bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the validity of two memory markers for Alzheimer’s disease to detect Mild Cognitive Impairments in community‐dwelling older adults from southern Colombia
Authors: Parra‐Rodriguez Mario A , Gonzalez‐Hernandez Alfredis , Bonilla‐Santos Jasmin , Cala Dorian , Gonzalez‐Montealegre Rodrigo A
Published: January 2025

Background

Traditional neuropsychological assessments have proved insensitive to identify the preclinical stages of Alzheimer’s disease (AD). Such a barrier has proved more challenging when assessing individuals from underrepresented populations (Parra et al., 2018; 2020; 2022). Two memory tests have been proposed as promising to identify people at risk of AD preclinically (Costa et al., 2017; Forno et al., 2022). These are the Visual Short‐Term Memory Binding Test (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT). These tests have never been used together to assess individuals from low socioeconomic backgrounds in their communities. This was the aim of this study.

Method

We recruited a sample of 390 volunteers from different community settings in Southern Colombia. After applying the classical clinical criteria, 142 were classified as healthy controls (HC), and 248 received a diagnosis of mild cognitive impairment (MCI). Participants were subjected to a neuropsychological assessment using a standardized battery (Bonilla‐Santos et al., 2023) and the two memory markers for AD (i.e., VSTMBT and FCSRT). We compared groups using their background assessments and these novel memory markers. We also compared the accuracy of these tests to discriminate between cognitively unimpaired older adults and patients with MCI.

Result

Patients with MCI were younger [t(388) = 7.2, p <0.001], had fewer years of education [t(388) = 10.42, p <0.001], and, after controlling for age and education, showed the typical amnestic multidomain profile. The VSTMBT revealed a Group by Condition interaction [F(1,388) = 5.60, p = 0.018], whereby MCI patients had significantly larger deficits when processing bound information than individual features. The FCSRT significantly discriminated between patients and controls being free recall the most sensitive variable. None of these outcomes changed after controlling for education, sex, and comorbidities. ROC analysis revealed an AUC of 79% and 72% for the VSTMBT and FCSRT, respectively.

Conclusion

The VSTMBT and FCSRT proved sensitive to identifying older people with MCI who had not sought medical advice at the time of testing. These two screening tools are useful for detecting people at risk of AD in community settings of underserved populations.
Cognitive Profile Subgroups Among Non‐demented Older Adults and their Associations with AD Neuroimaging Measures
Authors: Hahn Alice M , Volk Heather E , Albert Marilyn S. , Soldan Anja ,   The BIOCARD Research Team
Published: January 2025

Background

Although it is well established that lower cognitive performance, on average, is associated with a greater risk of developing Alzheimer’s disease (AD) dementia, it is unclear whether distinct cognitively‐defined subgroups exist among non‐demented older adults and whether such profiles map onto distinct AD neuroimaging measure profiles.

Method

The sample consisted of 167 non‐demented older adults from the BIOCARD study with comprehensive neuropsychological and clinical evaluations, amyloid PET and brain MRI scans. The MRI measure included: global cortical volume in AD‐signature regions and a medial‐temporal lobe composite; resting‐state functional connectivity within 5 large‐scale cognitive networks; global white matter microstructure, index by fractional anisotropy (FA) and radial diffusion (RD) on DTI scans; and global white matter hyperintensity (WMH) volume on FLAIR scans. A latent profile analysis (LPA) identified cognitively defined subgroups using standardized scores of 8 cognitive tests that cover AD‐related domains (episodic memory, executive functions, working memory, semantic memory, language, visuospatial function, and attention). Multiple linear regression models tested the associations between the group membership and neuroimaging measures adjusting for age, sex, and education.

Result

The LPA identified a model with 3 subgroups as the best solution (AIC = 3515; BIC = ‐3605; ICL = ‐3642; BLRT p = 0.001). The groups primarily differed in terms of performance level: high (36%); average (53%); low (11%). Each group showed distinctive diagnosis composition: high ─ 100% cognitively normal (CN); average ─ 91% CN and 9% mild cognitive impairment (MCI); low ─ 61% CN and 39% MCI. Compared to the high performance group, the low performance group had significantly lower cortical volume in AD vulnerable regions, lower salience/ventral attention network functional connectivity, lower global white matter microstructural integrity, measured by FA and RD, and higher global WMH burden. Amyloid load was not associated with group membership.

Conclusion

Distinct subgroups defined by cognitive performance exist among non‐demented older adults that are related to AD neuroimaging measures. Evaluating cognitive profiles among non‐demented older individuals may help identify individuals at greatest risk for future cognitive decline.
A Model of Subjective Cognition in Older Adults: Correspondence of cognitive complaints with wellbeing, mood symptoms, and cognitive performance
Authors: Stites Shana D. , Kuz Carolyn , Van Geen Camilla , Scavilla Bob , Kable Joesph , Barber Sarah
Published: January 2025

Background

Beginning new Alzheimer’s disease (AD) treatments before AD symptoms are prominent would optimize the benefits of these disease slowing treatments. To accomplish this goal, clinicians must identify measures of early disease progression. As a step in doing this, we set out to characterize the relationships between cognitive complaints, wellbeing, cognitive performance, and metacognitive calibration in older adults in order to inform a model of cognition in typical older adults.

Method

Sample of 344 adults aged 65+ completed an online task. Cognitive complaints were assessed with 7 domains on the Memory Function Questionnaire (MFQ). Wellbeing was measured with ratings of overall wellbeing, health, satisfaction with daily life, anxiety, depression, and Future Time Perspective (FTP) scale. Cognitive performance was captured through reaction times and accuracy on Forward and Backward Digit Span (DS) tasks and accuracy on a Dot Matrix Task (DMT). Participants provided confidence ratings before and after the DMT. Metacognitive calibration (MCC) was operationalized as the difference between trial accuracy reaction time and global post‐DMT confidence ratings. Results reported are statistically significant at P<0.05 unless otherwise stated.

Results

Fewer cognitive complains, as indicated by higher reports on all 7 MFQ domains, were associated with better health, wellbeing, and satisfaction with daily life. Most domains (6 of 7) were associated with more expansive FTP, higher anxiety (5 of 7), lower depressive symptoms (7 of 7), higher post‐task confidence (4 of 7), and better MCC (4 of 7). For 89% of participants, confidence ratings either decreased or remained unchanged from before to after the DMT; in the full multivariable model, the group that had confidence increase after the DMT showed lower accuracy (logit = ‐3.71, 95%CI ‐5.80, ‐1.61). In the full multivariable model, the group with low MCC (more confident than quick) demonstrated worse DMT accuracy (logit = ‐1.91, 95%CI ‐3.37, ‐0.45) and worse backward DS performance (logit = 0.25, 95%CI ‐0.04, 0.54, p = 0.09) compared to the typical MCC group (confidence∼reaction time).

Conclusion

Cognitive complaints, wellbeing, cognitive performance, post‐task appraisals of confidence in task accuracy, and the consistency between perceptions and performance (metacognition) are useful constructs for informing a model of subjective cognition in typical older adults.
Acceptability and validity of a smartphone‐administered word list learning test, LILA, in cognitively unimpaired adults
Authors: Lim Yen Ying , Cummins Hannah , Bransby Lisa , Stellman Gabriel , Fredrickson Amy , Edgar Chris J. , Maruff Paul
Published: January 2025

Background

The International Shopping List Test (ISLT) is a rater‐administered verbal list learning test, sensitive to memory dysfunction in early Alzheimer’s disease (AD). This study examined the acceptability of a self‐administered ISLT (called LILA) in cognitively unimpaired (CU) middle‐aged and older adults. The validity of LILA was determined by the nature of ISLT learning curves and from examination of the effects of age.

Method

CU adults (n = 113) completed LILA on their own smartphone device in a remote, unsupervised setting (n = 113). The LILA app administered a novel ISLT, where a list of 12 shopping list items was read aurally through the speaker to the participant. Participants were required to recall, into the smartphone, as many words as they could remember. This immediate recall trial was repeated three times (T1‐3). After a 10‐minute delay, participants recalled as many of the 12 words as they could. LILA performance measures included, number of words recalled on each trial, and on the delayed recall trial.

Result

10% of participants (n = 11) failed to provide a response on at least one learning trial (T1 = 3, T2 = 2, T3 = 4, DR = 2), with this data excluded from subsequent analyses. All participants reported feeling highly (74%) or moderately (26%) confident about using a smartphone, and reported using their phone daily. Improvement in immediate recall, known to occur for the ISLT was observed for LILA (Fig 1). Lower LILA immediate recall scores were associated with older age and higher depressive symptomatology (Table 1), but not sex, education or anxiety symptoms. Lower scores on delayed recall was associated with male sex and lower years of education (Table 1), but not age or mood symptoms.

Conclusion

The very low rate of data loss indicates high acceptability of LILA in CU middle‐ and older‐aged adults. Validity of performance was indicated by the learning curves, which were qualitatively similar to those of the rater‐administered ISLT, and the effect of age on the immediate recall outcome. These data provide a strong foundation for future studies of the sensitivity of LILA to memory impairment in AD.
Age and Sex Impact Alzheimer’s Disease‐associated Plaques and Tangles in Down Syndrome
Authors: Andrews Elizabeth J. , Phelan Michael J. , Ngo Phong , Rosa Alexis De La , Gonzalez Freddy , Pascual Jesse R. , Wright Sierra , Buckley Rachel F. , Coughlan Gillian T , Kofler Julia , Ikonomovic Milos D , Lai Florence , Ances Beau , Handen Benjamin L , Christian Bradley T. , Mapstone Mark , Head Elizabeth
Published: January 2025

Background

The prevalence of Alzheimer’s disease (AD) pathologies in people with Down syndrome (DS) is nearly 100%. In DS, overexpression of APP (on chr21) is associated with increased production of amyloid beta (Aβ) and the formation of phosphorylated tau (ptau) tangles. In the general population, women exhibit higher burdens of ptau compared to age‐matched men with AD. We hypothesized that in DS women would have higher ptau levels compared to men, and that age would significantly correlate with the presence of neuropathology.

Methods

We examined 88 brains (frontal and occipital cortices) of people with DS (age 1‐39yr; M/F = 19/12) and DSAD (age 42‐61yr, M/F = 20/19) and age‐matched controls. Serial sections were immunostained for ptau (AT8) and Aβ (6E10) and quantified using annotated regions of interest from whole slide images in QuPath. Spearman rank correlations of load data were calculated, the Mann‐Whitney U test was used to compare men (n = 20) and women (n = 16) with DS. Mean positivity data was modeled using beta binomial regression in our cohort.

Results

When comparing neuropathology loads of DS individuals (age 40+), women show consistently higher median levels of Aβ and ptau. Differences were not statistically significant. Aβ and ptau were both significantly correlated with age in the grey matter of the frontal (Aβ: r = 0.76, p≤0.001; ptau: r = 0.72, p≤0.001) and occipital cortices (Aβ: r = 0.72, p≤0.001; ptau: r = 0.70, p≤0.001). Interestingly, the positive correlation with ptau and age within the occipital cortex appears to be stronger in women (R = 0.80, p≤0.0001) than in men (R = 0.71, p≤0.01). We were able to determine that AD pathology presents in the frontal cortex approximately 10 years earlier than the occipital cortex and increases exponentially after age 40.

Conclusion

These results suggest age significantly impacts AD pathology in DS, with neuropathologies presenting in the frontal cortex approximately 10 years earlier than the occipital. Trends indicate sex does appear to have an impact on these pathologies, particularly in the occipital cortex where ptau was found to have a stronger association with age in women. Collectively, this warrants further investigation on the impact of sex and age on AD neuropathology in DS and the contributing mechanisms.
Cerebellar and cerebral contributions to social inference impairments in early stages of Alzheimer’s disease
Authors: Chen Yu , McEachen Bailey A. , Syed Faatimah , Antoniou Rea , Rijpma Myrthe Gwen , Rosen Howard J. , Kramer Joel H. , Miller Bruce L. , Rankin Katherine P.
Published: January 2025

Background

Despite the prevalent belief that socioemotional processing remains mostly intact in the early stages of Alzheimer’s disease (AD), impaired Theory of Mind – the ability to understand and interpret others’ thoughts, beliefs, and feelings – has been observed in persons with AD. During everyday conversations, the high cognitive loading of socioemotional interactions may adversely impact the ability of persons with AD to identify emotions and read others’ intentions. This study aimed to investigate socioemotional perception capabilities in early‐stage AD and to determine whether cerebellar and cerebral integrity predicts performance on socioemotional perception tests.

Method

Fifty‐two individuals meeting McKhann criteria for probable AD syndrome and 52 healthy older controls were evaluated with the Awareness of Social Inference Test (TASIT) – Emotional Evaluation Test (EET) and Social Inference‐Enriched (SIE). These tests use videos of conversations to evaluate the ability to identify basic emotions and understand intentions in realistic everyday scenarios. The EET evaluates emotion reading and the SIE examines social inference understanding. We further conducted voxel‐based morphometry with participants’ earliest structural magnetic resonance imaging scans to identify the relationship of cerebellar and cerebral integrity with individual task performance (p<.05 for cerebellar, p<.0005 for cerebral associations, family wise error corrected).

Results

Patients with very early‐stage AD (Global Clinical Dementia Rating = 0.8±0.4) performed worse on both TASIT‐EET and TASIT‐SIE relative to healthy controls (p<.05). Subregions of the cerebellum including bilateral lobules I‐VI, VIIIa, VIIIb, IV, Crus I, II, and the vermis were associated with TASIT‐EET performance. The entire left cerebellar hemisphere, right lobules VI, VIIIa, IX, Crus I, and the vermis were implicated in TASIT‐SIE performance. Cortical subregions in networks involved in memory, semantic comprehension, salience, and socioemotional interpretation were associated with TASIT performance, with TASIT‐SIE more right lateralized.

Conclusion

These results clarify that in early‐stage AD, cerebellar involvement and its interaction with corresponding cerebral regions may play a more important role in socioemotional processing than previously appreciated. Specifically, left‐lateralized cerebellar and right‐lateralized cerebral damage predicted poorer social inference understanding in persons with AD. Their emotion reading, in contrast, involved cerebellar and cerebral hemispheres more bilaterally.
Acceptability and validity of the smartphone‐administered version of the Cogstate Brief Battery in middle‐aged and older adults of the Healthy Brain Project
Authors: Cummins Hannah , Bransby Lisa , Fredrickson Amy , Stellman Gabriel , Maruff Paul , Edgar Chris J. , Lim Yen Ying
Published: January 2025

Background

Remote and unsupervised administration of neuropsychological tests may increase opportunities to understand cognition in everyday life compared to in‐clinic assessments. The technological sophistication and widespread use of smartphones now allows this platform to be used for remote neuropsychological testing. However, it is important to ensure that the validity of neuropsychological tests extends to remote and unsupervised administration. As the Cogstate Brief Battery (CBB) has been validated for remote use on computers, the aim of this study was to now examine whether the acceptability and validity holds when administered via smartphone to cognitively unimpaired (CU) middle‐aged and older adults.

Method

CU adults (n = 173) aged 41‐75 years (M(SD) = 62.72 (7.18)) enrolled in the Healthy Brain Project completed the smartphone CBB remotely. The mean speed and accuracy of performance on the Detection (DET, psychomotor function), Identification (IDN, attention), One Back (OBK, working memory) and One Card Learning (OCL, visual learning) tests were used to define performance. Acceptability was determined by the percentage of participants completing the full CBB. Relationships between CBB performance with age and test difficulty were described to inform validity. Relationships between objective CBB performance and subjective ratings of how participants felt about their overall performance, obtained via survey, were also explored.

Result

100% of participants completed the smartphone CBB. Increasing age was associated with slower performance on all tests (Figure 1a‐1d), and reduced accuracy on the OBK (Figure 1h). Older adults (66+ years) performed slower than middle‐aged adults (40‐65 years) on all CBB tests, and with less accuracy on OBK (Table 1). Performance speed across all tests slowed with increasing test difficulty (Figure 2). Whilst a ceiling effect was observed for accuracy of simpler tests (DET, IDN, OBK), accuracy was lowest for the most difficult test (OCL) (Figure 2). Subjective ratings of overall CBB performance was significantly, albeit weakly, correlated with OCL accuracy (r = 0.23, p = .003).

Conclusion

The results support the acceptability and validity of the remote, unsupervised administration of the smartphone CBB in CU middle‐aged and older adults. These results provide a foundation for gaining further understanding of the performance of the smartphone CBB in diverse and impaired populations.
Extracellular Vesicles Treatment Induces Pro‐resolutive Microglial Changes in Experimental Models of Ischemic Stroke: A Systematic Review and Meta‐analysis
Authors: Bernardi Luis Pedro , Schlickmann Thomas Hugentobler , Carello‐Collar Giovanna , Rohden Francieli , Souza Diogo O. , Zimmer Eduardo R.
Published: January 2025

Background

Ischemic stroke (IS) is a risk factor for developing Alzheimer’s disease (AD). In this context, microglial activation is a shared cellular response to these two conditions that can be either beneficial or detrimental. Previous research has established that mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) treatment leads to enhanced functional recovery and reduced brain infarct volume in animal IS models. However, current literature findings are unclear when addressing the effects of MSC‐EVs treatment on microglial activation. Thus, we aimed to investigate how MSC‐EVs treatment alters microglial activation parameters in IS models.

Method

The protocol of this systematic review was registered in PROSPERO (CRD42023463152) and followed the PRISMA 2020 statement. We searched EMBASE, PubMed, and Web of Science from database inception to October 2023 for studies with animal or cell culture IS models using MSC‐EVs as intervention and measuring microglial activation outcomes compared to control. We performed a random‐effects meta‐analysis using standardized mean differences (SMD) as the effect measure with the metafor and metaviz packages in R (v4.2.1) (FDR‐adjusted p‐value<0.05).

Result

The database search identified 294 records, from which 27 were included (Fig. 1). Meta‐analysis showed that in vivo MSC‐EVs treatment resulted in a lower number of total microglia (Iba1+ cells) (SMD = ‐1.45 [‐2.19,‐0.71 95%CI] p<0.001, Fig. 2A) and CD16+ microglia (SMD = ‐1.84 [‐2.62,‐1.05 95%CI] p<0.001, Fig. 2B), but in a higher number of CD206+ microglia (SMD = 1.95 [1.01,2.88 95%CI] p<0.001, Fig. 2C) in the brain across different IS models and age groups. In microglia cell cultures submitted to oxygen‐glucose deprivation, MSC‐EVs treatment decreased the levels of TNF‐α (SMD = ‐3.32 [‐4.95,‐1.69 95%CI] p<0.001, Fig. 3A), IL‐1β (SMD = ‐3.45 [‐5.57,‐1.32 95%CI] p<0.001, Fig. 3B), and IL‐6 (SMD = ‐2.95 [‐4.50,‐1.40 95%CI] p<0.001, Fig. 3C) in the culture medium, while increasing the gene expression levels of Arg‐1 (SMD = 5.41[3.54,7.29 95%CI] p<0.001, Fig. 3D).

Conclusion

We demonstrated that MSC‐EVs treatment in IS models reduces the expression of pro‐inflammatory microglial activation markers (CD16) and cytokines (TNF‐α, IL‐1β, IL‐6) while increasing the expression of anti‐inflammatory markers (CD206, Arg‐1). Our results suggest that MSC‐EVs treatment modulates microglia towards a pro‐resolutive state, potentially contributing to the recovery of damaged brain tissue in IS and, consequently, in AD.
Navigating the Longitudinal Maze: Unravelling Challenges in the Follow‐up of a Dementia Cohort Study
Authors: HS Sunitha , Lingegodwa Abhishek Mensegere , Partha Ajith , Arvind Prathima , NM Divya , CM Amitha , HS Deva Kumar , Narayanasamy Rajitha , R Meghana , Menon Meenakshi , Vishwanath Vindhya , Velavarajan Goutham , Singh Sadhana , Malo Palash K , Stezin Albert , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Dementia, a global health challenge, drives the need for comprehensive understanding. Longitudinal cohort studies are vital, yet maintaining follow‐up in dementia cohorts poses challenges. This study explores challenges in follow‐up, refines protocols, and develops strategies that can elevate dementia research quality.

Method

This is an ongoing longitudinal cohort study on dementia named TLSA (Tata Longitudinal Study of Ageing) in which healthy volunteers are recruited in the community through various strategies such as awareness talks, advertisements, and referrals from other volunteers. All of them undergo a set of clinical assessments, cognitive, blood biochemistry, and MRI examinations at baseline and annual follow‐up visits and are informed about the results of the same by clinicians, thereby maintaining contact regularly. For follow‐ups, each of them is contacted via calls, messages, and Emails once a year. To enlighten them on the findings of research, regular participant meets are conducted, and monthly newsletters are issued. House visits (via mobile unit customized for various assessments) were conducted for participants who were unable to come to the research center but did not want to drop out. This study explored the distinct reasons for dropouts when the volunteers were called for follow‐ups.

Result

The total number of participants is 1484 till December 2023. The total number of dropouts is 113(7.6%). The reasons for dropouts were death 11 (9.7%), unable to contact 35 (30.9%), loss of interest in the study participation 30 (26.5%), relocation 10 (8.8%), health issues 17 (15%), family restrictions 5 (4%), and other unreported reasons 5 (4%).

Conclusion

Enhancing motivation strategies tailored to specific groups such as those who lack interest, have relocated, or face family restrictions can effectively boost follow‐up participation, consequently reducing dropout rates. Tailoring strategies using technology such as social media, infographics, and messaging applications to each group’s unique circumstances can reignite interest in participating in the study, ultimately leading to improved follow‐up rates, and enhancing the overall quality of the research.
Bridging the Gap between Cognition and Everyday Functioning: A linking Study in Amyloid Positive Participants
Authors: van der Putten‐Toorenburg Angela , Butterbrod Elke , Postema Merel C. , van der Veere Pieter J. , Tewolde Mukrabe E. , Schalet Benjamin D. , van Harten Argonde C. , van de Giessen Elsmarieke , Teunissen Charlotte , van der Flier Wiesje M. , Sikkes Sietske A.M
Published: January 2025

Background

It remains unclear to what extent global cognition translates to everyday functioning, although this is essential to interpreting the clinical meaningfulness of cognitive deficits. Here, we investigate potential linking between the Mini‐Mental State Examination (MMSE) and the proxy‐based Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q).

Methods

Cross‐sectional data from 1228 amyloid‐positive participants (age = 64±7yrs; 51.1%F), with Subjective Cognitive Decline(n = 156), Mild Cognitive Impairment(n = 228) or Probable Alzheimer’s Disease(n = 844) were included from the Amsterdam Dementia Cohort. Amyloid positivity was based on amyloid PET or cerebrospinal fluid, according to local cut‐off values. All participants completed MMSE, and all proxies A‐IADL‐Q. Equipercentile linking, unidimensional Item response theory (IRT) calibration and multiple regression analyses were explored as linking methods. For each MMSE quartile, we explored the proportion of reported problems on the A‐IADL‐Q total score and each A‐IADL‐Q item. We described the most commonly affected activities.

Results

Assumptions for direct linking (equipercentile/IRT) were not met (r = 0.53,95%CI[0.48,0.57]). We proceeded with multiple regression analyses, with MMSE as independent variable and A‐IADL‐Q as dependent variable (adjusted for age, sex and education). Higher MMSE scores were associated with higher everyday functioning in the total sample (B = .96;95%CI[0.87,1.04]), with a one‐point increase in MMSE corresponding to nearly one additional point in A‐IADL‐Q scores. In the highest MMSE quartile (27‐30), 35% of participants experienced ‘no problems’, while 47%,17%, and 1% experienced 'mild,’ ‘moderate,’ and ‘severe problems’ respectively (Figure 1). In the lowest quartile, 5% reported 'no problems‘, with 22%,44%, and 29% experiencing 'mild,’ ‘moderate,’ and 'severe problems’. Most commonly affected activities in the highest MMSE quartile were working (74% at least mild problems), followed by using a computer (52%) and managing the household budget (47%). The latter two activities were also most commonly affected in the lowest MMSE quartile, but to a much higher degree (93%,95%) alongside filling in forms (96%).

Conclusion

Although direct linking between cognition and daily functioning was not possible, our findings support more functional dependencies with increasing cognitive problems. Functional difficulties in the highest MMSE group suggest limited sensitivity of cognitive screening. Our findings suggest a nuanced link between global cognition and everyday functioning, supporting complementary use of both instruments.
Impaired Recovery Sleep in Individuals with Alzheimer’s Disease – The RESTED Study
Authors: Blackman Jonathan , Gabb Victoria Grace , Morrison Hamish , Turner Nicholas , Biswas Bijetri , Li Haoxuan , Whone Alan , Coulthard Elizabeth
Published: January 2025

Background

Homeostatic sleep regulation is theorized to be governed by the ‘Two Process Model’ where circadian rhythm (process C) and homeostatic sleep pressure (process S) interact to determine sleep versus wakefulness. Sleep pressure accumulated during prolonged wakefulness increases the duration and intensity of subsequent ‘recovery’ sleep. Multiple sleep abnormalities are associated with Alzheimer’s Disease (AD) Dementia and Lewy Body Dementia (LBD). This study seeks to determine whether recovery sleep duration may also be compromised.

Method

RESTED (Remote Evaluation of Sleep To enhance understanding in Early Dementia) was an observational cohort study with three subgroups: AD MCI/dementia, LBD MCI/dementia, and healthy controls (HC). Participants wore a wrist actigraph for 55 nights continuously and provided daily sleep diaries. Recovery sleep was assessed using a random intercept lagged panel model with a dependent variable of total sleep time (TST). Prespecified covariates included age, sex, Geriatric Depression Score, Generalised Anxiety Disorder 7‐Score and participant subgroup (AD/LBD/HC). Compensatory sleep represented a ‘within‐person’ carry‐over effect modelled with an autoregressive parameter (alpha). A negative value implies low TST nights are typically followed by higher TST nights, indicating compensatory or recovery sleep Interaction terms determined if alpha was affected by participant group or age.

Result

40 participants (AD = 10, LBD = 10, HC = 20) underwent full study procedures. Mean (SD) age was 70.9 (5.9) [AD = 69.2(7.9), LBD = 73.9(2.8), HC = 70.2(5.7)]. 9/40 (22.5%) participants were female (AD = 2/10, LB = 2/10, HC = 5/20). Mean (SD) Montreal Cognitive Assessment Score was 24.8 (4) [AD = 23.0(5), LBD = 21.9(4), HC = 27.1(1)].

Age (β = ‐0.11, SE = 0.05, p = 0.036), diagnosis of AD (β = ‐1.75, SE = 0.57, p = 0.004) and alpha (β = ‐0.94, SE = 0.31, p = 0.002) were all negatively associated with sleep duration. There were significant positive interactions between alpha and diagnosis of AD (β = 0.13, SE = 0.06, p = 0.026) and alpha and increasing age (β = 0.01, SE = 0.004, p = 0.001). No statistically significant effects were found linking LBD to sleep duration.

Conclusion

Low TST nights were typically followed by higher TST nights suggesting that compensatory mechanisms were present. However, this relationship was attenuated both by the presence of AD and increasing age (approximately 10% per decade). Further research is needed to confirm these findings in larger cohorts and determine underlying pathophysiological mechanisms by which sleep recovery is compromised.
Random Forest Classifiers to predict psychotic symptoms in Alzheimer’s disease
Authors: Scarfo Sara , Moshfeghi Yashar , McGeown William J
Published: January 2025

Background

Psychotic symptoms (delusions and/or hallucinations) are among the most common and impactful neuropsychiatric symptoms that occur within Alzheimer’s disease (AD): present in around half of AD patients, they are associated with increased distress for the individual and their families, poorer disease outcome, and greater risk of hospitalization and death. Using Random Forest analyses, aim of this study is to provide clarity on the value of neuroanatomical, neuropsychological, and neuropsychiatric features when predicting the presence of psychotic symptoms in AD.

Method

Data used in preparation for this study was obtained from the Alzheimer’s Disease Neuroimaging Initiative database (adni.loni.usc.edu). Based on the scores of the Neuropsychiatric Inventory, participants were selected with the criterion of presenting with psychotic symptoms (either delusions, or hallucinations, or both). Controls were subsequently matched, who did not present with any psychotic symptom, and did not differ from the psychosis group for disease stage, age, gender, education, genetic profile, and overall cognitive and neuropsychiatric status. The predictors were derived from: Neuropsychiatric Inventory’s scores for the other neuropsychiatric symptoms; Alzheimer’s Disease Assessment Scale‐Cognitive Subscale, to select different cognitive functions; brain metrics derived from the FreeSurfer software (available via ADNI), as measures of cortical and subcortical volumes, cortical thickness, and surface area.

Result

The Random Forest Classifiers were employed to generate feature importance ranking. While further analyses are currently underway, preliminary results suggest that it is possible to understand how the different variables interact to predict the presence of psychotic symptoms, and which of those variables hold greater importance. Among neuropsychiatric symptoms, apathy has emerged; short‐term and long‐term memory and orientation resulted as best predictors among the cognitive functions. Lastly, the anterior and posterior cingulate cortex and insula (bilaterally), and right frontal areas were identified as the most important brain areas. Overall, the brain region metrics appear to have better discriminatory ability compared to neuropsychological and neuropsychiatric data.

Conclusion

The results of this study indicate (albeit preliminarily) that a machine learning technique such as the Random Forest Classifier can be used to advance our understanding of the complex interaction of different predictors in the manifestation of psychotic symptoms in AD.
Longitudinal cognitive trajectories in sporadic early‐onset Alzheimer’s Disease: Findings from LEADS
Authors: Hammers Dustin B. , Eloyan Ani , Thangarajah Maryanne , Taurone Alexander , Wong Bonnie , Dage Jeffrey L. , Nudelman Kelly N. , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Bradford C. , Apostolova Liana G. ,   and ‐ LEADS Consortium
Published: January 2025

Background

Early Onset Alzheimer’s Disease (EOAD) is a rare condition that manifests prior to the age of 65, and affects approximately 5% of patients with Alzheimer’s disease. The Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS) is the largest prospectively‐evaluated cohort of participants with sporadic EOAD in the United States, initiated to better understand the features of this condition. The current analyses sought to examine longitudinal cognitive trajectories of patients with EOAD over time.

Method

Data from 100 participants with amyloid‐positive EOAD, 30 participants with amyloid‐negative cognitive impairment (EOnonAD), and 65 cognitively normal age‐matched participants were compared. All had at least three study visits. Cognitive trajectories across a comprehensive cognitive battery across 24‐56 months were examined using mixed‐effects modeling, including the years of onset x diagnostic group interaction controlling for years since onset, education, sex, and the random effect of each participant.

Result

Across all measures, clinical groups generally displayed declines over time, with performances for the EOAD group tending to approach the lower limit of performance ranges (Figure 1). Relatedly, significantly greater slopes of decline were seen over time for the EOAD group than the CN group across all cognitive domains evaluated (ps<.001; Table 1). When comparing between clinical groups, greater declines were also evident for the EOAD group relative to the EOnonAD group for a screener of global cognition, and for specific measures of attention, verbal fluency, processing speed, language, and delayed story recall (ps .001 to .049; Table 2). No differences in trajectory were observed between clinical groups for unstructured verbal memory, visual memory, or visuospatial skills (ps>.05; Tables 1 and 2).

Conclusion

In addition to worse cognition at baseline, sporadic EOAD participants displayed pronounced declines in cognition over 24‐56 months across all domains evaluated. Relative to the EOnonAD group, cognitive trajectories appear to be worse predominantly for executive and attentional processes, with variability across episodic memory tasks. This suggests that EOAD pathology is not solely directed at memory functioning. Future research will focus on comparing cognitive trajectories of EOAD and late‐onset AD, in an effort to understand similarities and differences in the types and rates of cognitive trajectories.
Computerized testing to detect cognitive decline in biomarker‐confirmed Alzheimer’s disease: Longitudinal findings from the ARMADA study.
Authors: Jutten Roos J , Ho Emily , Karpouzian‐Rogers Tatiana , Van Hulle Carol A. , Dodge Hiroko H , Nowinski Cindy J. , Gershon Richard C. , Weintraub Sandra , Rentz Dorene M
Published: January 2025

Background

The National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) was developed to address the need for a brief yet comprehensive instrument to facilitate more uniform assessment in large‐scale research studies. Here, we investigated whether the cognitive measures of the NIHTB detect cognitive decline in biomarker‐confirmed Alzheimer’s disease (AD).

Method

We used data from N = 178 participants (age 76.5±8; 53% female) from the Assessing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study, who were recruited across nine research centers in the United States and had amyloid PET or amyloid‐beta42/tau CSF data available within two years of their baseline NIHTB assessment. Participants’ cognitive status (normal (CN) or impaired (CI), based on standardized protocols) and amyloid status (Aβ‐/Aβ+, based on site‐specific cut‐offs) were combined to create three groups: healthy controls (CN Aβ‐, n = 113), asymptomatic AD (CN Aβ+, n = 24), and prodromal‐to‐mild AD (CI Aβ+, n = 34) (Table 1). The NIHTB was assessed at baseline, 12 and 24 months and includes five tasks measuring fluid cognition (attention, executive functions, processing speed, working memory, and episodic memory) and two tasks reflecting crystallized cognition (oral word reading and auditory word comprehension). Linear mixed‐effect models correcting for age, sex, and education were used to examine cross‐sectional and longitudinal NIHTB scores in the three study groups.

Result

Compared to healthy controls, the prodromal‐to‐mild AD group had lower baseline scores on most NIHTB fluid tasks (Flanker Inhibitory Control and Attention, Dimensional Change Card Sort, Picture Sequence Memory, List Sort Working Memory) and showed accelerated decline over 12‐24 months on Pattern Comparison Processing Speed, List Sorting Working Memory and Picture Vocabulary (Figure 1). None of the NIHTB tasks detected cross‐sectional or longitudinal differences in the asymptomatic Aβ+ group compared to healthy controls over the course of this study.

Conclusion

The NIHTB detects cross‐sectional impairment in episodic memory, attention, executive functions and working memory and longitudinal change in processing speed, working memory and auditory word comprehension in prodromal‐to‐mild AD. These findings further support the use of the NIHTB in AD research, but also imply that the optimal NIHTB composite to detect cognitive decline may differ across AD clinical stages.
Accuracy of clinical diagnostic criteria for behavioral/dysexecutive Alzheimer’s Disease in patients presenting with mild behavioural or dysexecutive symptoms
Authors: Iacovino Najara , Tondelli Manuela , Carbone Chiara , Gallingani Chiara , Molinari Maria Angela , Chiari Annalisa , Zamboni Giovanna
Published: January 2025

Background

Diagnosis in patients with Mild Behavioural Impairment (MBI) and with Mild Cognitive Impairment (MCI) with predominant executive deficits (eMCI) is often challenging, as they may be representing the early phase of both Alzheimer’s Dementia (AD) as well as behavioural variant Frontotemporal Dementia (bvFTD). If neuropathology biomarkers aren’t available, diagnosis is even more difficult. We evaluated the performance of classification of different clinical diagnostic criteria for behavioural/dysexecutive AD (without biomarkers) in MBI and eMCI.

Method

Consecutive patients with a clinical diagnosis of MBI or eMCI seen in our Cognitive Neurology Clinic from January 2022 to December 2023 were retrospectively recruited, irrespectively of the presence of other cognitive signs. To be included they needed to have undergone measurement of biomarkers of amyloidosis and neurodegeneration (p‐tau, t‐tau, Abeta42‐40 ratio in cerebrospinal fluid or (18F) Flutemetamol‐PET) and extended neuropsychological evaluation. Blind to biomarkers, we classified patients according to the following different clinical criteria: (i) Behavioural or Dysexecutive predominant AD (Ossenkoppele 2015), (ii) Progressive dysexecutive syndrome (Townley 2020), and (iii) behavioural variant of AD (bvAD) (Ossenkoppele 2022). Diagnostic accuracy of each criterion was then compared to biomarkers’ classification for differentiating AD (positive biomarkers) from bvFTD continuum (negative biomarkers). Sensibility and specificity were determined for each criterion and Kappa coefficient used for assessing agreement between different sets of criteria.

Result

Forty‐six consecutive eligible patients were included. Among them, 45.6% fulfilled criteria for Behavioural predominant AD, 21.7% for Dysexecutive predominant AD, 2.1% for Progressive dysexecutive syndrome, and 52.1% for bvAD. Diagnostic accuracy analyses using biomarkers showed that criteria for Behavioural predominant AD correctly classified 78.2% of patients (sensibility 77.7%, specificity 78.9%), criteria for Dysexecutive predominant AD 67.3% (sensibility 88.8%, specificity 38.8%), criteria for Progressive dysexecutive syndrome 60%, and bvAD criteria 80.4% of patients (sensibility 74%, specificity 89.4%). Higher kappa coefficient (k = 0.85) was found between Behavioural‐predominant AD and bvAD criteria.

Conclusion

Clinical criteria to diagnose patients presenting with mild behavioural or dysexecutive symptoms have poor diagnostic accuracy in absence of biomarkers measurement. Among the criteria available, the definition of bvAD proposed by Ossenkoppele (2022) achieves the more accurate performance in distinguishing AD from bvFTD continuum.
The outcome‐representation learning model of decision‐making capacity in mild cognitive impairment
Authors: Zhang Mang , Zhang Ying , Xie Yuhan , Zheng Yaonan , Wang Luchun , Li Huizi , Yu Xin , Wang Huali
Published: January 2025

Background

The decision‐making capacity of persons with mild cognitive impairment (MCI) has not been fully explored. This study aimed to examine the decision‐making capacity in MCI using the outcome‐representation learning model.

Method

52 persons with MCI and 49 healthy controls were recruited in the study. The Iowa Gambling Task (IGT) was administered to measure decision‐making under ambiguity situations. Five parameters, including the reward learning rate, the punishment learning rate, forgetfulness, win perseverance and deck perseverance, were included in the outcome‐representation learning (ORL) model to capture changes in decision‐making abilities in MCI patients.

Result

Individuals with MCI exhibited reduced learning from losses outcomes and similar learning from wins outcomes compared to healthy controls. Additionally, MCI individuals exhibited less susceptibility to forgetfulness in the IGT compared to controls, suggesting that memory fading of choices made by MCI patients was not improved. Although MCI individuals still favored high‐win frequency decks like controls, their preference appeared to dimmish from the first to second completion of the IGT.

Conclusion

The findings suggest that individuals with mild cognitive impairment have difficulty in learning lessons from decision‐making failures in complex contexts. It offers a potential novel computational neurocognitive marker for mild cognitive impairment.
Evidence for a protective effect of hormone replacement therapy on Alzheimer’s disease neuropathological and clinical outcomes across cohorts
Authors: Bruno Jennifer , Shaw Jacob , Henderson Victor W. , Hosseini Hadi
Published: January 2025

Background

More than 2/3 of Alzheimer’s Disease (AD) patients are women, which has led to increased interest in the neurophysiological impact of estrogen decline during menopause. While early evidence suggested that hormone replacement therapy (HRT) may be protective against dementia, more recent studies have found inconclusive or even harmful effects.

Method

We tested the association between HRT use (estrogen or estrogen + progestin) and AD‐related neuropathological outcomes measured on autopsy data in females from the National Alzheimer’s Coordinating Center (NACC) (N = 3423). We also sought to test the association between HRT use and molecular imaging and fluid biomarker measures of AD‐related neuropathology measured in‐vivo in females from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (N = 2422). Finally, we tested the association between HRT use and clinical outcomes, including Clinical Dementia Rating (CDR) and memory performance, in both ADNI (N = 2422) and NACC (N = 20151) datasets.

Result

We found evidence for a protective effect of HRT on the NIA‐AA AD Neuropathologic Change score (ABC score), hippocampal atrophy, and cerebrovascular disease. We also found evidence for a protective effect of HRT on amyloid burden measured via positron emission tomography (PET) and via cerebrospinal fluid as well as on brain metabolism measured via fluorodeoxyglucose PET. Finally, we found evidence for a protective effect of HRT on dementia diagnosis, CDR and memory performance. All results were significant after controlling for age, APOE genotype and educational level.

Conclusion

We found evidence for small but significant protective effects of HRT across multiple pathological and clinical measures in two different cohorts. First, the protective effect of HRT on neuropathology measured post‐mortem indicates that HRT use is associated with a lower risk of pathology, relative to no HRT use, on this most definitive and final outcome. Second, the protective effect of HRT extended to amyloid biomarkers measured in vivo indicating that future work can utilize these biomarkers to better understand the protective mechanism by which HRT may act. Finally, the protective effect extended beyond pathology to more subtle cognitive outcomes. Together, these results lend understanding to the effects of HRT (or lack thereof) on the aging brain.
Lower entorhinal cortex thickness is associated with greater temporal discounting in cognitively unimpaired older adults
Authors: Fenton Laura E. , Salminen Lauren , Samek Anya , Weissberger Gali H , Lim Aaron C , Nguyen Annie , Axelrod Jenna , Noriega‐Makarskyy Daisy , Herrera Jennifer , Wei Nathan , Erdman Elizabeth , Han S. Duke
Published: January 2025

Background

Alzheimer’s disease (AD) neuropathology may impact brain regions involved in decision making. Because of this, changes in decision making (e.g., economic preferences) may be an early behavioral manifestation of preclinical AD. The current study investigated relationships between temporal discounting (the tendency to choose smaller, more immediate rewards over larger, delayed rewards) and brain structures implicated early in preclinical AD.

Method

The sample included 92 cognitively intact older adults (mean age = 68.8±7.43; mean education = 16.62±2.15; 75% female; 79% White). Temporal discounting was characterized using a paradigm in which participants choose between earlier or later payments of varying amounts. In the first section (T1), participants choose between payments today vs. 2 weeks from today. In the second section (T2), choices were between today vs. 4 weeks from today. In the third section (T3), choices were between 2 weeks vs. 4 weeks from today. Temporal discounting rates were calculated for each time point. Due to most participants clustering around a low modal value of temporal discounting, participants were categorized as “low” on temporal discounting if they were at or below the mode and “high” if they were above the mode. Brain structural MRI estimates were acquired on a 7 Tesla scanner and processed using FreeSurfer‐v.7.2.0. The regions of interest (ROIs) included the entorhinal and parahippocampal cortex and hippocampus. Differences in ROIs between the two groups were tested using one‐way ANOVA models adjusted for age, sex, and education.

Result

Individuals who exhibited higher temporal discounting rates at T1 and T2 had significantly lower entorhinal cortex thickness (F = 6.06, p = 0.02 and F = 6.18, p = 0.01 respectively). No significant relationship was observed at T3. Additionally, no significant relationships were observed between temporal discounting and parahippocampal cortex thickness or hippocampal volume.

Conclusion

Results showed that lower entorhinal cortex thickness is associated with greater temporal discounting in cognitively intact older adults. This supports the idea that changes in economic preferences may be an early behavioral manifestation of preclinical AD. Due to the cross‐sectional nature of the study, it will be important to validate these findings in longitudinal studies.