic sensitivity of the FCSRT in AD is likely impacted not only by reduced episodic memory but also by reduced semantic memory and access. Understanding what underlies the sensitivity of the FCSRT may ultimately help improve the detection of early cognitive changes in AD.
A qualitative study of the experiences of male and female spousal and adult children caregivers across the caregiving trajectory
Authors: Kokorelias Kristina Marie , Gignac Monique AM , Naglie Gary , Rittenberg Nira , Cameron Jill I 
Published: December 2020

AbstractBackgroundCaregiving is not static and changes across the illness trajectory. Our first research objective was to determine phases of caregiving throughout the Alzheimer’s disease trajectory. Our second objective was to explore the similarities and differences in the experiences of male and female adult children and spousal caregivers to persons with Alzheimer’s disease over time.MethodWe applied a constructivist grounded theory approach to data collection and analysis. Forty spousal (10 husbands+ 10 wives) and adult children (10 sons+ 10 daughters) caregivers to persons with Alzheimer’s disease were recruited and interviewed using a semi‐structured interview guide.ResultWe identified 5 phases reflecting caregiving roles related to: 1) monitoring initial symptoms, 2) navigating diagnosis, 3) assisting with instrumental activities of daily living, 4) assisting with basic activities of daily living, and 5) preparing for the future. We were not able to identify any differences by gender or relationship in the caregiving phases. However, our results suggest that when looking at the experiences of caregiving from a gender‐and‐relationship lens experiences across the phases become complex and variable. For instance, spousal caregivers approach a dementia diagnosis with denial, with wives being optimistic for a slow progression of the disease for long periods of time. Adult children caregivers are concerned about the ways the caregiving role will impact their personal and career obligations and seek ways to mitigate the changes to their daily lives. Male caregivers largely utilize home and community health services to assist with personal care tasks whereas female caregivers utilize the same services to allow them to complete other caregiving tasks.ConclusionWe identified five distinct phases of caregiving and revealed that gender and relationship influence caregiving experiences across the Alzheimer’s disease trajectory. Recognition of the differential impact of gender and relationship on caregiving can inform future intervention efforts by suggesting ways to tailor interventions based upon gender and/or relationship to best support caregivers.
APOE genotype, sex, and ovariectomy influence anxiety‐like behaviors in an EFAD mouse model of Alzheimer’s disease
Authors: Philippi Sarah M , Taxier Lisa R , York Jason , LaDu Mary Jo , Frick Karyn M 
Published: December 2020

AbstractBackgroundBehavioral changes accompanying the cognitive decline associated with Alzheimer’s disease (AD) are a growing concern. Symptoms of anxiety occur in 50‐75% of AD patients and increase throughout disease progression (Gustavson and Cummings, 2004; de Toledo et al., 2004). APOE4 genotype, the leading genetic risk factor for AD, may influence symptoms of anxiety in AD patients. Women APOE4 carriers are at greatest risk of developing AD, perhaps due in part to estrogen loss after menopause. However, contributions of APOE4 genotype, sex, and estrogen loss to anxiety in AD remain unclear.MethodEffects of APOE status, sex, and ovariectomy (OVX) on anxiety‐like behaviors in an open field were measured. First, effects of sex and APOE genotype were examined in gonadally‐intact transgenic male and female mice expressing 5 familial AD mutations (5xFAD+/‐) and human APOE3
+/+ (E3FAD) or APOE4
+/+ (E4FAD). We next examined effects of APOE genotype and OVX in female EFADs. Mice were trained in object recognition (OR) and object placement (OP) tasks. Anxiety‐like behaviors were measured using open field (OF) data collected during the first habituation trial of OR or OP testing, during which mice had 5 minutes to explore an empty box (60 cm x 60 cm x 47 cm). Total distance traveled, average speed, and time spent in the center of the apparatus were measured.ResultSex influenced total distance and average speed, such that females traveled further at faster speeds than males. Only APOE genotype affected the time spent in the center of the OF apparatus, with E3FADs spending more time in the center than E4FADs, regardless of sex. OVXed E3FADs exhibited similar anxiety‐like behaviors as both intact and ovariectomized E4FADs.ConclusionE3FADs spent more time in the center of an OF than E4FADs of both sexes, suggesting an association between APOE4 and increased anxiety‐like behavior. OVX increased anxiety‐like behaviors in E3FADs to similar levels observed in intact and OVXed E4FADs, suggesting that the loss of estrogens in E3FAD females heightens anxiety‐like behaviors. These findings suggest significant interactions among APOE genotype, sex, and estrogens that may influence the incidence of anxiety in women with AD.