bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Moringa oleifera‐supplemented diets on cognition, neurochemicals, and inflammation makers in the Brain diabetic‐encephalopathic rats treated with Acarbose
Authors: Oyeleye Idowu Sunday , Oboh Ganiyu , Ijomone Omamuyovwi
Published: January 2025

Background

The progression of diabetes mellitus (DM) has been associated with changes in brain structure and function, often referred to as “diabetic encephalopathy,” which is characterized by cognitive and neurochemical dysfunction, and identifiable structural changes in brain imaging. This study investigated the effect of Moringa leaf‐supplemented diets (MLSD) on cognition, acetylcholinesterase (AChE), adenosine deaminase (ADA) and arginase activities, reactive oxygen species (ROS), total‐thiol (T‐SH), inflammatory cytokines (TNF‐α, NF‐κB, IL‐6, and IL‐10) levels, caspase‐3 expression, and nuclear factor erythroid 2–related factor‐2 (Nrf2) levels in the brain of DM rats treated with 25 mg/kg bwt acarbose (ACA).

Method

The normal control (NC) rats and diabetic rats were grouped as follows: NC rats, untreated DM rats, DM rats plus ACA, DM rats plus ACA and 2% MLSD, and DM rats plus ACA and 4% MLSD. The NC, DM, and DM plus ACA rats were fed basal diets (i.e., without test samples), while other groups received the corresponding test samples for 28 days. On the last day, cognitive function was assessed using the Morris water Maze and Y‐maze tests. AChE, ADA, ROS, T‐SH levels, TNF‐α, NF‐κB, IL‐6, IL‐10, caspase‐3 expression, and nuclear factor erythroid 2–related factor 2 (Nrf2) levels were measured in the brain.

Result

The untreated DM rats had altered cognition, increased ROS, TNF‐, NF‐B, and IL‐6, caspase‐3 expression and NrF2 levels, and AChE, ADA, and arginase activities, but decreased T‐SH and IL‐10 levels when compared to the NC group. These, however, were reversed in DM rats fed MLSD but were highly significant in DM rats co‐treated with MLSD plus ACA.

Conclusion

The findings suggested that a combination of MLSD plus ACA could be explored to combat DM‐induced cognitive dysfunction
“They are perceived to be witches, and some are killed”: Community perceptions of elderly people living with Dementia in Kilifi, A Costal County in Kenya
Authors: Aballa Andrew Okoth , Khakali Linda N , Njoroge Willie , Kamau Lucy Wambui , Shah Jasmit N , Blackmon Karen , Udeh‐Momoh Chi , Nesic‐Taylor Olivera , Merali Zul , Bosire Edna N
Published: January 2025

Background

Population growth and an increase in the number of Africans who survive to old age puts them at a higher risk of developing neurodegenerative diseases such as dementia and Alzheimer’s. Little research has been conducted on community knowledge and perceptions of dementia in rural settings in Kenya.

Method

Community health volunteers, healthcare workers (HCWs), chiefs and assistant chiefs (n = 35) participated in five focus group discussions, each comprising seven‐ eight people. Key informant interviews (n = 25) were conducted with HCWs, County managers, community leaders and gatekeepers such as chiefs, traditional healers, and faith healers. Audio recordings were transcribed verbatim and thematic analysis used to extract themes.

Result

Four main themes identified included: (a) understanding of dementia (b) perceived causes of dementia (c) community perceptions of dementia (d) threats exposed to elderly people suspected of having dementia. Community members did not understand the word “Dementia”. They used a local word “Kusahau sahau” meaning forgetfulness to describe dementia. People with dementia were labelled using stigmatizing words such as “Uendawazimu‐ (madness”, “craziness”), or elderly with “child‐like behavior.” Dementia was perceived as a natural process of aging not requiring intervention. Witchcraftcurses, depression, trauma, substance abuse and HIV/AIDS were other factors attributed to dementia. Limited understanding of dementia led to isolation, neglect, sometimes killing of those suspected to have dementia with the assumptions they were witches.

Conclusion

There is poor community understanding of dementia in rural areas of Kenya increasing stigma and discrimination for people with dementia. Retrogressive beliefs and myths predispose people with dementia to neglect, social exclusion, and violent attacks. Social and medical support programs for people with dementia and culturally acceptable tools for quickly diagnosing dementia are lacking. There is need for more research on dementia and Alzheimer’s disease, community awareness creation and policy development aimed to protect elderly populations living with Dementia.
Loneliness as a Predictor of Cognitive Decline in Older Adults: Insights from a Measurement Burst Design Using the Einstein Aging Study
Authors: Kang Jee Eun , Sliwinski Martin J. , Oravecz Zita , Engeland Christopher G. , Katz Mindy J. , Graham‐Engeland Jennifer E.
Published: January 2025

Background

Loneliness is linked with risk for cognitive decline and dementia among older adults, but the degree to which it predicts future risk is unclear. To investigate if loneliness acts as a predictor of cognitive decline, this study employed a measurement burst design using data from the Einstein Aging Study, where loneliness and cognition were repeatedly assessed daily, for several days, across several years. In this type of data, a major challenge to detecting subtle cognitive changes is the presence of retest/practice effects. We employed a novel process modeling approach (Bayesian Double Exponential Model; BDEM) to distinguish retest learning effects from genuine longitudinal cognitive changes.

Method

Participants (n = 313; English‐speaking, community‐residing adults aged ≥70) underwent up to six waves of annual assessments. Each wave included a 16‐day ambulatory ecological momentary assessment (EMA) burst on mobile phones. Ambulatory assessments consisted of self‐report (including a question about feeling lonely now) and cognitive tests, conducted multiple times daily. This study analyzed the spatial working memory task.

Cognitive parameters capturing retest learning rate, peak performance (disentangled from retest learning) and long‐term changes in peak performance were estimated simultaneously using the BDEM. Regression analyses examined associations between mean and standard deviation (SD) of EMA loneliness at baseline and cognitive markers, controlling for demographics and mild cognitive impairment (MCI) status at baseline.

Result

A higher mean and a higher variability (SD) of EMA loneliness at baseline predicted higher baseline asymptotic (peak) performance, suggesting worse peak cognitive performance at baseline. However, neither mean level nor variability of EMA loneliness at baseline predicted changes in peak performance after baseline. Notably, a higher variability of EMA loneliness was also associated with slower learning rates from repeated testing across bursts.

Conclusion

This study reveals that the level and variability of loneliness in daily life, measured in near‐real time, predict concurrent peak performance and long‐term learning rates in working memory among older adults. Results, particularly regarding loneliness variability, suggest that the experience of loneliness has implications for long‐term learning rates. Not only the mean level of loneliness, but also variations in loneliness, have separate predictive value for cognitive performance over time.
Mediation of Physical Activity Patterns between Whiter Matter Microstructure Alteration and Cognitive Decline According to the Progression of Alzheimer's Disease
Authors: Kim Narae , Roh Hyun Woong , Son Sang Joon , Park Bumhee
Published: January 2025

Background

We aimed to clarify the role of physical activity patterns on cognitive function decline caused by white matter structure alteration following the progression of Alzheimer’s disease(AD). Physical activity has been reported as having a close association with various pathological factor of dementia, especially it has been proved as a protective factor of disease advancement. Comparing the mediating models between Mild Cognitive Impairment (MCI) and AD, we aspire to elucidate how activity patterns, as a biomarker, undergo progression in the pathogenesis of the disease.

Method

Data from Biobank Innovation for chronic Cerebrovascular disease With ALZheimer’s disease Study (BICWALZS, N=131, 93 females, age = 71.66 ± 7.51) were used and we divided the cohort into three subtype groups of dementia; MCI with Amyloid beta negative(MCI‐), MCI with Amyloid beta positive(MCI+) and AD. Fractional Anisotropy (FA) was extracted from 48 regions as defined at JHU atlas and 6 activity pattern parameters (L5, M10, IS, IV, kRA, kAR) were calculated. Mediation analysis was conducted regional FA values as a predictor, a standardized score of Mini‐Mental State Examination as a response variable and the physical activity parameters as a mediator for each group separately.

Result

We found significant mediation effect in the MCI+ group after adjusting age, sex, and education year (FDR corrected P < 0.05). 20 white matter regions showed significant mediation effect with mean physical activity intensity during most active 10 hours (M10) and 24 regions showed significant mediation effect of Intraday variability (IV). Although there was similar result in AD group, but the only one region showed, and the effect size of mediation path was quite small. There was not any significant result in the MCI‐ group.

Conclusion

Summing up, these results can be interpreted as that the protective effects of physical activity on the cognitive decline caused by white matter alteration is far larger to patient with amyloid deposition and the effects can be decreased after the onset of AD. Therefore, enhancing physical activity patterns can be an effective strategy to slow down the progression of the disease, particularly in amyloid‐positive patients, prior to the onset of AD.
Sex differences in the association between amygdala volumes and non‐emotional memory retrieval performance
Authors: Esiaka Darlingtina , Willis Emily , Broster Lucas , Powell David K , Jicha Gregory A , Jiang Yang
Published: January 2025

Background

Past studies show that amygdala atrophy may be involved in the early stages of Alzheimer's disease (AD). AD is characterized by progressive cognitive decline, and changes in the amygdala—interconnected with various brain regions involved in cognition—could contribute to memory and emotional processing impairments. Specifically, changes in amygdala volumes may affect these neural networks, contributing to cognitive decline through disrupted communication between brain regions. The present study tests the association between amygdala volumes and non‐emotional memory retrieval and the sex differences in the association.

Method

Participants (mage= 77.05, SD = 7.48; 25 females) from the University of Kentucky Alzheimer’s Disease Center cohort completed two trials of delayed match to sample task inside the 3T Siemens magnetic resonance imaging scanner.

Result

We found that increased volume in the left hippocampus (p < .05, r = .31) and left amygdala (p < .05, r = .30) were associated with faster non‐match distractor response times (RTs) in the second trial. The result further shows significant sex differences whereby there was a significant negative association between the left hippocampus volume and RTs of non‐match distractors in the first trial (r = .40, p < .05) in females but not in males. Also, in females, the left amygdala volume had a significant positive association with accuracy (R2 = .40, p < .05) and a negative association with RTs of non‐match distractors for both trials (Trial 1: r = .43, p < .05; Trial 2: r = .47, p < .05).

Conclusion

Investigating correlations between amygdala volumes and non‐emotional memory retrieval has implications for understanding cognitive processes, identifying markers of neurological disorders, addressing individual differences, and advancing both clinical and basic neuroscience research.
Multimodal Perspective on the Influence of Physical Activity on Alzheimer’s Disease
Authors: Haeger Alexa , Romanzetti Sandro , Hohenfeld Christian , David Shari , Costa Ana Sofia , Haberl Luisa , Hildebrand Frank , Schulz Jörg B. , Reetz Kathrin
Published: January 2025

Background

Physical exercise presents a viable low‐cost, low‐risk, individual, and widely available non‐pharmacological treatment candidate in cognitive decline such as in Alzheimer’s disease (AD). There are even indications that it can reduce the risk of developing dementia in the first place (Livingston et al., The Lancet, 2020). However, the impact of physical activity and fitness on the multimodal facets of AD, encompassing brain function, cognition and metabolism is still poorly understood.

Method

In the Dementia‐MOVE pilot trial (Multi‐Objective Validation of Exercise), 46 patients diagnosed with Alzheimer’s disease were initially included, randomized to either an intervention arm comprising a 6 months‐supervised sports program or a control condition with a psychoeducational program at the RWTH Aachen University Hospital. Participants underwent a comprehensive multimodal assessment of AD relevant parameters, including multimodal MRI, fitness and activity, neuropsychological assessments, blood examinations and the assessments of neuropsychiatric symptoms (Haeger et al., Alzheimers’s & Dementia TRCI, 2020).

Result

In the intervention group, cardiorespiratory fitness change, i.e. ΔVO2max, showed a positive association with changes in the Montreal Cognitive Assessment (MoCA), in the executive functions score, and in volumes of the temporal lobe. It also showed a negative correlation with baseline cognitive levels (see also Figure 1 on the multiple regression analysis). High physical activity levels were associated with improved quality of life in the overall sample. In functional MRI using resting state and graph theory (n = 20 subjects), we found prediction by ΔVO2max for changes on the degree, betweenness, triangles, transitivity, hubness, closeness and Katz centrality, with the last showing the most effects in regions in the temporal lobe. Metabolic MRI comprising 23Na‐MRI and 31P‐MRS pointed to possible associations of VO2max and/or group attribution with changes in brain sodium concentrations/cerebral metabolites.

Conclusion

We show that cardiorespiratory fitness and physical activity examined during an intervention with physical activity can have an impact on different aspects of AD, from cognition, to structural, functional, and metabolic brain alterations. Our results suggest that even patients who are more severely affected by the disease could benefit from interventions in these domains.
Hepatic fat is related to neurodegeneration in midlife obesity
Authors: Kasani Sara Hosseinzadeh , Dolatshahi Mahsa , Naghashzadeh Mahshid , Commean Paul K. , Rahmani Farzaneh , Liu Jingxia , Lloyd LaKisha , Nguyen Caitlyn , Hantler Nancy , McBee‐Kemper Abby , Ly Maria , Yu Gary Z , Ippolito Joseph E. , Weeks Jake , Ceriani Lael , Sirlin Claude , Morris John C. , Benzinger Tammie L.S. , Raji Cyrus A.
Published: January 2025

Background

Obesity in midlife, defined as body mass index (BMI) of 30 kg/m2 or higher in those between 40‐60 years, is related to higher Alzheimer’s disease (AD) later in life. Non‐alcoholic fatty liver disease, as a complication of obesity is associated with impaired cognitive function. We investigated the relationship between hepatic fat quantification by use of MRI‐derived Positron Density Fat Fraction (PDFF) and brain cortical thickness in cognitively normal midlife individuals.

Method

Overall, 63 cognitively normal middle‐aged participants (Age: 50.46±6.19 years, female: 22 (71%), obesity: 32 (50.28 %), BMI: 36.46±4.9 kg/m2) underwent brain and abdominal 3T MRI. PDFF values were calculated using a trained U‐Net convolutional neural network (CNN) model to infer the hepatic PDFF maps from conventional T1‐weighted images. The CNN included the Adam optimizer for training with a learning rate of 1e‐4. Visceral and subcutaneous adipose tissue (VAT, SAT) were automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas, followed by visual inspection and if needed, manual editing. A multivariable linear regression analysis was carried out to test the association of PDFF, VAT, SAT, and BMI with brain cortical thickness, with age and sex as covariates.

Result

We observed a statistically significant association between PDFF and VAT (p=3e‐7), BMI (p=2e‐4), and insulin resistance (1e‐4). Among late‐onset AD (LOAD) cortical regions, there was a significant inverse correlation (Adjusted R²=0.19, p<0.001) between left temporal pole thickness and PDFF. Similarly, higher VAT was associated with thinning in left temporal pole (Adjusted R²=0.22, p<0.001) and middle temporal lobe (Adjusted R²=0.12, p=0.014).

Conclusion

Overall, our data suggest a potential role of hepatic fat fraction in promoting neurodegeneration in cognitively normal midlife individuals. These findings lend insight into a pathway that can be utilized for future AD risk reduction.
Multisite Chronic Pain Accelerates Cognitive Decline Particularly in APOE e4 Allele Carriers
Authors: Bell Tyler R. , Franz Carol E. , Lerman Imanuel , Fennema‐Notestine Christine , Panizzon Matthew S. , Bennett David A. , Elman Jeremy A. , Kremen William S.
Published: January 2025

Background

Chronic pain is a predictor of cognitive decline and dementia, but whether risk is related to a specific site of pain versus multisite pain is unclear. Multisite chronic pain is theorized to involve hyper‐excitability in pain receptors and pain‐processing brain regions, possibly caused by neuroinflammation. These factors may increase vulnerability to cognitive decline, particularly in those at elevated risk for Alzheimer’s disease. We examined how multisite chronic pain relates to cognitive decline in older adults, the possible moderating role of APOE‐ε4 allele status, and—in a postmortem subsample—associations with amyloid and tau.

Method

We examined 751 participants without dementia at baseline from the Religious Orders Study/Rush Memory and Aging Project (ROSMAP; Mean age = 79.47, SD = 6.93, Mean education = 6.42, SD = 3.63; 64% women) followed for up to 30 years with repeated cognitive testing measuring episodic memory, working memory, perceptual orientation, and processing speed (Mean years followed = 7.32, SD = 4.51). Individuals with multisite chronic pain, defined as joint pain in >2 body regions over the first 2 study waves, were compared to those without pain. Amyloid‐beta and tau were measured in a postmortem subsample assessed around 10 months after their last clinical evaluation using computer‐assisted immunoreactivity assays across 8 regions associated with Alzheimer’s disease (hippocampus; entorhinal cortex; midfrontal cortex; inferior temporal; angular gyrus; calcarine cortex; anterior cingulate cortex; superior frontal cortex

Result

Multisite chronic pain (n = 105) was associated with accelerated decline in episodic memory (b = ‐.03, p = .016) and processing speed (b = ‐.06, p<.001), particularly in APOE‐ε4‐positive individuals (bs = ‐.05 and ‐.04, respectively, ps<.01). Only APOE‐ε4‐positive individuals with multisite chronic pain showed significant decline in perceptual orientation (b = ‐.08, p = .015). Only APOE‐ε4‐positive individuals with multisite chronic pain had higher levels of amyloid‐beta load compared to those without chronic pain (b = .51, p<.001). No differences in tau burden were detected. People with single‐site chronic pain showed no significant differences from people without chronic pain.

Conclusion

The results suggest that multisite chronic pain exacerbates cognitive decline, particularly in those at genetic risk for Alzheimer’s disease. In addition, the postmortem analyses suggest that early treatment of multisite chronic pain—a modifiable risk factor—might help to reduce amyloid accumulation.
Does attachment get under our skin? Midlife attachment style predicts mild cognitive impairment and cumulative deficit frailty in old age
Authors: Buchholz Erik , Franz Carol E. ,   Vietnam Era Twin Study of Aging (VETSA) group
Published: January 2025

Background

Poor social relations of older adults have been linked to cognitive decline, dementia risk, morbidity and mortality. However, this history of poor social relations may have started earlier in life and may be related to personality traits. Here we investigate how attachment style, a personality trait, can function as a protective factor for Alzheimer’s Disease and overall health. Specifically, we evaluated whether attachment style at midlife predicted two types of frailty in early old age: cognitive frailty and cumulative deficit frailty. Furthermore, to better understand these pathways, we have investigated several mediators: perceived stress, smoking, alcohol consumption, doctor visits, and social isolation.

Method

Participants were 1275 community‐dwelling men from the Vietnam Era Twin Study of Aging (VETSA) at average ages 56, 62, and 68. Attachment style was assessed at age 56, health mediators at age 62. Frailty at age 68 included cognitive frailty (operationalized as mild cognitive impairment; MCI) and cumulative deficit frailty, a frailty index (FI) comprising 37 items assessing multiple physiological systems. Structural Equation Modeling (SEM) assessed mediators between attachment style and FI/MCI.

Result

Age 56 attachment avoidance predicted age 68 MCI (β = 0.132); attachment anxiety predicted age 68 FI (β = 0.179). In mediation models, age 62 social isolation mediated associations between attachment avoidance (β = 0.169) and FI (β = 0.192). Attachment avoidance directly predicted MCI (β = 0.134). Age 62 perceived stress, doctor visits, and smoking acted as mediators between attachment anxiety (βs = 0.400, 0.069, 0.088, respectively) and FI (β = 0.284, 0.278, 0.134, respectively). Perceived stress mediated associations between attachment anxiety (β = 0.400) and MCI (β = 0.230). There was no direct effect of attachment anxiety on MCI.

Conclusion

Personality traits involving viewing others as trustworthy and dependable may function as protective factors against frailty in old age. Attachment avoidance and anxiety influence frailty through different pathways, such as social isolation compared to perceived stress and smoking. Thus, to mitigate risk for either cognitive or cumulative deficit frailty, clinicians may wish to evaluate personality characteristics related to the quality of interpersonal relationships (e.g., attachment style) in addition to health factors.
Associations of education and modifiable lifestyle factors with CSF biomarkers of neurodegeneration, neuroinflammation, and Alzheimer’s disease
Authors: Planalp Beth M. , Hulle Carol A. Van , Bendlin Barbara B. , Blennow Kaj , Quijano‐Rubio Clara , Engelman Corinne D. , Kollmorgen Gwendlyn , Ma Yue , Okonkwo Ozioma C , Carlsson Cynthia M. , Johnson Sterling C. , Zetterberg Henrik , Merten Natascha
Published: January 2025

Background

Alzheimer’s disease (AD) and related dementias can have long preclinical phases; thus, midlife intervention and prevention methods could prove efficacious. Multiple health‐related lifestyle factors have been associated with risk for AD. However, research on lifestyle factors has focused on clinical outcomes such as cognitive decline, mild cognitive impairment and/or AD dementia; their associations with potential early changes in cerebrospinal fluid (CSF) biomarkers are less understood. Our aim was to determine whether key lifestyle factors are associated with CSF biomarkers for neurodegeneration, glial activation, and neuroinflammation.

Method

Participants were N=653 adults (aged 43—93 years) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center, two on‐going, longitudinal studies of preclinical AD. We assessed CSF biomarkers using the NeuroToolKit (NTK), a panel of robust prototype biomarker assays (Roche Diagnostics International, Switzerland). Participants completed demographic and health questionnaires and a physical assessment (Table 1). Linear regression models assessed standardized effects of associations between lifestyle factors (education, smoking, obesity, and physical activity) and CSF biomarkers, adjusting for age and sex.

Result

After correcting for false discovery rate, preliminary results (Table 2) showed that participants with more years of education had higher CSF Aβ42/40 and lower pTau181 concentrations (Est. = 0.006, or 1 unit increase in Aβ42/40 per year increase in education, 95% confidence interval: 0.001–0.011; p =.008, adjusted p = .061; Est.= ‐0.007, or 1 unit decrease in pTau181 per year increase in education, 95% confidence interval: ‐0.013–‐0.002; p=.026, adjusted p=.061). No other biomarker associations withstood correction for multiple comparisons.

Conclusion

Education has been discussed as an early modifiable risk factor for AD, likely through a mechanism of cognitive resilience. We found that higher education was associated with less AD proteinopathy (e.g. better Ab42/40 and pTau181 profiles). Future studies should explore the potential underlying mechanisms for this association. Longer follow‐up will help to understand how these findings relate to biomarker levels and cognitive changes at a later stage of disease progression.
Association of Chronic pain with Alzheimer’s‐related brain structure and plasma biomarkers in older men
Authors: Bell Tyler R. , Franz Carol E. , Fennema‐Notestine Christine , Panizzon Matthew S. , Lyons Michael J. , Elman Jeremy A. , Kremen William S.
Published: January 2025

Background

Chronic pain leads to tau accumulation and hippocampal atrophy in mice. Tau accumulation in the locus coeruleus (LC) precedes medial temporal accumulation in humans. Here we provide one of the first human studies examining the association of chronic pain with hippocampal volume, LC integrity, and Alzheimer’s Disease (AD)‐related plasma biomarkers. We predicted associations with rostral‐middle, but not caudal, LC because the former is more aging‐ and Alzheimer’s‐related.

Method

Data were from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) at average ages 56, 62, and 68. Chronic pain was defined as moderate‐to‐severe pain occurring >2 waves. At wave 3, 424 participants (mean age = 67.06) underwent LC‐sensitive MRI scans from which we calculated an LC contrast‐to‐noise ratio (LCCNR), an index of LC integrity. We measured hippocampal volume with traditional structural MRI. At wave 3, biomarkers were obtained from fasting blood draws taken the morning of the medical interview and cognitive testing, typically a day prior to the MRI exam. Immunoassays calculated levels of plasma total tau, beta‐amyloid (Aβ) 40, Aβ42, Aβ42/Aβ40 ratio, and neurofilament light (NfL). All biomarkers were log‐transformed and adjusted for site and storage time. Analyses accounted age, major health conditions, depressive symptoms, and opioid use.

Result

Men with chronic pain had smaller hippocampal volume (β=‐0.24, p=.039) and lower rostral‐middle LCCNR (β=‐0.38, p=.004) but not caudal LCCNR (p=.750). Men with chronic pain also had higher levels of plasma total tau (β=‐0.32, p=.047), Aβ42 (β=.42, p=.033), and Aβ40 (β=.31, p=.032) compared to men without chronic pain. However, men with chronic pain did not differ from men without chronic pain on Aβ42/Aβ40 ratio (p=.979) or NfL (p=.313).

Conclusion

Extending the animal model, these findings suggest that chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected very early in the development of AD. Increases in individual Aβ measures associated among those with chronic pain but lack of association with the Aβ42/Aβ40 ratio may reflect non‐AD‐specific health‐related factors rather than brain amyloid, or alternatively, might be due to the relatively young age of the sample or the sensitivity of the assay.
Analyzing Attention Focus in the Cookie TheftPicture Description Task Using Word Alignment
Authors: Favaro Anna , Thebaud Thomas , Dehak Najim , Butala Ankur , Oh Esther S , Moro‐Velazquez Laureano
Published: January 2025

Background

Visuospatial problems are one of the possible signs of Alzheimer’s Disease (AD). Notably, various studies on eye movement in static image searches reveal that individuals with dementia fixate on fewer Areas of Interest (AoIs) for a significantly shorter duration than normal controls (CTLs). Building on prior works on speech and eye movement, in this study we examined word timestamps to infer each subject’s focus of attention while describing the Cookie Theft picture. Namely, we computed various interpretable features encoding attention focus and compared them across different neurological disorders.

Method

Cookie Theft Picture description tasks were recorded from subjects with AD (n=20), Parkinson’s Disease (PD) (n=43), Parkinson’s disease mimics (PDM) (n=16), and CTLs (n=33). First, speech transcriptions and word timestamps were generated using WhisperX automatic speech recognizer. The following features were then computed using word timestamps: time spent in the AoIs, time to approach the first AoI, number of visits to the AoIs, transition time from one AoI to another, and time elapsed between the first and last AoI mentioned. Features were computed considering all the animate AoIs, all the inanimate AoIs, and all AoIs collectively. Completed the feature extraction, non‐parametric pair‐wise Mann‐Whitney U tests of significance were conducted to determine whether there were significant differences between experimental groups for each feature. To control the False Discovery Rate, we applied the Benjamini–Hochberg correction.

Result

Results from the statistical analysis showed that subjects with AD reported a significantly fewer number of visits to the AoIs and a shorter amount of time spent on inanimate external AoIs than CTLs. The AD group also reported a greater variability in the transition time from one AoI to another. Moreover, the PDM group spent significantly more time (on average) than the PD group on animate AoIs but reported a fewer number of visits to inanimate AoIs located internally to the house than PDs.

Conclusion

Our preliminary analysis confirmed the difficulties of subjects with cognitive decline to voluntarily direct attention to central cues and maintain attention focus on given AoIs. Our future work will include eye‐tracking technology to analyze the relationship between attention focus from speech and eye movement.
The unique contribution of tau pathology in the amygdala to depressive symptoms in cognitively normal older adults
Authors: Markova Teodora Z. , Fonseca Corrina S. , Ciampa Claire J. , Murphy Alice , Landau Susan M. , Harrison Theresa M. , Jagust William J. , Berry Anne S.
Published: January 2025

Background

Although most PET imaging studies have focused on entorhinal cortex as an early site of medial temporal lobe tau accumulation, the amygdala displays substantial tau deposition in cognitively normal individuals. We examined amygdala tau in relation to changes in affective health that often precede Alzheimer’s disease (AD).

Methods

We ran parallel analyses in non‐depressed, cognitively normal older adults from ADNI (60‐91 years) and the Berkeley Aging Cohort Study (BACS, 60‐96 years). Participants in both cohorts had cross‐sectional and longitudinal tau PET scans, Aβ status, APOE ε4 status, longitudinal Geriatric Depression Scale (GDS) scores, longitudinal memory performance, and longitudinal non‐memory cognition composites. Longitudinal slopes reflecting changes over time were calculated using linear mixed effects models. Group‐level differences in amygdala tau were established using ANCOVAs (adjusting for age), and multiple linear regressions tested direct and interactive effects between tau and Aβ/APOE/sex.

Results

Compared to non‐carriers, APOE ε4 carriers had higher levels of amygdala tau in ADNI (F(1,371)=18.81, p<.001) and BACS (F(1,124)=3.70, p=.057, marginal), as did Aβ positive individuals compared to negative (ADNI F(1,404)=34.25, p<.001, BACS F(1,128)=8.14, p=.005). APOE ε4 carriers also had greater longitudinal increases in amygdala tau in ADNI (ADNI F(1,155)=10.26, p=.002, BACS F(1,71)=2.48, p=.120), as did Aβ positive individuals in both samples (ADNI F(1,157)=11.53, p<.001, BACS F(1,72)=5.85, p=.018, Figure 1). There were no direct relationships between amygdala tau and longitudinal GDS in ADNI (cross‐sectional t(344)=0.65, p=.520, longitudinal t(152)=‐0.87, p=.384) or BACS (cross‐sectional t(127)=0.44, p=.661, longitudinal t(71)=0.44, p=.661). In APOE ε4 carriers, higher baseline amygdala tau predicted worsening GDS in ADNI (t(320) = 2.43, p = .016), while longitudinal amygdala tau predicted worsening GDS in BACS (t(64) = 2.34, p = .022, Figure 2). Results remained significant with adjustments for entorhinal tau or entorhinal tau slopes, respectively. Neither Ab status nor sex predicted GDS change, and amygdala tau did not predict memory or non‐memory change in either sample.

Conclusions

These results demonstrate relationships between amygdala tau pathology and depressive symptoms that are related to APOE genotype, but are independent of the effects of entorhinal tau alone. Given the nuanced effects observed, future research in understanding amygdala tau accumulation is critical.
Validation of Remote Neuropsychological Testing with the California Cognitive Assessment Battery (CCAB)
Authors: Baldo Juliana , Lwi Sandy J. , Herron Timothy J , Chok Jas M. , Curran Brian , Spinelli Maria G , Santavicca Isabella , Thomas Lexie , Schendel Krista , Hall Kathleen , Geraci Kristin , Blank Michael , Pebler Peter , Woods David L.
Published: January 2025

Background

Paper‐and‐pencil neuropsychological tests have traditionally been considered the “gold standard” for clinical testing in AD/ADRD, but they have significant limitations: They are time‐consuming, costly to administer, vulnerable to examiner bias and error, and unavailable to some patients due to location, transportation challenges, and cost. Manual tests also fail to comprehensively analyze many aspects of test performance. Computerized neuropsychological test batteries have been developed to address these shortcomings. However, most computerized tests cannot score verbal responses and correlate poorly with gold standard manual tests. In the current study, we evaluated the validity and reliability of a new computerized battery, the California Cognitive Assessment Battery (CCAB), which includes 15 non‐verbal and 17 verbal cognitive tests. The CCAB utilizes speech‐to‐text technology for automatic recording and scoring of patients’ verbal responses.

Method

85 healthy adults were tested remotely on the CCAB at home and were also assessed with traditional in‐person neuropsychological testing, in counterbalanced order. The in‐person neuropsychological battery included standardized, paper‐and‐pencil versions of the most widely used equivalent manual tests (e.g., CVLT, digit span, etc.). The CCAB was re‐administered to evaluate test‐retest reliability. Sessions lasted approximately 1.5 hours.

Results

Strong correlations were observed between the CCAB and traditional in‐person tests of episodic memory for word lists and face‐name recall (.60‐.73), working memory (.61‐.66), processing speed (.69), executive functioning (.63‐.71), and vocabulary (.82). Test‐retest reliability on the CCAB was also high across measures (.65‐.80).

Conclusion

The CCAB is a valid and reliable means of assessing cognitive functioning in remote settings: Correlations with traditional paper‐and‐pencil tests were strong and test‐retest reliability was robust. The CCAB provides comprehensive assessment with sensitive measures and state‐of‐the‐art technology, and it overcomes limitations of other computerized tools and also that of traditional testing by allowing for efficient, reliable, remote assessment of neuropsychological functioning that can address the critical need for longitudinal monitoring of individuals with AD/ADRD. Early diagnosis of dementia risk with accessible remote testing provides patients the best opportunity to take advantage of new treatment interventions that slow cognitive decline in AD/ADRD, which can prolong quality of life for patients and their families.
Comparing plasma Aβ42/40 and pTau217 to predict Amyloid‐β status across the Alzheimer’s disease continuum
Authors: Doecke James D. , Chenna Ahmed , Lo Mintzu , Badal Youssouf , Yee Brandon , Martone Robert L. , Petropoulos Christos , Fowler Christopher J , Laws Simon M. , Smith Stephanie Rainey , Martins Ralph N , Rowe Christopher C. , Masters Colin L , Winslow John W
Published: January 2025

Background

Recent advances in immunoassays have enabled sensitive detection of Aβ42/40 and pTau217 in plasma, components of Alzheimer’s disease (AD) neuropathological markers. Further characterization of increased diagnostic accuracy with PET Amyloid‐β (Aβ) across the AD continuum is needed for clinical application.

Method

Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing (N=197) representing a cross‐sectional population of four clinical and PET‐Aβ subgroups: cognitive unimpaired (CU) Aβ‐ (n=75), CU Aβ+ (n=48), mild cognitive impairment (MCI) Aβ+ (n=26), and AD Aβ+ (n=48). EDTA plasma was analyzed with Aβ42/40 (Quanterix Simoa & Fujirebio Lumipulse) and pTau217 (ALZpath Simoa & Lumipulse). Data were investigated using Cohen’s D for effect size, Receiver Operating Characteristic (ROC) analyses to define AUC values for PET‐Aβ positivity and Spearman’s Rho for correlation between biomarkers and Centiloid.

Result

Lower Lumipulse and Simoa plasma Aβ42/40 ratios were observed in Aβ+ vs Aβ‐ groups (p<0.0001; with effect size Cohen’s D indices = 1.39 and 1.07, respectively). Aβ42/40 ratios initially decreased with increasing amyloid PET Centiloid levels through the positivity threshold (25CL), levelling off with increasing Centiloid values across the disease continuum (Figure 1A). Highest effects sizes were seen for pTau217 when comparing Aβ+ vs Aβ‐ groups (p<0.0001; Cohen’s D: 1.54 [Simoa] and 1.49 [Lumipulse]), with stepwise increases per Centiloid group (Figure 1B). Biomarker AUC values to predict PET‐Aβ were highest for pTau217 in the complete sample compared with the CU sample (Simoa AUC: 0.947/0.906, Lumipulse AUC: 0.941/0.906). For the Aβ42/40 ratio, AUC values were higher in the CU group as compared with the complete sample (Lumipulse AUC: 0.896/0.889, Simoa AUC: 0.885/0.849 (Figure 1C). Adding in age, gender, and APOE ε4 allele status improved prediction of PET‐Aβ, with AUC values reaching 0.97 for pTau217 (Figure 1C). Correlations between biomarker and Centiloid were higher for pTau217 (Simoa: r=0.744 (Figure 1D), Lumipulse r=0.732) as compared with the Aβ42/40 ratio (Lumipulse r=‐0.509, Simoa r=‐0.462).

Conclusion

Sensitive assays for the Aβ42/40 ratio may be more appropriate to detect Aβ burden in CU participants while p‐Tau217 appears to be more accurate and has the highest effect size and AUC values to predict Aβ‐PET across the AD continuum.
Evaluation and Modification of the 10‐Item Short Form Communicative Participation Item Bank for Persons with Primary Progressive Aphasia and their Communication Partners
Authors: Fegter Ollie , Shaunfield Sara , Bona Matthew , Roberts Angela C , Rogalski Emily J
Published: January 2025

Background

Primary progressive aphasia (PPA) is a dementia syndrome characterized by language and communication impairments, with relative sparing of other cognitive domains. As a relatively rare dementia syndrome, there are few measures developed and validated for individuals with PPA. Development of outcome measures tailored to the communication experiences of persons with PPA (PwPPA) is critical for the accurate assessment of interventions success. The 10‐item Communicative Participation Item Bank (CPIB) has been used as a measure for communication participation in PPA. However, the CPIB was validated as a disorder‐agnostic measure and its content validity for PPA has not been evaluated. This study aims to evaluate the face and content validity of the 10‐item CPIB for PwPPA and their communication partners (CP).

Method

Cognitive interviews were conducted with participants (N = 12) who had previously completed the CPIB during the Communication Bridge 2 randomized controlled trial (NCT03371706) and with four participants unfamiliar with the CPIB. PwPPAs and CPs completed the CPIB during a semi‐structured interview assessing measure format, instructions, response options, item comprehension, and item relevance. To evaluate content validity, participants were asked open‐ended questions to elicit relevant communication participation experiences missing from the questionnaire. Closed‐ended responses (e.g., clarity, relevance) were tabulated, and open‐ended responses (e.g., item comprehension, missing content) were thematically analyzed. Summaries of measure format, instructions, and response options were generated, as well as item‐level findings regarding comprehension, relevance, and missing content.

Result

Both PwPPAs and CPs: a) considered the instructions to be clear (n = 16, 100%); b) recommended adding a fifth response option (e.g., “Somewhat; n = 11) to better represent the range of communication situations; c) reported all items except one (“persuade…to see a different point of view”) were relevant (n≥13; ≥81%, for 9 items); and d) talking on the phone was the most reported missing communicative participation situation (n = 12; 75%). Further, 3 participants reported talking over videochat, and 4 participants reported email/texting as missing. Results were similar between CPIB‐experienced and CPIB‐naïve participants.

Conclusion

Findings indicate that modifications to the 10‐item CPIB short form may be needed for use with PwPPA and their CPs to more fulsomely capture communication participation in PPA.
Association of frailty and neuropathology of neurodegenerative and brain vascular diseases
Authors: Soares Felipe Bozi , Leite Renata Elaine Paraizo , Grinberg Lea T. , Paes Vitor Ribeiro , Rodriguez Roberta Diehl , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Suemoto Claudia Kimie
Published: January 2025

Background

Frailty, characterized by increased physical vulnerability, is associated with a higher incidence and severity of cognitive impairment and also a higher burden of neurodegenerative and cerebrovascular diseases. This study investigates the association between frailty and neurodegenerative and cerebrovascular pathologies.

Method

Cross‐sectional analysis using clinical and neuropathological data from individuals aged 60 or older, enrolled in the Biobank for Aging Studies between 2004 and 2023. A 42‐item frailty index was constructed. Cognitive impairment was defined as a clinical dementia rating score (CDR) of 0.5 or over and participants were stratified according to cognitive status. Linear regression models, adjusting for age, sex, education and race, explored the association between frailty and neuropathology, including Alzheimer´s disease (AD), argyrophilic grain disease (AGD), Lewy‐type pathology (LBP), hippocampal sclerosis, cerebral amyloid angiopathy (CAA), lacunar infarcts, hyaline arteriosclerosis, TDP‐43 pathology and a neuropathological comorbidity score (NPC).

Results

We examined data from 1.343 subjects. The group with cognitive impairment was older, predominantly female, had lower education, a higher frailty index, and no race differences (Table 1). This group also exhibited a higher prevalence of all neuropathologies previously described (Table 2). In adjusted analyses, frailty was associated with AD Braak staging (β = 0.022, 95% CI=0.017; 0.028, p<0.001 ), CERAD score (β = 0.021, CI 95% = 0.013; 0.029 p<0.001), CAA (β = 0.065, 95% CI = 0.039; 0.092 p<0.001), LBD (β = 0.051, 95% CI = 0.027; 0.075 p<0.001), hippocampal sclerosis (β= 0.053, CI 95% = 0.008; 0.100 p=0.022), lacunar infarcts (β=0.071, CI 95%= 0.046; 0.097 p<0.001), siderocalcinosis (β=0.033, CI 95%= 0.015; 0.051 p<0.001), hyaline arteriosclerosis (β=0.065, CI 95%= 0.050‐0.081 p<0.001) and NPC score (Table 3) (β=0.032, CI 95%= 0.024; 0.040 p<0.001). Frailty was not associated with AGD and TDP‐43.

Conclusion

Frailty was associated with several neuropathological markers of neurodegenerative and cerebrovascular diseases. More studies are warranted to investigate how this association relates to relevant outcomes such as cognitive impairment.
Healthy Dietary Intake Diminishes the Effect of Vascular Pathology on Cognitive Performance in Older Adults
Authors: Bauer Christopher E. , Zachariou Valentinos , Pappas Colleen , Maillard Pauline , Caprihan Arvind , Satizabal Claudia L , Gold Brian T
Published: January 2025

Background

Cognitive reserve (CR) in the context of Alzheimer’s’ disease has been widely studied, yet less is known about how CR protects against vascular brain pathologies. Here, we explored whether dietary factors might attenuate the association between magnetic resonance imaging (MRI)‐derived vascular biomarkers and cognition.

Method

Seventy‐one older adults (ages 60‐85) were scanned using a 3‐Tesla MRI Siemens Magnetom Prisma at the University of Kentucky. Data from a 3D T1‐weighted sequence, a 3D fluid‐attenuated inversion recovery sequence, and a 126‐direction diffusion MRI sequence were acquired. The vascular biomarkers used [White Matter Hyperintensity Volume (WMHV), Free Water (FW), and Peak Width of Skeletonized Mean Diffusivity (PSMD)] were developed and validated through the MarkVCID consortium (https://markvcid.partners.org). WMHV was computed using a 4‐tissue segmentation model, mean FW in all white matter was calculated using a two‐compartment model, and PSMD was calculated as the difference between the 95th and 5th percentiles in white matter MD values. Grey matter volume (GMV; non‐vascular biomarker) and intracranial volume (ICV) were estimated using FreeSurfer. The “Newly Developed Antioxidant Nutrient Questionnaire” was used to quantify dietary‐intake for the preceding month. Nutrients were grouped into nutrition factors based on previous literature and factor analysis (Factor 1= representing fruits and vegetables; Factor 2= representing nuts, healthy oils, and fish; Factor 3= representing green tea). All participants completed the Montreal Cognitive Assessment (MoCA). Multivariate linear regression models tested whether dietary factors, vascular biomarkers, and/or their interaction (i.e. moderation) were associated with MoCA scores. All models controlled for age, sex, ICV, and education.

Result

There were no significant main effects of WMHV, FW, PSMD, or GMV on MoCA scores. However, Factor 2 (but not other factors) positively moderated all 3 vascular biomarkers [WMHV (β=0.309, p=0.009); FW (β=0.324, p=0.007); PSMD (β=0.354, p=0.008)] such that a negative association between vascular markers and MoCA scores was only present in those with low but not high Factor 2 intake (Figure 1). Factor 2 did not moderate the association between non‐vascular biomarkers (i.e. GMV) and MoCA scores.

Conclusion

Our results suggest that consuming more nuts, healthy oils, and fish may help protect against vascular contributions to cognitive impairment.