bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amygdalar pathology in early neuropsychiatric phenotypes due to 3R‐Pick disease
Authors: Keszycki Rachel M , Kawles Allegra , Minogue Grace , Zouridakis Antonia , Macomber Alyssa , Lubbat Vivienne , Coventry Christina , Rogalski Emily J , Weintraub Sandra , Flanagan Margaret E , Castellani Rudolph J , Mesulam Marsel , Geula Changiz , Gefen Tamar 
Published: December 2023

AbstractBackgroundPersons with dementia syndromes such as primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD) often develop neuropsychiatric symptoms (NPS). Various neurodegenerative diseases may cause PPA or bvFTD, including frontotemporal lobar degeneration (FTLD) with 3‐repeat tau pathology (Pick disease, “PiD”). Limbic regions implicated in mood and behavior, such as the amygdala, are highly impacted in FTLD with PiD. This study quantified Pick bodies and activated microglia in the amygdala of individuals with antemortem diagnosis of PPA or bvFTD and postmortem PiD neuropathology and examined associations with initial NPS.MethodWe identified 16 right‐handed cases from the Northwestern University Alzheimer’s Disease Research Center brain bank with bvFTD (N = 8) or PPA (N = 8) due to PiD with unilateral amygdala tissue (basolateral region) available. Fifteen cases had data on 12 NPS assessed via the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q) from their earliest visit. We performed AT‐8 or HLA‐DR immunohistochemistry on amygdala sections to visualize Pick bodies or HLA‐DR+ activated microglia, respectively. We quantified the density of Pick bodies per mm3 via modified unbiased stereology and used HALO software (Indica Labs) to quantify percent area of HLA‐DR immunopositivity. We assessed differences between clinical groups via Welch’s t‐test (Pick bodies) or repeated‐measures two‐way ANOVA (HLA‐DR). Pearson clinicopathologic correlations were examined between Pick bodies or HLA‐DR immunopositivity and initial endorsement of total (out of 12) or behavioral/comportmental (apathy, disinhibition, motor stereotypies, or appetite disturbance) NPI‐Q symptoms.ResultAmygdalar Pick body densities were similar between PPA (M = 28,822/mm3) and bvFTD (M = 29,114/mm3) cases. Compared to bvFTD, PPA cases trended towards a lower percent area of HLA‐DR immunopositivity (5.54% vs. 2.39%, p<0.10). There was no significant relationship between Pick Body density and initial NPIQ symptoms endorsed across all cases. However, area of HLA‐DR immunopositivity was positively correlated with initial endorsement of total (r = 0.47, p<0.10) and behavioral/comportmental (r = 0.54, p<0.05) NPI‐Q symptoms.ConclusionOur findings suggest that microglial pathology in the amygdala contributes to early neuropsychiatric presentations in PiD, particularly symptoms reflective of behavioral/comportmental disturbance. Future study will investigate the impact of neuronal size and density in the amygdala on NPS in these dementia syndromes due to PiD.
Investigating the interplay between age and apolipoprotein E
Authors: Liu Jun , Ulm Brittany , Bonnechère Bruno , Nevado‐Holgado Alejo J , Amin Najaf , Van Duijn Cornelia M 
Published: December 2023

AbstractBackgroundAge is the major driver of dementia and aging is considered to be an independent, causal risk factor of dementia and Alzheimer’s disease (AD). We have examined whether the effect of age on dementia and AD is modified by genetic risk factors including the apolipoprotein E gene (APOE).MethodWe studied 204113 participants of the UK biobank who were over age 37 years at baseline (mean 64 years, SD=2.85) and were followed up with for dementia over time (mean 10.2 years). The study is based on 4,578 patients with dementia, including 1,741 with Alzheimer disease. We investigated whether APOE and other genes implicated in dementia modified the effect of age on dementia and AD. To study the effect of the other genes, a genetic risk score (GRS) was constructed for the genes other than APOE based on Bellenguez et al. Those in the highest and lowest quintile were compared across four APOE genotype groups (APOE22/23, APOE33, APOE34/APOE24, and APOE44).ResultThe effect of age on the risk in all dementia and AD differed significantly between carriers of the APOE44 and APOE24/34 and non‐APOE*4 carrier (APOE33 and APOE22/23) groups. Within the APOE44 genotype, the effect of age on the risk of dementia also differed significantly between those in the highest and lowest quintile of the GRS. In APOE24/34 carriers, a similar pattern was seen. In APOE22/23 carriers, we found that the association between age and dementia and AD does not differ between those in highest and lowest quintile of the GRS.ConclusionIn UK Biobank, the association between age and the risk of dementia and AD is modified by APOE genotype and other genetic risk factors. Our data show that calendar age by itself is not a sufficient cause of dementia or AD but that the effect of age is conditional of the person’s APOE genotype and other genetic risk factors.Bellenguez C, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022 Apr;54(4):412‐436. doi: 10.1038/s41588‐022‐01024‐z.
Insulin family receptors (IR and IGF‐IR) in astrocytes exert different Alzheimer’s‐like pathology and effects on behavior
Authors: Zegarra‐Valdivia Jonathan Adrian , Fernandes Jansen , Aleman Ignacio Torres 
Published: December 2023

AbstractBackgroundPleiotropic actions of insulin and insulin‐like growth factor I (IGF‐I) in the brain are context‐ and cell‐dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF‐I receptor (IGF‐IR), respectively), is less clear.MethodsWe compared mice lacking IR or IGF‐IR in glial fibrillary astrocytic protein (GFAP)‐expressing astrocytes in a tamoxifen‐regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons.ResultsWe observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross‐bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF‐IR in GFAP astrocytes (GFAP‐IGF‐IR KO mice) show cognitive disturbances, maintained mood tone, and show control‐dependent changes in AD‐like pathology.ConclusionsThese observations confirm that the role of IR and IGF‐IR in the brain is cell‐specific and context‐dependent.
The Early Detection of Neurodegenerative diseases initiative: emerging insights from the initial implementation of a digital toolkit
Authors: Whitfield Tim , Bhogal Sharandeep , Wing Kieran , Bond Simon , Morrell Rachel , Bass Nicholas , Chouliaras Leonidas , Wilson Sarah , Beswick Emily , Slight Sarah , Everson Richard , Hinds Chris , Chan Dennis , Llewellyn David J , Walker Zuzana ,   The Early Detection of Neurodegenerative diseases (EDoN) initiative
Published: December 2023

AbstractBackgroundThe benefits of the early detection of the neurodegenerative and vascular pathologies which cause dementia are widely acknowledged. These include the opportunity to initiate risk‐reduction strategies, disease‐modifying therapies, and future care planning. However, current pathological biomarkers have several important drawbacks, as they are typically invasive, expensive, impractical, insensitive, or lack real‐world validation. Conversely, the targeted utilization of non‐invasive and inexpensive digital technologies which can be integrated into everyday life raises the possibility of capturing a ‘digital‐fingerprint’ of early disease.MethodThe Early Detection of Neurodegenerative diseases (EDoN) initiative is a meta‐cohort study spearheaded by Alzheimer’s Research UK. EDoN is acquiring high‐dimensional data from a ‘digital toolkit’ comprising a smartwatch (Fitbit Charge 4/5), smartphone software (Mezurio and Longevity), and an electroencephalography headband (Dreem 3). In combination with conventional digital, cognitive and biological markers, these data will inform the development of powerful machine learning models to detect dementia‐causing diseases at the very earliest stages. The initial phase, incorporating four cohorts across three continents, is already underway, and will recruit nearly 900 participants. Cohorts are recruiting healthy individuals, as well as patients with subjective/mild cognitive impairment, or established dementia. Data from version‐1 of the toolkit is being collected over two‐week periods at 3‐monthly intervals for a minimum of 12 months.ResultWe will present early insights from the implementation of the EDoN digital toolkit version‐1. These will include sample characteristics, feasibility and acceptability, and participants’ compliance. PPI data confirmed good acceptability but the potential for inequity due to technical problems and poor digital literacy. Pilot data indicate that six‐month adherence to the EDoN digital tools varies between 82‐89%. The forthcoming AAIC presentation will include important recruitment, toolkit acceptability and analytic updates.ConclusionThe initial implementation of the EDoN digital toolkit suggests that it is feasible and acceptable to collect high‐dimensional digital data over a six‐month period. These ‘digital‐fingerprints’ will form the basis of the initial development of machine learning models to identify dementia‐causing pathologies substantially earlier. The insights gained will also inform the development of version‐2 of the EDoN digital toolkit which will be incorporated into the next meta‐cohort prospective study of around 4,000 participants.
Relationship of peripheral inflammation and discrimination with memory: a study of Black and Latinx middle‐aged adults
Authors: Seblova Dominika , Higgins Cesar , Mazen Jessica , Starks Tiara M. , Kraal A. Zarina , Turney Indira C , Adkins‐Jackson Paris AJ , Elyaman Wassim , Bradshaw Elizabeth M , Brickman Adam M. , Manly Jennifer J. 
Published: December 2023

AbstractBackgroundMinoritized groups experience higher stress due to structural racism and discrimination. These exposures have been linked to lower cognitive test scores and inflammation is a potential biological pathway underlying this association. Yet studies with multiple inflammatory markers in diverse populations remain limited.MethodWe assessed 635 community‐dwelling adults (mean age = 54.5, SD = 11; 66% women; 67% Latinx, 33% non‐Latinx Black) from the Offspring Cohort. We characterized peripheral inflammation using principal component analysis on 33 serum inflammatory markers. Discrimination was ascertained by the Everyday and Major Discrimination Scales. Episodic memory was measured using the Selective Reminding Test and working memory by the Digit Span Test. Linear models stratified by racialized/ethnic group tested the cross‐sectional relationship between inflammation and memory adjusting for age, sex, and diabetes. Further, we examined if relationship between discrimination and memory (adjusted for age, gender, and education) was attenuated when inflammation was added. Due to smaller sample size, the magnitude of associations corresponding to change in cognitive score associated with >1 year of chronological age, rather than statistical significance, was used to highlight important associations.ResultTwo inflammatory factors were derived, with component 1 including FGF2, Fractalkine, GM‐CSF, IFNg, IL13, MCP3, TNFa, and TNFb, and Component 2 including IFNa2, IL1b, IL1ra, IL5, IL9, and MIP1a. Among Spanish‐speaking participants racialized as Latinx, both inflammatory factors were associated with lower memory scores. Only the first factor was associated with lower memory for English‐speaking participants racialized as Latinx. For participants racialized as Black, only the second factor associated with lower memory. Among Spanish‐speaking Latinx, Everyday Discrimination was associated with lower working memory. Everyday Discrimination was associated with lower episodic memory among Black respondents; this association was attenuated by 20% with inclusion of the inflammatory factor 1 in the models. Several associations that were opposite to hypothesized relationships were observed.ConclusionElevated peripheral inflammation was associated with worse memory among individuals racialized as Black and Latinx. Our results indicate peripheral inflammation may contribute to disparities in cognition and may be one of the ways in which disadvantage due to structural racism and discrimination is embodied among minoritized groups in the United States.
Psychometric evaluation of the Everyday Discrimination Scale in KHANDLE
Authors: Deters Kacie D , Medina Luis Daniel , Corrada María M. M. , Pa Judy , Tommet Douglas , Vila‐Castelar Clara , Tsoy Elena , Gilsanz Paola , Whitmer Rachel A. , Mungas Dan M. 
Published: December 2023

AbstractBackgroundStructural racism manifests in differential experiences of everyday discrimination for racialized and minoritized groups. The Everyday Discrimination Scale (EDS) assesses subjective experiences of unfair treatment in everyday social situations. The goal of this study is to evaluate the psychometric performance of the EDS within racialized groups and specifically to evaluate if the EDS measures a unidimensional construct.MethodData was from a diverse sample of community‐dwelling older adults in Northern California (N = 1,590 participants) from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study (Non‐Hispanic (NH) Black = 411; NH Asian = 380; NH white = 477; LatinX = 322). The EDS is a 9‐item scale with six response categories that range from “almost everyday” to “never”. The EDS was administered to each participant at baseline. We used confirmatory factor analysis to evaluate unidimensionality in the combined sample and in the 4 racialized subgroups. We identified model modifications that improved fit in a random 50% subsample of each group and tested fit of the modified model in the other random 50%.ResultLoadings for all items on the main factor were > 0.50 for each racialized group and for the full sample. There were issues with model fit with the full sample, which were improved when residual correlations were set between items “courtesy” and “respect” and between “insult” and “threat”. Cross‐validated model fit was improved after adding these parameters to the model and was best in groups racialized as Black and LatinX (Table 1).ConclusionThe EDS is a commonly used assessment in aging studies purporting to capture effects of discrimination on a variety of health and psychosocial outcomes. Our study show that all EDS items are strongly associated with underlying construct of discrimination in all groups, though differentially. Further work is needed to determine if the identified residual correlations point to additional factors that are important to measure. Model fit suggests the EDS is better suited to capture discrimination in groups racialized as Black and LatinX groups, which is consistent with the development of the scale. This study expands the literature by carefully examining the measurement properties of the EDS among four racialized groups.
Protective effects of gestational folic acid and egg yolk powder solution intubation on motor coordination, anxiety, cognition, acetylcholinesterase activity and DNA fragmentation in prenatal alcohol exposed rats
Authors: Obajuluwa Adejoke Olukayode , Iyiola Oluyinka , Morakinyo Joseph Akintade , Obajuluwa Tiwalola Madoc 
Published: December 2023

AbstractBackgroundDevelopment of neurobehavioural disorders can occur in the postnatal life of foetuses prenatally exposed to alcohol, regardless of the alcohol type consumed during pregnancy. Hence, the need to investigate the efficacy of proposed pharmaco‐nutritional therapy in mediating potential behavioural and cholinergic impairments in prenatal alcohol exposed (PAE) fetuses.MethodWe investigated whether PAE exacerbates anxiety, motor coordination, cognitive function, cerebral cortex acetylcholinesterase (ACh) activity, DNA fragmentation and assessed associations among parental and PAE rats’ cerebral cortex ACh activity. Thirty female Wistar rats were mated in the following groups (n = 6): 1: Negative control (distilled water only), 2: Positive control (40% EtOH), 3: local gin (LG), 4: local gin+egg yolk solution(LGEY) 5: local gin +egg yolk solution+folic acid(LGEYFA). Statistical significance of obtained data was measured at p<0.05 using regression model, ANOVA and Tukey’s PostHoc tests (GraphPad 5).ResultWhen compared to the negative control, all alcohol groups (supplemented or not) had significantly lower latency of fall, working memory, percentage alternation etc. Although the brain weight of PAE rats in group 2 (positive control) did not change significantly (p = 0.159), critically reduced brain weights seen in group 3 (LG, p<0.001) were normalized in the supplemented groups (4‐LGEY and 5‐LGE). Cortex protein levels was unchanged in all maternal rats regardless of alcohol intubation. However, ACh cerebral cortex activity was significantly reduced in PAE rats from non‐supplemented groups (2 and 3). Necrosis and fragmentation were also seen in agarose gel electrophoregram (AGE) of gDNA isolated from PAE rats’ brain.ConclusionPrenatal alcohol exposure predisposes to severe neurobehavioural and cognitive deficits while gestational folic acid+egg yolk solution may be a therapeutic target for high risk PAE pregnancies.
The dirt under the rug: prevalence and adverse outcomes associated with undiagnosed dementia during hospitalizations
Authors: Aliberti Márlon Juliano Romero , Avelino‐Silva Thiago J , Covinsky Kenneth E , Silva Vinicius B. O. , Suemoto Claudia Kimie ,   CHANGE Study Group
Published: December 2023

AbstractBackgroundWhile dementia affects about 40% of older people admitted to hospitals and requires adaptations in acute care, many cases remain undiagnosed. Nevertheless, the occurrence and consequences of undiagnosed dementia during hospitalizations have received little attention. We estimated the prevalence and adverse outcomes associated with undiagnosed dementia in hospitals.MethodWe used data from the CHANGE Study, an ongoing cohort of people aged 65 years and older admitted to 21 acute hospitals throughout Brazil. Participants underwent comprehensive assessments on admission. Previous dementia diagnosis was determined by reviewing hospital records and asking patients and families. Trained investigators also completed the Clinical Dementia Rating (CDR) with family informants, using the patients’ cognitive status three months before admission as the reference, avoiding possible effects of acute cognitive impairments. Combining clinical history and CDR scores, we defined patients as: without dementia (no previous diagnosis and CDR = 0), with diagnosed dementia (previous diagnosis and CDR ≥1), and with undiagnosed dementia (no previous diagnosis and CDR ≥1). We investigated whether patients with undiagnosed dementia were associated with prolonged stays, delirium (brief‐CAM on admission + CHART‐DEL assessments at discharge), and mortality in hospitals than those without dementia and those with diagnosed dementia using Poisson regression models adjusted for age, sex, race/ethnicity, education, Charlson comorbidity index, and study center.ResultWe included 736 patients (mean age = 81±8 years; women = 62%; non‐White = 44%). We observed that 230 (27%) had diagnosed dementia, but 122 (14%) had undiagnosed dementia, meaning that 35% of patients with preexisting dementia were undiagnosed. During hospitalizations with a median of 9 days (interquartile range = 5; 19), 317 (43%) presented delirium at some point, and 119 (16%) died. Patients with undiagnosed dementia were associated with more prolonged stays, higher delirium occurrence, and mortality in hospitals than those without dementia (Figure 1). Comparing diagnosed and undiagnosed dementia, we found similar risks of delirium and mortality, but patients with undiagnosed dementia had more prolonged stays (Figure 2).ConclusionOne in three hospitalized older adults with dementia in Brazil had not been diagnosed before admission. Hospital providers should be attentive to identifying patients with undiagnosed dementia and be aware that they might present worse outcomes.
Predicting change in depressive symptoms using longitudinal regional amyloid and cognition in cognitively unimpaired older adults
Authors: Munro Catherine E , Farrell Michelle E. , Hanseeuw Bernard J , Rentz Dorene M. , Buckley Rachel F. , Properzi Michael J , Vannini Patrizia , Amariglio Rebecca E. , Quiroz Yakeel T. , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Marshall Gad A , Gatchel Jennifer 
Published: December 2023

AbstractBackgroundDepression is a neuropsychiatric symptom of Alzheimer’s disease (AD) and has been linked to greater cortical amyloid burden in preclinical AD. We sought to examine whether amyloid accumulation in brain regions subserving emotional control and changes in cognitive performance may contribute to increased depressive symptomatology over time.Method155 cognitively unimpaired participants who were below the cortical amyloid (<0.86DVR) and clinical depression thresholds (<12 on Geriatric Depression Scale (GDS); mean age = 72.6) at baseline were included from the Harvard Aging Brain Study, with annual GDS and Preclinical Alzheimer Cognitive Composite (PACC) assessment and MRI/PiB‐PET every three years (mean years follow‐up = 7.06). PiB slopes were calculated for FreeSurfer‐defined bilateral regions of interest (ROI) implicated in emotional control: amygdala, medial and lateral orbitofrontal cortices (mOFC, lOFC), superior and middle frontal (MFC) cortices, anterior cingulate (ACC), posterior cingulate (PCC), and isthmus cingulate (IC). Linear mixed‐effects models assessed whether main‐effects of ROI PiB slope and PACC slope predicted longitudinal GDS scores for each ROI, covarying for age, sex, education, and random intercept/slope, adjusted for multiple comparisons. Post‐hoc linear regression models assessed relationships between PiB and PACC slopes.ResultSteeper PiB slopes in the mOFC, MFC, ACC, and IC were associated with increasing GDS scores over time, while a decreasing PACC slope was predictive of increasing GDS scores over time in all regions (Table 1). Post‐hoc analyses indicated that PiB slopes were not significantly correlated with PACC slope (Figure 1).ConclusionIn a cohort of cognitively unimpaired older adults with low cortical amyloid and no/subclinical depressive symptoms at baseline, increasing depressive symptoms over time were significantly associated with both amyloid accumulation in specific regions associated with emotional control (i.e., mOFC, MFC, ACC, and IC) and worsening cognitive performance. Furthermore, changes in cognition were not significantly associated with changes in amyloid accumulation in regions involved in emotional control, suggesting that different factors may be independently influencing trajectories in depression versus cognition over time. These results shed light on the neurobiology of depression in older individuals and underscore the importance of monitoring new and increasing neuropsychiatric symptoms in addition to cognitive symptoms when screening for AD.