bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating depressive symptoms and risk of cognitive decline using longitudinal electronic health records
Authors: Wang Liqin , Yang Richard , Laurentiev John , Gatchel Jennifer , Blacker Deborah , Amariglio Rebecca E. , Sperling Reisa A. , Zhang Yuqing , Zhou Li , Marshall Gad A
Published: December 2023

Background

Depression is associated with increased risk of Alzheimer’s disease and related dementias (ADRD). Many population‐based and convenience sample studies have examined depression and depressive symptoms in this context. However, fewer studies employed electronic health records (EHR) to assess this relationship. Because depression might be under‐ or mis‐diagnosed, diagnostic codes alone may be insufficient. We aimed to assess whether prior depression diagnosis and/or depressive symptoms–derived from natural language processing (NLP) in the EHR–predicts future mild cognitive impairment (MCI)/dementia using a large EHR‐based dataset.

Method

The Massachusetts Electronic Health Records Aging Dataset (MEAD) is a retrospective cohort of patients who were ≥50 years old with normal cognition at their first encounter between 1/1/2000‐12/31/2005. Depression diagnoses and incident MCI/dementia were identified from structured encounter diagnoses and problem lists, and depressive symptoms from clinical notes using NLP. Follow‐up time was calculated from index date until date of cognitive diagnosis, death, loss to follow‐up or end of study (12/31/2021). We performed Cox proportional hazards models using age as the time scale to examine the association of depression and incident MCI/dementia, using the Fine‐Gray approach to account for competing risk of death.

Result

The MEAD cohort included 162,069 patients. Of those, 135,272 did not have depressive symptoms or a depression diagnosis at their first encounter, 14,985 had only depressive symptoms, 4,883 had only a depression diagnosis, and 6,929 had both depressive symptoms and a depression diagnosis. The incidence rate of MCI/dementia per 1,000 person‐year was 7.8 for patients without depressive symptoms or depression diagnosis, 10.0 for depressive symptoms only, 12.4 for depression diagnosis only, and 10.3 for both. Compared with those without depressive symptoms or depression diagnosis, the multivariable‐adjusted hazard ratios for incident MCI/dementia were 1.05 (95% confidence interval [CI] 0.99,1.11) for depressive symptoms only, 1.45 (95% CI 1.34,1.56) for depression diagnosis only, and 1.15 (95% CI 1.07,1.23) for both, respectively.

Conclusion

In a large sample, diagnosis of depression appears to be a stronger predictor than depressive symptoms of all‐cause MCI/dementia. Further research is needed to understand the utility of reported depressive and other neuropsychiatric symptoms in clinic notes for predicting cognitive decline.
Examination of plasma YKL‐40 as a clinical biomarker for Alzheimer’s disease
Authors: Sugarman Michael A , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J. , Karikari Thomas K , Pase Matthew P. , Himali Jayandra Jung , Beiser Alexa S. , Seshadri Sudha , Budson Andrew E , O'Connor Maureen K. , Au Rhoda , Goldstein Lee E , Qiu Wei Qiao , Kowall Neil W , Stern Robert A , McKee Ann C. , Mez Jesse B. , Alosco Michael L , Aparicio Hugo J
Published: December 2023

Background

Blood biomarkers represent a potential non‐invasive and cost‐effective strategy for the clinical detection and monitoring of neurodegenerative conditions including Alzheimer’s disease (AD). YKL‐40 is a secreted glycoprotein associated with inflammatory processes, and elevated cerebrospinal fluid levels have been observed in AD and other neurodegenerative conditions. Fewer studies have examined plasma YKL‐40. We examined relationships between plasma YKL‐40 and clinical indices of AD in a large cross‐sectional sample from a clinical cohort registry.

Method

The sample included 569 participants from the Boston University Alzheimer’s Disease Research Center, including participants with normal cognition (NC; n = 235), mild cognitive impairment due to suspected AD (MCI; n = 181), and AD dementia (n = 153). Blood plasma samples were analyzed using standard ELISA methods; values were log transformed and standardized into z‐scores. Cross‐sectional analyses investigated the relationships between YKL‐40 and clinical indices of functioning including diagnostic status, dementia severity (on the Clinical Dementia Rating scale [CDR]), and neuropsychological test performance. Age, sex, education, race, and APOE ε4 carrier status were included as covariates in all analyses.

Result

No significant differences in plasma YKL‐40 were observed between participants with NC, MCI, and AD dementia after accounting for covariates. The comparison between MCI and dementia was marginally significant (p = .07), with an adjusted mean difference of Z = 0.19. For participants with dementia (CDR scores 1‐3), non‐significant trends were observed for relationships between plasma YKL‐40 values and dementia severity, including for Sum of Boxes (Pearson partial correlation: r = .14, p = .10) and Total Score (ordinal logistic regression: OR = 1.38; 95% CI: [0.98,1.93]), p = .06. Modest but significant correlations were observed between YKL‐40 and performance on 4/12 neuropsychological tests including Animal Fluency (r = ‐.10), Vegetable Fluency (r = ‐.09), and Neuropsychological Assessment Battery List Learning Trials 1‐3 (r = ‐.10) and Short Delay (r = ‐.12).

Conclusion

Plasma YKL‐40 biomarker levels were modestly related to neuropsychological assessments of language and memory but not significantly related to cognitive diagnosis of AD or dementia severity. This biomarker may reflect underlying inflammatory processes in the context of AD. However, the use of plasma YKL‐40 to assess the presence and severity of AD in a larger cross‐sectional sample size, and using a multiple biomarker approach, warrant further study.
Amyloid and tau pathology are associated with white matter properties in cognitively unimpaired older adults at risk of AD dementia
Authors: Qiu Ting , Rheault François , Soucy Jean‐Paul , Spreng R. Nathan , Binette Alexa Pichet , Descoteaux Maxime , Villeneuve Sylvia ,   the PREVENT‐AD Research Group
Published: December 2023

Background

White matter changes are hypothesized to be among the earliest changes occurring in the course of Alzheimer’s disease (AD). We investigated associations between AD pathology, namely amyloid and tau, and white matter microstructural changes in cognitively unimpaired individuals at risk of AD dementia. We expected higher levels of pathology to be related to lower free‐water‐corrected fractional anisotropy.

Method

We studied 223 cognitively normal older adults with PET and multi‐shell diffusion MRI from the PREVENT‐AD cohort. We first measured standardized uptake value ratios (SUVRs) in 40 brain regions for amyloid‐β (Aβ, i.e., lateral and medial prefrontal, parietal, lateral temporal, and cingulate cortical regions in both hemispheres) and 26 brain regions for tau (i.e., Braak stages I, III, and IV). We then used TractSeg, a deep learning framework, to segment 49 well‐established white matter bundles. We mapped free‐water‐corrected fractional anisotropy (FAT) in those bundles. Lastly, to explore the relationships between AD pathology and white matter microstructure across bundles, we applied two separate partial least squares analyses: one for Aβ pathology and one for tau (Figure 1).

Result

We found one significant latent variable relating Aβ pathology to FAT. Specifically, higher levels of Aβ pathology were associated with the combination of higher levels of FAT within the rostral body of the uncinate fascicle and superior longitudinal fascicle (Figure 2A). We found two significant latent variables relating tau pathology to FAT for which higher levels of tau pathology were associated with elevated FAT within the uncinate fascicle, thalamo‐occipital bundle, optic radiation, inferior occipitofrontal fascicle, inferior longitudinal fascicle, middle longitudinal fascicle, etc. (Figure 2B).

Conclusion

In cognitively unimpaired individuals at risk of AD, increased Aβ and tau pathology were associated with higher levels of FAT in AD‐related bundles. These unexpected findings may suggest an inverted U‐shape pattern between AD pathology and FAT in the preclinical phase of AD for which FAT values would start by increasing before decreasing later in the course of the disease. This first increase might be a marker of early pathological processes such as neuroinflammation or swelling.
Accelerated aging in gait patterns is a leading indicator for cognitive decline
Authors: Barnard Leland R , Ali Farwa , Botha Hugo , Christianson Teresa J. , Vemuri Prashanthi , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Graff‐Radford Jonathan , Jones David T.
Published: December 2023

Background

Quantified accelerated aging, or “age gap,” defined as the difference between a person’s estimated age using a biological measurement, such as a brain image, and their true age, has strong associations with multiple neurodegenerative etiologies. As an alternative to imaging‐based measurements, in this study we developed an age prediction model based on gait patterns and used this model to quantify accelerated aging as an indicator of cognitive impairment and predictor of future cognitive decline.

Method

A database of 16,917 pressure sensitive walkway exams from 5,307 participants in the Mayo Clinic Study of Aging was used to develop an age estimation model that included two main components. First, a novel dimensionality reduction and feature selection algorithm was used to extract gait features. Second, a regularized linear model was trained using these features to produce a sparse, clinically interpretable estimator. This model was used to calculate a gait age gap metric, which was tested for association with measures of cognitive impairment and future cognitive decline.

Result

The distributions of gait age gap in age‐matched participants defined as having no cognitive impairment (CU, n = 573), mild cognitive impairment (MCI, n = 520), or a clinical diagnosis of dementia due to Alzheimer’s (AD, n = 53) are shown in Fig 1a. A significant shift in the mean is observed between all three groups. Fig 1b. shows the distributions of baseline gait age gap values amongst individuals categorized by cognitive decline: stable CU (n = 644), MCI converters (n = 89), stable MCI (n = 78), and significant impairment converters (SI, n = 35). The baseline gait age gap in stable CU individuals was found to be significantly lower than in the already impaired or converter groups.

Conclusion

In this study, we developed a model for estimating accelerated aging from gait variables in the form of a gait age gap metric. This metric was shown to be strongly associated with AD‐driven cognitive impairment as well as predictive of future cognitive decline. These results highlight the potential clinical utility of quantitative gait analysis in behavioral neurologic assessment of cognitive impairment in AD.
The Association of Plasma Biomarkers and Survival in the Oldest Old
Authors: Lorenz Linda M.C. , Tesi Niccoló , van der Lee Sven J , Hulsman Marc , Gouda Mariam , Sikkes Sietske A.M. , Teunissen Charlotte E. , Holstege Henne
Published: December 2023

Background

Previous research showed that plasma NfL (neurofilament light chain) associated with survival. Here we perform exploratory analyses to associate a broader range of plasma biomarkers Amyloid‐βeta‐40 (Aβ40), Amyloid‐βeta‐42 (Aβ42), phosphorylated Tau‐181 (pTau‐181), NfL and glial fibrillary acidic protein (GFAP), with survival after reaching 100 years.

Method

The longitudinal Dutch 100‐plus study cohort comprises of self‐reported cognitively healthy centenarians. Biomarkers were measured in 202 centenarians (137 females, ISCED education level median [IQR] 3 [2–4]) on the Simoa platform. Information on survival was obtained via family report until January 2023. Centenarians who were alive were censored at date of last visit or date last confirmed alive. We investigated the relationship between biomarkers and survival by cox regression analyses, adjusting for age at blood draw, sex and cognitive functioning. We performed maximally selected log‐rank statistics between all plasma biomarkers and survival rate to find an optimal cut‐off, and constructed Kaplan‐Meier survival curves.

Result

Of 202 centenarians (median age [IQR] at blood draw 101.4 [100.4‐102.9]), 173 (85.6%) were deceased (median age [IQR] at death 103.2 [102.0‐104.3]). The median (IQR) survival time after blood draw was 14.4 (5.5‐25.1) months. All biomarkers Aβ40, Aβ42, pTau‐181, NfL and GFAP intercorrelated (rs = 0.17–0.79; all P‐values<0.05). Cox regression analyses showed that for each standard deviation increase in NfL, adjusted for age, sex, and MMSE score, the risk of mortality increased by 28% (HR 1.28; 95% CI, 1.11–1.47; P<0.001), Table 1. Maximally selected log‐rank statistics split up NfL into survival groups high and low (cut‐off 70.34 pg/mL, M = 3.803, P = 0.003, Figure 1). The median (IQR) shorter survival time of high versus low NfL was 7.8 (5.38‐9.27) months. No statistically significant cut‐off values were identified for the remaining biomarkers.

Conclusion

Our results indicate that elevated levels of NfL, but not Aβ40, Aβ42, pTau‐181 and GFAP, associate with lower survival. Furthermore, we were able to find an optimal cut‐off for NfL at which survival in centenarians could be split twofold.
Hypertension is associated with reduced medial temporal lobe neural flexibility in older African Americans
Authors: Gills Joshua L. , Fausto Bernadette A. , Osiecka Zuzanna , Malin Steven K. , Gluck Mark A.
Published: December 2023

Background

Hypertension disproportionately affects African Americans (AA) and is an established mid‐life risk factor for Alzheimer’s disease (AD). However, previous research suggests there is inconclusive data examining late‐life hypertension and Alzheimer’s risk. Recently, a dynamic rearrangement (neural flexibility) imaging method was validated for evaluating cognitive decline in the medial temporal lobe (MTL), which is a key region affected by AD. But whether hypertension mediates MTL neural flexibility in older AA individuals is unknown. Therefore, we investigated MTL flexibility in older hypertensive and normotensive AA.

Method

One hundred and thirteen AA (60‐74y) completed demographic surveys, weight and height measurements, resting blood pressure (BP) screening procedure, and a 6‐minute walking distance test as an indirect measure of aerobic capacity. All individuals also completed a 10‐minute resting‐state functional magnetic resonance screening to assess MTL neural flexibility. Participants were separated into normotensive (systolic BP < 130mmHg, n = 36, 83% female, 64.8 ± 0.4y; 13.8 ± 0.2y of education) vs. hypertensive (systolic BP ³ 130mmHg, n = 77, 82% female, 66.4 ± 0.3y; 14.1 ± 0.1y of education). An ANCOVA was used to examine group differences in MTL neural flexibility with age, sex, and education used as covariates.

Result

Although individuals with hypertension had a higher BMI (36.9 ± 1.8 vs. 31.3 ± 2.6 kg/m2, p = .070), this was not statistically different. However, normotensive participants had significantly higher MTL neural flexibility compared to hypertensive individuals (.42 ± .23 vs. .32 ± .25, p = .04), and this was independent of estimated aerobic capacity (14.9 ± 2.3 vs. 14.9 ± 2.5 ml/kg/min; ml/kg/min; p = .864).

Conclusion

Hypertensive AA between the ages 60‐74 years old demonstrated lower MTL neural flexibility compared to their normotensive counterparts. These results were independent of obesity and aerobic fitness, suggesting additional work is needed to understand how blood pressure mediates neuronal connectivity to prevent and/or treat AD cognitive decline in AA.
Association of Epigenetic Aging with Cognitive Aging in Diverse Hispanics/Latinos
Authors: Xia Rui , Márquez Freddie , Tarraf Wassim , Gallo Linda C , Talavera Gregory A , Sofer Tamar , Decarli Charles , González Hector M , Fornage Myriam
Published: December 2023

Background

Age‐related DNA methylation (DNAm) changes occur in specific regions of the genome and have been shown to be correlated with an individual’s chronological age. Multiple “epigenetic clocks” have been developed to estimate an individual’s DNAm age, which reflect different aspects of the multidimensional aging process. Age acceleration, the deviation of the DNAm‐estimated age from the chronological age, has been proposed as a novel biomarker of aging. We investigated the association between multiple measures of age acceleration and cognitive aging phenotypes in diverse Hispanic and Latino adults.

Methods

We estimated epigenetic age acceleration from 5 epigenetic clocks in 2188 Hispanic and Latino adults (mean age 56.7 years; 64.6% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) who had available blood DNA methylation data at the baseline visit and neurocognitive data. These included first generation clocks, Horvath and Hannum clocks; second generation PhenoAge and GrimAge; and third generation DunedinPACE (Pace of Aging). We used mixed models to test the association of each of these measures with a global measure of cognitive function (PC1) at the baseline visit and with mild cognitive impairment at a follow‐up visit approximately 7 years later.

Results

There were significant cross‐sectional associations between lower global cognitive function and greater age acceleration based on Hannum, Horvath, PhenoAge, and DunedinPACE algorithms. In addition, a greater age acceleration based on DunedinPACE was strongly associated with a higher risk of MCI 7 years later (Table).

Conclusion

Biological aging is associated with lower cognitive function and risk of MCI in diverse Hispanic and Latino adults. DunedinPACE, a third generation epigenetic clock, may be a more sensitive predictor of cognitive aging outcomes than previous generation clocks.
The cytoskeletal protein Plectin regulates Tau‐induced neurotoxicity in Alzheimer’s Disease
Authors: Lee Tom V , Chen Catherine , Allison Katherine S , Li Yarong , Al‐Ramahi Ismael , Bagchi Pritha , Levey Allan I. , Botas Juan , Seyfried Nicholas T , Shulman Joshua M
Published: December 2023

Background

The genetic causes for most cases of Alzheimer’s disease (AD) and the underlying biology of pathogenesis remain unknown. Recent large scale proteomics studies on AD patient brains have identified novel protein networks and targets that are highly correlated with AD diagnosis and neuropathology. The most significantly AD‐correlated protein network identified contains the cytoskeletal protein Plectin (PLEC) as a network hub. PLEC functions to crosslink different cytoskeletal components and plays a role in axonal transport of synaptic proteins. Considering that microtubule associated protein‐Tau (MAPT) dysfunction is an AD hallmark, we hypothesize that PLEC dysfunction increases AD susceptibility by disrupting cytoskeletal homeostasis and synaptic function.

Method

Utilizing a combination of genetic and proteomic analyses, we validate Plectin as a potential AD risk factor. We assessed the role of PLEC in Tau‐induced neurotoxicity in the animal model Drosophila melanogaster and human neuronal cell culture. Furthermore, we have also elucidated PLEC mutant neurodegenerative phenotypes independent of Tau overexpression in the fly. Immunoprecipitation‐mass spectrometry (IP‐MS) analysis was performed to define a Drosophila Plectin protein‐protein interaction network in adult brains. This network will serve as the basis for cross‐species analysis of protein networks.

Result

The Drosophila homolog of Plectin (dPLEC) is ubiquitously expressed within the adult brain with strong enrichment in neuronal rich tissues. Using Drosophila models of human tauopathy, dPLEC regulates age dependent Tau‐induced neurotoxicity and locomotor dysfunction. Plus, altering levels dPLEC regulates Tau‐phosphorylation in both adult Drosophila brains and human neurons. In the absence of Tau overexpression, dPLEC functions in light‐induced neuronal transmission confirming its role in normal neuronal function. Continued mechanistic analysis in both Drosophila and human neuronal cultures will determine PLEC’s role in AD neuropathogenesis and elucidate the underlying role of the cytoskeleton in AD susceptibility. To that end, we generated an endogenous GFP‐tagged dPLEC (dPLEC‐GFP) and performed immunoprecipitation‐mass spectrometry (IP‐MS) analysis to identify dPLEC protein interactors. Several cytoskeletal and synaptic proteins were identified and are currently being tested for their role in Tau‐induced neurodegeneration and synaptic dysfunction.

Conclusion

We functionally validate the AD target PLEC as a regulator of Tau‐induced neurodegeneration and identify PLEC as a regulator of Tau dynamics and neuronal function.
The dynamics of auditory working memory impairment in logopenic aphasia and Alzheimer’s disease
Authors: Levett Benjamin , Kalian Iris , Core Lucy , Jiang Jessica , Warren Jason D , Hardy Chris JD
Published: December 2023

Background

Impaired auditory verbal working memory is a diagnostic hallmark and integral driver of the clinical phenotype in logopenic aphasia. However, the physiology of the working memory buffer in this syndrome is poorly characterised. Here we addressed the temporal dynamics of auditory verbal working memory in patients with logopenic aphasia and typical Alzheimer’s disease.

Method

In a cohort of patients with logopenic aphasia and typical Alzheimer’s disease and in healthy age‐matched controls, we assessed how temporal manipulations of standard auditory verbal working memory tasks (forward and reverse digit span and phrasal repetition) affected performance. We varied tempo of delivery and inter‐trial gap and performed a detailed analysis of error types. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.

Result

Compared with healthy controls, patients with logopenic aphasia and Alzheimer’s disease showed increased sensitivity to temporal manipulation of auditory verbal working memory tasks and error profiles suggesting a dynamic physiological lesion of the working memory buffer. These effects were particularly marked in the logopenic group.

Conclusion

Our findings open a novel physiological window on working memory dynamics in Alzheimer’s disease syndromes. Further work is warranted to assess how this dynamic deficit impacts communication in patients’ daily lives, how it can best inform management interventions and its potential as a novel, rapid read‐out of neural function in the era of disease‐modifying therapies.
Spatial proteomics and cell‐type specific changes in the basal ganglia of different neuropathologic vascular dementing lesions
Authors: Zamudio Carlos , Danner Benjamin , Ajroud Kaouther , Pladies Erica , Matos Arleen , Spencer Callen , White Lon R , Flanagan Margaret E
Published: December 2023

Background

Vascular dementia (VD) is the second most common cause of dementia behind Alzheimer’s disease. VD has been associated with various cardiovascular maladies, which are thought to contribute to the white matter abnormalities associated with dementia. Cerebrovascular impairment disrupts CNS blood supply resulting in inflammation, oxidative stress, and hypoxia. The aim of this project is to study the impact of the cytotoxic environment created by disruptions to the CNS vasculature, which could be detrimental to glial (microglia, astrocyte) viability and function. We examined age and sex‐matched VD and control human autopsy brain from the Honolulu Asia Aging Study.

Method

Utilizing Nanostring’s GeoMx™ Digital Spatial Profiling (DSP), we analyzed autopsy brain to compare neuropathologic vascular dementia lesions (lacunar, macro, and chronic microinfarcts) in the basal ganglia across the disease spectrum (absent/mild, moderate, severe). DSP enables spatial analysis of expression levels for 73 proteins in multiple regions of interest on formalin‐fixed paraffin‐embedded sections. Morphology markers were IBA1 (microglia) and GFAP (astrocytes) (Figure 1a‐b).Indica Labs’ HALO object co‐localization module was used to determine astrocyte, microglia, and total nuclei counts.

Result

For chronic microinfarct severity, astrocyte and microglial counts decreased as the number of microinfarcts increased. By contrast, for macroinfarcts, astrocyte counts increased in addition to microglia steadily decreasing as the number of macroinfarcts increased. Analyses comparing increasing chronic microinfarct severity revealed numerous proteins with differential expression in both microglia and astrocytes, including pTauS404, IDE, p62, ATG5 and P2RX7 (Figure 2 microglia; Figure 3 astrocytes).

Conclusion

Using a spatial proteomic technique, we demonstrated that various vascular dementing lesions have unique glial autophagy and inflammatory profiles at different disease stages. Overall, lower levels of vascular dementia lesions display lower levels of inflammation and increased upregulation of protective pathways that may contribute to maintenance of cognitive function. We also demonstrated basal ganglia cell population changes across different disease severities for chronic microinfarcts and macroinfarcts. Findings suggest that there is progressive astrocyte and microglial loss in the setting of chronic microinfarcts and increased astrogliosis in the setting of macroinfarcts. Whether there is a definitive inverse relationship in astrocyte counts between chronic microinfarcts and macroinfarcts remains unclear.
Cerebrovascular disease is associated with memory function in the Health and Aging in Africa Longitudinal Study of an INDEPTH community in rural South Africa
Authors: Cotton‐Samuel Dejania , Farrell Meagan T. , Wagner Ryan G. , Bassil Darina T. , Mahlalehla Nomsa , Igwe Kay C. , Ohene‐Kwofie Daniel , Manly Jennifer J. , Mngomezulu Victor , Tollman Stephen , Berkman Lisa F. , Brickman Adam M.
Published: December 2023

Background

Health and Aging in Africa Longitudinal Study of an INDEPTH community in South Africa (HAALSI) is a sister study to the US‐based Health and Retirement Study. The purpose of HAALSI is to characterize the social, economic, biological, physical, and mental health factors in a population‐representative cohort of older adults in a rural community in Agincourt, South Africa. Beginning in 2020, as part of an Alzheimer’s disease and related disorders (ADRD) substudy, we conducted neuropsychological evaluations and structural magnetic resonance imaging (MRI) in a subset of HAALSI participants. Here, we report preliminary observations on the relationship of white matter hyperintensity (WMH) volume, a marker of small vessel cerebrovascular disease, and hippocampal volume, a marker of neurodegeneration, on memory function in a group of substudy participants.

Method

Ninety‐nine HAALSI ADRD participants with available MRI scans and neuropsychological outcomes at time of analysis (mean ± SD; age = 70.3 ± 10.9, 87% with no formal education or some primary education) were included in these analyses. Participants received research‐grade, harmonized 1.5T MRI scanning at a private hospital and were evaluated with a battery of neuropsychological tests. Using in‐house developed software and FreeSurfer, respectively, we derived total WMH volume and total hippocampal volume. We examined the association of these variables with memory function, operationalized as the delayed recall score of the Logical Memory Test, adapted for context.

Result

Adjusting for education level, increased WMH volume was associated with poorer performance on the Logical Memory Test (standardized β = ‐0.21, p<0.05) but hippocampal volume was not (standardized β = 0.09, p = 0.41). Associations of these MRI markers with memory function did not interact with education level.

Conclusion

In these preliminary analyses of older adults in a rural South African community, markers of small vessel cerebrovascular disease but not neurodegeneration are associated with poorer cognitive outcomes. Future work will examine the pathways that give rise to cognitive impairment and dementia in this rural South African population and track cognitive trajectories over time.
A logarithm derived from Mokken scaling analysis of the Addenbrooke’s Cognitive Examination–Revised discriminates with high accuracy Alzheimer’s disease from behavioral variant frontotemporal dementia
Authors: Amaral‐Carvalho Viviane , Lima‐Silva Thais Bento , Mariano Luciano Inácio , de Souza Leonardo Cruz , Guimarães Henrique Cerqueira , Bahia Valeria S , Nitrini Ricardo , Barbosa Maira Tonidandel , Yassuda Monica Sanches , Caramelli Paulo
Published: December 2023

Background

The ACE‐R is an accurate and brief cognitive battery for the detection of mild dementia, especially for the discrimination between Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). The aim of this study was to develop a logarithm based on discriminative items of the ACE‐R for AD combined with relevant demographic characteristics that may help to differentiate AD from bvFTD.

Method

The ACE‐R was administered to 102 patients with mild dementia due to probable AD and 37 patients with mild bvFTD from two Brazilian research centers. All individuals were submitted to the Mattis Dementia Rating Scale (DRS) and the ACE‐R. The performance of the patients was compared and analyzed. Mokken scaling analysis was applied to identify the latent trait on the AD Group, and later, multivariate logistic regression and ROC curve analysis were carried out to assess the ACE‐R’s ability to discriminate AD and bvFTD.

Result

Mean ± SD total scores in the ACE‐R were 70.2 ± 10.8 in AD and 72.2 in bvFTD. AD Mokken ACE‐R (MokACE‐R‐AD) comprises 12 items measuring the same latent concept. In our sample, logistic regression with cross‐validation pointed that MokACE‐R‐AD, Age, Male sex, and items Orientation to time and location and the item of Memory (name and address recall) share importance as independent variables (p<0.05) to differentiate AD from bvFTD. The proposed logarithm reached an area under the ROC curve of 0.922, with 88% sensitivity, 88% specificity, 71% PPV and 96% NPV.

Conclusion

The new logarithm using the ACE‐R items achieved high diagnostic accuracy in identifying mild AD versus bvFTD. Furthermore, the final ROC curves showed the superiority of the model proposed in relation to the analysis of the subscales individually or the VLOM ratio, as the literature previously reported. Further analysis in larger samples, with biomarkers or pathological confirmation, are necessary to confirm these findings.
Cerebellar‐cortical functional connectivity is associated with Alzheimer’s disease pathology and cerebellar atrophy
Authors: Kim Soyun , Adams Jenna N. , Stith Lea , Taylor Lisa M. , Harris Alyssa L. , McMillan Liv , Yassa Michael A. ,   The Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Brain atrophy has been associated with Alzheimer’s disease (AD) pathology. Previous research also suggests that functional connectivity (FC) among distributed neural networks is disrupted in preclinical AD. The cerebellum has been thought to play a crucial role in motor control, yet recent evidence points to its additional role in non‐motor domains as well as cognitive decline in AD. Cerebellar volume has been shown to decline along the course of AD progression. Moreover, neuroimaging studies have delineated intrinsic cerebellar‐cortical functional networks that presumably support cognitive functions. Despite the accumulating findings on neurodegeneration or FC, how cerebellar FC and atrophy relate to AD pathology in the early stage has not been extensively investigated.

Method

Data from 83 cognitively normal older adults (mean 71.0 yrs, 66% females) in the Alzheimer’s Disease Neuroimaging Initiative were analyzed. Volumetric data were obtained from FreeSurfer 6.0 segmentation. Resting state fMRI scans were preprocessed using the CONN Toolbox. Aβ and tau standardized uptake value ratio (SUVR) data were obtained from [18F]‐Florbetapir or [18F]‐Florbetaben (Aβ) and [18F]‐Flortaucipir (tau) PET scans. For Aβ, SUVR values were transformed to the Centiloid scale, and a global summary measure was used. For tau, SUVR values in the temporal meta regions of interest were used. Seed‐based functional connectivity metrics were computed using the 7 cerebellar parcellations (Buckner et al., 2011) that are functionally coupled to different cortical networks (Yeo et al., 2011).

Result

Cerebellar volume showed no significant relationship with amyloid or tau SUVR. By contrast, hippocampal atrophy was positively associated with amyloid or tau SUVR and showed trending significance (ps < 0.1). Increased Aβ burden was associated with increased cerebellar‐cortical FC in the attention, frontoparietal, and default mode networks. Increased tau load was associated with increased cerebellar‐cortical FC in the visual, somatomotor, and attention networks. Cerebellar volume was associated with cerebellar‐cortical FC in the visual, somatomotor, attention networks, but not with the limbic, frontoparietal, or default mode networks.

Conclusion

Our findings suggest that functional cerebellar‐cortical connectivity varies with amyloid and tau pathology in different networks, and such functional changes may precede cerebellar atrophy in preclinical AD.
Relationship for co‐trajectories of cognitive decline and late‐life depression with postmortem neuropathology
Authors: Yang Mu , Tio Earvin S. , Schneider Julie A , Bennett David A. A , Felsky Daniel
Published: December 2023

Background

The etiopathological relationship between late‐life cognitive decline and symptoms of depression remains unclear. Existing longitudinal studies have mostly grouped participants into distinct groups based on clinical diagnoses, and very few have analyzed postmortem neuropathology. Here we identified trajectories of both cognition and depressive symptoms in an elderly cohort over up to 27 years using growth mixture modeling (GMM), identifying co‐trajectory subgroups, and characterizing them with respect to postmortem neuropathologies.

Method

We analyzed 3,010 participants enrolled without dementia (mean age = 78) from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). All included participants were evaluated for at least three annual visits for both depressive symptoms (using a modified Center for Epidemiologic Studies Depression Scale) and 19 cognitive tasks (yielding a global cognitive function summary score). A subset of 1,732 participants had complete postmortem neuropathological assessment data available. Latent trajectory subgroups were identified independently for global cognition and depressive symptoms using GMM with non‐linear time effects. Interaction effects of cognitive and depressive trajectory subgroups on neuropathologies were assessed using linear models.

Result

Three trajectory subgroups (Figure 1) were identified for both cognitive decline (minimal (n = 1,232), slow (n = 1,325) and fast (n = 302)) and depressive symptoms (sustained low (n = 1,815), moderately increasing (n = 762) and consistently elevated (n = 433)). These subgroups showed significant overlap (chi‐square p = 0.0001), and their intersections defined nine co‐trajectories. A significant interaction effect (p = 0.0062) was identified between cognitive decline and depressive symptom trajectory subgroups for brain‐wide levels of paired helical filament tau; among only individuals experiencing fast cognitive decline, sustained lower depressive symptoms were associated with higher levels of tau (Figure 2).

Conclusion

Longitudinal cognitive decline and depressive symptom trajectories in late‐life are not independent. Intriguingly, we observed the highest tau burden in those individuals with both sustained low depressive symptoms and fast rates of cognitive decline. Given that use of antidepressants may lower tau levels (Dafsari & Jessen, 2020), future models of neuropathology in trajectory‐based analyses will incorporate patterns of medication status.
Associations between physical activity and sedentary behaviour patterns and cognition: A cross‐sectional analysis of the Canadian Longitudinal Study on Aging
Authors: Balbim Guilherme Moraes , Falck Ryan S , Liu‐Ambrose Teresa
Published: December 2023

Background

Engaging in regular physical activity (PA) and limited sedentary behaviour (SB) are critical for healthy cognitive aging. However, it is unclear what combination of PA and SB patterns (e.g., high PA and low SB, high PA and high SB, etc.) is most beneficial for cognition. We thus examined how different combinations of PA and SB were associated with cognitive performance in community‐dwelling middle‐aged and older adults.

Method

A cross‐sectional analysis using baseline data from the Comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA; 2010‐2015) among participants with complete PA and SB data (n = 23,125; age range 45‐86 years). PA and SB were indexed using the Physical Activity Scale for the Elderly (PASE) and cognition using a three‐factor structural equation model (i.e., memory, executive function, and verbal fluency). Participants' PA and SB levels were classified as 1) low PA and high SB; 2) low PA and low SB; 3) high PA and high SB; and 4) high PA and low SB. Linear regressions assessed associations between PA and SB combinations and cognition, adjusted for age, sex, activities of daily living, income level, educational attainment, and depression. Contrasts with Bonferroni correction tested associations of combinations of PA and SB with cognition.

Result

High PA was associated with better cognition whether combined with low or high SB. A high PA and low SB combination was associated with better executive function (Estimated mean difference = ‐0.24, 95%CI ‐0.39 to ‐0.10, p<0.001) and verbal fluency (Estimated mean difference = ‐0.29, 95%CI ‐0.42 to ‐0.16, p<0.001) vs. low PA and low SB. A combination of high PA and high SB was associated with better executive function (Estimated mean difference = 0.17, 95%CI 0.01 to 0.33, p = 0.034) and verbal fluency (Estimated mean difference = 0.20, 95%CI 0.05 to 0.34, p = 0.002) vs. high PA and low SB. Surprisingly, low PA and high SB was associated with better executive function vs. low PA and low SB (Estimated mean difference = 0.26, 95%CI 0.11 to 0.41, p<0.001) (Table 1 and Figure 1).

Conclusion

High PA, irrespective of SB, is associated with better cognition. Low PA levels may be more detrimental to cognition than high SB levels.
Elevated Tau burden in Amygdala and Hippocampus amongst older participants with psychosis
Authors: Johnson Aubrey S. , Ziaggi Galen , Smith Anna C. , Guzmán Diana S. , Okafor Amarachukwu , Huey Edward D. , Kreisl William Charles , Talmasov Daniel , Lao Patrick J.
Published: December 2023

Background

Psychosis is a debilitating cluster of symptoms occurring in some Alzheimer’s Disease (AD) patients, and is defined by the presence of delusions and/or hallucinations. Previous studies suggest that psychosis in AD patients is associated with increased tau burden and accelerated cognitive decline. We sought to assess differences in tau burden between cognitively impaired patients with psychosis(+P) and those without psychosis(‐P).

Method

Twenty‐six ADNI participants with psychosis (+P; 11.5% CDR0, 42.3% CDR0.5, 30.7% CDR1, 11.5% CDR2, 4% CDR3, 77±7yr old, 50% women, 16±3yr education, 92% White) and 26 without psychosis were matched by CDR, age, sex, education, and race (‐P; 11.5% CDR0, 42.3% CDR0.5, 30.7% CDR1, 11.5% CDR2, 4% CDR3, 77±6yr old, 54% women, 15±3yr education, 92% White). The +P group was defined based on any endorsement of hallucinations or delusions on Neuropsychiatric Inventory. Flortaucipir PET data were processed according to ADNI methods. Difference in tau burden was assessed using a paired t‐test on the ROI and voxel‐level between +P and ‐P groups in Braak regions as well as the amygdala, hippocampus, and frontal, temporal, and parietal lobes A follow‐up voxelwise t‐test was performed within the +P group between those with and without concurrent symptoms at the time of their scan. Analyses were corrected for amyloid‐level and voxel‐wise analyses were evaluated at p<0.001 without multiple comparisons correction.

Result

Descriptively, participant‐level scans demonstrated a variety of tau patterns, often with right laterality. Tau was elevated for +P participants compared to ‐P in the amygdala (0.6 [0.25, 0.96]; p = 0.003) and the hippocampus (0.3 [0.04, 0.55]; p = 0.03), while marginally elevated in the frontal cortex (0.09 [‐0.002, 0.189]; p = 0.06) [Figure1]. Voxel‐wise, elevated tau was localized to the amygdala, hippocampus, thalamus, and right frontal lobe [Figure2]. Additionally, with concurrent delusion symptomatology, elevated tau was localized to Braak III/IV regions [Figure3].

Conclusion

Tau burden in the amygdala may be a potential biomarker of psychosis across the AD continuum. Right‐sided laterality is consistent with psychosis‐related structural changes and psychosis‐related tau binding needs to be assessed further. Given that early psychosis in AD is associated with faster cognitive decline, these results could inform the development of prognostic biomarkers.
Sex and genotype dependent differences in amyloid beta levels and lipid metabolism in type 2 diabetic APPxhQC transgenic mice
Authors: Babalola Joshua Adekunle , Lang Magdalena , George Meekha , Stracke Anika , Loeffler Tina , Schilcher Irene , Flunkert Stefanie , Neddens Joerg , Prokesch Manuela , Leitinger Gerd , Lass Achim , Hoefler Gerald , Hutter‐Paier Birgit
Published: December 2023

Background

Accumulation of amyloid beta (Aβ) and tau proteins have for decades been thought to be central in the pathogenesis of Alzheimer’s disease (AD). More recently, a plethora of evidence emerged that links metabolic dysfunctions such as obesity, type 2 diabetes (T2D), and dyslipidemia with the pathophysiology of AD. In this study, we investigated the effects of streptozocin and high fat diet (HFD) induced T2D on lipid and amyloid beta metabolism in APPxhQC transgenic mice and their wild‐type littermates.

Method

APPxhQC mice were generated by crossbreeding APPSL with hQC mice. As controls wild‐type littermates were used. APPSL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice express human glutaminyl cyclase (QC) enzyme on B6CBAF1/J background. Plasma lipids (triglycerides and cholesterol) and liver function enzymes (aspartate aminotransferase and alanine transaminase, ALT and ALT, respectively) were determined by ELISA. Brain concentrations of soluble and insoluble Aβ 1‐38, 1‐40 and 1‐42 peptides were determined using an immunosorbent assay (Mesoscale discovery immunosorbent assay) while pGlu Aβ1‐42 was measured by ELISA. Hepatic mRNA expression levels of genes involved in cholesterol efflux and lipid metabolism were determined by quantitative real time polymerase chain reaction (qRT‐PCR).

Result

T2D induced increased concentrations of plasma cholesterol as well as AST and ALT levels. The magnitudes, however, were dependent on sex and genotype and were statistically significant in female wild‐type mice, while a similar pattern was observed in APPxhQC transgenes. These increased plasma concentrations were accompanied by a down‐regulation of hepatic gene expression levels of LRP1, ABCA1, PPARα, PBC1β, and NEP that were statistically significant in female wild‐type mice, while a similarly pattern was observed in APPxhQC transgenic mice. More interestingly, T2D provoked a progressive shift of brain Aβ 1‐38 and 1‐40 from soluble to insoluble forms in male APPxhQC mice and a significant increase of pyroglutamate modified Aβ 1‐42 in female mice.

Conclusion

T2D in APPxhQC mice provokes a shift from soluble to large insoluble polymers of Aβ in the brain, corroborates the deteriorating role of T2D in the progression of AD
The TIE‐93 : a cross‐cultural facial emotion recognition assessment adapted for multicultural Alzheimer’s dementia patients
Authors: Bourdage Renelle , Franzen Sanne , Papma Janne M. , Palisson Juliette , Joy Charlotte , Garcin Béatrice , Narme Pauline
Published: December 2023

Background

Facial emotion recognition testing in patients with Alzheimer’s disease (AD) dementia has been recently identified as essential for early detection and differential diagnostics (García‐Casal et al., 2019; Strijkert et al., 2022). However, experts in neuropsychology identified that emotion recognition remains one of the most difficult domains to assess in culturally diverse populations due to a lack of culturally adapted tools (Franzen et al., 2021). To address this resource gap, this study validated a cross‐cultural test for emotion recognition; the TIE‐93.

Method

Fifty‐six patients with AD and 240 healthy controls (aged 60 years and older), from French and multicultural backgrounds, were included in the study. The TIE‐93 is composed of eight panels with six photos of actors displaying six different emotions (happiness, anger, disgust, fear, sadness and neutral). The participant is given a scenario with an emotion cue and are asked to identify which of the six emotions displayed matches the scenario.

Result

In healthy controls, analyses showed a negative correlation between performance and age (r = ‐.15, p<.05), and a positive correlation with education level (r = .4, p<.001). Given the difference in education level between French and multicultural participants, comparisons were made within cultures. Multicultural AD patients (n = 23) were compared to multicultural controls (n = 148) using an ANCOVA with education as a covariate. A significant effect was found for diagnosis (F(1, 168) = 6.6; p<0.01), with lower scores in AD patients compared to controls, as well as a significant emotion x diagnosis interaction (F(1, 168) = 5; p<0.05). The intergroup effect was significant only for disgust (p<0.001), fear (p<0.05) and anger (p<0.01). French AD patients (n = 33) were compared to French controls (n = 93) using an ANOVA, as education did not differ between groups. Results showed a significant effect for diagnosis (F(1, 123) = 10.3; p<0.005) with a non‐significant emotion x diagnosis interaction (F(1, 123) = 3.1; p = 0.08). However, the diagnosis effect was significant for all emotions except happiness: disgust (p<0.05), sadness (p<0.01), neutral (p<0.05), fear (p = 0.005), anger (p<0.05).

Conclusion

The TIE‐93 seems valid for assessing facial emotion recognition in multicultural populations, demonstrating a decline in facial emotion recognition in patients with AD as compared to healthy controls.