bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of FTD clinical diagnostic features in patients with TDP‐43 pathology
Authors: Chatterjee Atri , Hirsch‐Reinshagen Veronica , Ducharme Blake , Leung Bonnie , Mousavi Ali , Hsiung Ging‐Yuek Robin , Mackenzie Ian R.
Published: December 2020

Background

Frontotemporal dementia (FTD) is a heterogeneous syndrome which includes three main clinical subtypes, behavioural variant FTD (bvFTD) and the non‐fluent and semantic variants of primary progressive aphasia (nfvPPA, svPPA). The pathology underlying clinical FTD, referred to as frontotemporal lobar degeneration (FTLD), is also heterogenous with transactive response DNA binding protein Mw 43 (FTLD‐TDP) present in ∼50%. In this study we investigate the proportion of FTLD‐TDP cases that fulfil diagnostic criteria for each of the clinical FTD subtypes.

Method

We retrospectively reviewed charts of patients with autopsy proven FTLD‐TDP. Patients with additional pathology, (e.g. Alzheimer’s disease, AD), were excluded. We extracted clinical data regarding behaviour, language and cognition, and compared these against the current FTD clinical diagnostic criteria.

Result

Fifteen of 24 patients (62.5%) with autopsy‐confirmed FTLD‐TDP pathology met diagnostic criteria for possible bvFTD (n=9), nfvPPA (n=3) or svPPA(n=3). The clinical diagnosis of the nine patients who did not match criteria for any of the three FTD syndromes included FTD with motor neuron disease (n=5), AD type dementia (n=3), progressive supranuclear palsy (n=1), corticobasal syndrome (n=1) and FTD with Parkinsonism linked to chromosome 17 (n=1). Patients with motor neuron disease developed 1 (n=2) or 2 (n=3) diagnostic features of bvFTD.

Among the bvFTD diagnostic features, executive dysfunction was the commonest (79.2%), followed by apathy (37.5%) and disinhibition (33.3%). 70.8% of all patients and 42.9% of bvFTD patients developed clinical features of aphasia. Cognitive screening tests revealed a high prevalence of impaired short‐term recall (79.2%) and language dysfunction (83.3%) irrespective of the clinical diagnosis.

Conclusion

bvFTD is the commonest presentation of FTLD‐TDP; however, a significant proportion of patients do not match diagnostic criteria for FTD. Additionally, the high prevalence of impaired short‐term recall suggests it may not be practical to use this as an exclusionary criteria for FTD. We recognize the selection bias in our sample which was derived exclusively from a dementia clinic population.
Association of cardiovascular risk and sex with cortical tau deposition in cognitively normal and at‐risk Alzheimer’s subjects
Authors: Kleniuk Julia , Edison Paul
Published: December 2020

Background

Epidemiological data shows co‐incidence of cardiovascular (CV) disease and Alzheimer’s disease (AD), however the relationship between CV risk and specific AD biomarkers is not clear. Both CV disease and AD affect men and women differently. Here, we investigated the relationship between CV risk and cortical tau deposition in two regions, the entorhinal cortex (ETC) and the inferior temporal cortex (ITC). We hypothesised that high CV risk will be associated with increased cortical tau deposition.

Method

Cross‐sectional data of 197 subjects (mean age 78.4, 113 male, 84 female, 107 cognitively normal) who underwent AV‐1451 tau PET imaging were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. CV risk was calculated using the Framingham Heart Study 10‐year risk score for Cardiovascular Disease (FHS‐CVD) modified for age. Regional AV‐1451 uptake between the low‐risk (bottom 25% of the sample) and high‐risk (top 25%) subjects was compared.

Result

High‐risk men showed significantly higher AV‐1451 uptake than their low‐risk counterparts in both the ETC (p=0.002) and in the ITC (p=0.02). After adjusting for age as a covariate, the difference remained significant for the ETC, but not the ITC. High‐risk and low‐risk women did not differ significantly in AV‐1451 uptake in neither of the regions studied.

Conclusion

The results show that high CV risk is associated with increased cortical tau deposition in men, but not in women. These findings highlight the sex differences in AD trajectory and the need for stratification of subjects by sex in clinical trials.
The effect of global ancestry and diabetes on the 3MS score in older Puerto Ricans
Authors: Tejada Sergio J. , Rajabli Farid , Mena Pedro Ramon , Martin Eden R. , Rodriguez Vanessa C. , Celis Katrina , Adams Larry D. , Bussies Parker , Prough Michael , Hamilton‐Nelson Kara L. , Silva‐Vergara Concepcion , Acosta Heriberto , Vance Jeffery M. , Feliciano‐Astacio Briseida E. , Beecham Gary W. , Pericak‐Vance Margaret A. , Cuccaro Michael L.
Published: December 2020

Background

There is limited study of the effect of genetically determined ancestral background and diabetic risk on cognitive status in admixed populations. Puerto Ricans are an admixed population with European (EU), African (AF), and Amerindian (AI) backgrounds. We analyzed the impact of ancestry and diabetes on cognitive status in older Puerto Ricans.

Method

The dataset consisted of Puerto Ricans > 60 years of age enrolled in the Puerto Rican Alzheimer Diseases Initiative (PRADI). At study entry, all participants were administered the 3MS to screen for cognitive problems. Medical history, including the presence of hypertension, diabetes, and cholesterolemia was also collected at that time. Model building analyses indicated that diabetes was the sole vascular predictor. Admixture proportions were estimated using the ADMIXTURE software. Using a Generalized Estimating Equations (GEE) approach, we modelled the contribution of sex, age at 3MS testing, global ancestry proportion, and diabetes to the participants 3MS score.

Result

The dataset consisted of 689 Puerto Ricans (70% female) with a mean age at 3MS of 74.9 years (SD=8 years). Mean global ancestry proportions were highest for EU (71%) followed by AF (18%) and AI (11%). As expected, we found significant associations between age, sex, and an age‐sex interaction and the 3MS score. However, we also found significant interactions between ancestry proportions and diabetes as predictors of 3MS score. Specifically, when compared to the effects of combined EU and AI ancestry on the 3MS score, the effect of diabetes on 3MS score is larger in individuals with higher proportions of AF ancestry (p < 0.01).

Conclusion

Cognitive decline can be secondary to many different deleterious factors. Along with Alzheimer disease, small vessel vascular disease is a major contributor to the development of dementia. Indeed, diabetes affects small blood vessels, and these data support the importance of controlling diabetes in the Puerto Rican population, particularly those with a strong AF ancestry. This highlights the importance of looking for a history of diabetes when evaluating cognition in dementia‐related disorders in Hispanic populations with AF admixture.
Principal components from untargeted CSF metabolomics associated with tau
Authors: Dong Ruocheng , Deming Yuetiva , Lu Qiongshi , Ma Yue , Carlsson Cynthia M. , Johnson Sterling C. , Asthana Sanjay , Blennow Kaj , Zetterberg Henrik , Engelman Corinne D.
Published: December 2020

Background

There has been increasing evidence for metabolic contribution in Alzheimer’s disease (AD) pathology aided by recent advancements in metabolomics which allow measurement of a large number of metabolites reflecting changes downstream of genomic, transcriptomic and proteomic fluctuations (Trushina, & Mielke, 2014). Studying the correlation between cerebrospinal fluid (CSF) metabolites and AD endophenotypes may offer a window to the alterations of the brain metabolome and unveil potential biological mechanism underlying AD.

Method

CSF samples from 139 unrelated cognitively unimpaired individuals from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and 313 cognitively unimpaired and MCI individuals from the Wisconsin Alzheimer’s Disease Research Center (W‐ADRC) were analyzed to determine the relative abundance of untargeted metabolites via Metabolon’s UHPLC/MS platform. This resulted in 308 CSF metabolites that were included in a principal component analysis (PCA). Longitudinal values were averaged and data from WRAP and W‐ADRC were combined. After PCA, the principal components (PCs) explaining most of the variance in all CSF metabolites, were tested for association with CSF total tau (T‐tau), phosphorylated tau (P‐tau), and amyloid β 42/40 (Aβ 42/40) using linear regression models adjusting for age, sex, race, years of education, and cohort. Pathway analysis was employed for metabolites with top loadings in each significant PC.

Result

32 PCs explained up to 90% of the variance in the 308 CSF metabolites. Among them, four PCs, PC20, 21, 22 and 23, were significantly associated with CSF T‐tau and P‐tau after Bonferroni adjustment (Table 1). No PCs were associated with Aβ 42/40. Pathway analysis of the four significant PCs suggested that caffeine metabolism, nicotinate and nicotinamide metabolism, glycerophospholipid metabolism, and vitamin B6 metabolism, which had significant FDR p values (<0.05) or reached the significant impact score threshold (≥0.15), might be of interest for future research (Table 2).

Conclusion

This study provides evidence that CSF metabolites are related to AD pathology through T‐tau and P‐tau and, thus, may provide insight into the mechanisms involved in tau tangles.
Identifying key features for dementia diagnosis using machine learning
Authors: Guest Felicity , Kuzma Elzbieta , Everson Richard , Llewellyn David J.
Published: December 2020

Background

Diagnosing dementia is clinically challenging due to substantial heterogeneity in presenting symptoms and underlying pathologies. However, machine learning provides a powerful approach to uncover hidden patterns in complex data that may in turn inform clinical practice.

Method

We used patient data from the National Alzheimer’s Coordinating Center Uniform Data Set (versions 1.2 and 2) collected at 35 Alzheimer’s Disease Centers across the United States between September 2005 and February 2015. All 32,573 patients (median age=73 years, 57% female) were assessed according to standardized protocols involving extensive clinical and neuropsychological assessments which resulted in a pool of 260 continuous, binary, ordinal or categorical features. Patients were randomly split 70:30 into training (n=22,801) and test (n=9,772) samples. All‐cause dementia and dementia subtypes (Alzheimer’s disease, vascular, Lewy body, frontotemporal and ‘other’) were diagnosed by either a single clinician or consensus panel using established international criteria. Random forests (Extra‐Trees algorithm) were used to differentiate between all‐cause dementia and no dementia, and between different subtypes, through the construction of an ensemble of decision trees which makes classifications via voting. We used similarity‐based imputation and the missingness incorporated in attributes approach to deal with missing data whilst preserving relationships between variables.

Result

The all‐cause dementia classifier incorporating all 260 features was able to differentiate between dementia and no dementia with an accuracy of 94.2% in the test sample (sensitivity 92.8% and specificity of 95.1%). The most important features related to impaired cognitive domains, particularly judgement, planning or problem solving and orientation, and everyday activities such as home and hobbies, community affairs and difficulty with bills. It was found the performance of the original classifier could be matched with just the 42 most important features. Subtype classifiers ranged in accuracy from 80.8% for frontotemporal dementia versus ‘other’ dementia to 99.4% for Alzheimer’s disease versus vascular dementia. The most important features for differential diagnosis included stroke history, visual hallucinations and Parkinson’s disease.

Conclusion

Machine learning can be used to uncover hidden patterns in high‐dimensional clinical data and identify the most important characteristics for accurately diagnosing dementia.
Synaptic proteins relate to memory scores in preclinical Alzheimer’s disease and cognitively healthy controls depending on amyloid
Authors: Wesenhagen Kirsten E.J. , Visser Pieter Jelle , Gobom Johan , Bos Isabelle , Vos Stephanie J.B. , Martinez‐Lage Pablo , Tainta Mikel , Popp Julius , Peyratout Gwendoline , Tsolaki Magda , Vandenberghe Rik , Freund‐Levi Yvonne , Verhey Frans R.J. , Lovestone Simon , Streffer Johannes , Blennow Kaj , Scheltens Philip , Teunissen Charlotte E. , Zetterberg Henrik , Tijms Betty M. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Memory loss is central to Alzheimer’s disease (AD), but the precise underlying mechanisms remain unclear. Post‐mortem research suggests that synaptic loss best explains symptoms. Here, we investigated in cerebrospinal fluid (CSF) whether levels of synaptic proteins are related with memory scores in older individuals with normal cognition and in preclinical AD.

Method

Participants were selected from ADNI and EMIF‐AD MBD if they had CSF proteomics and memory scores available. In total, we selected 85 controls (i.e., normal cognition (CN) and normal CSF amyloid‐1‐42 and tau levels; mean±sd age 69±9 years, 58% female) and 46 preclinical AD (i.e. normal cognition and abnormal CSF amyloid‐1‐42 level, normal or abnormal CSF t‐tau and p‐tau; mean±sd age 74±7 years, 50% female). Age‐, sex‐ and education‐specific norms were used to normalize memory tests (ADNI: 30‐minute delayed Rey auditory verbal learning test (ADNI), EMIF: centre‐specific delayed memory tests). We selected 37 proteins available in both cohorts that were specific for synapses according to synGO (https://www.syngoportal.org/), Z‐transformed protein levels relative to controls, and pooled these across cohorts. Protein‐memory associations were assessed with linear models; model1: including covariates education, sex and age; model2: model1 + covariate amyloid status; and model3: model2 + protein level‐amyloid status interaction.

Result

Memory scores were similar in the preclinical AD and control groups (P=0.52, Figure 1). Three proteins (NCSTN, FGA and NRGN) had increased levels in preclinical AD vs. controls. Across the total group, no proteins were associated with memory functioning. Repeating models including an interaction term with amyloid status showed that 9 synaptic proteins (24.3%) were associated with memory depending on amyloid status. In controls, lower protein levels related with better memory, while in preclinical AD, lower protein levels tended to be related with worse memory (Figure 2).

Conclusion

Of the synaptic proteins tested, associations with memory were mediated by amyloid status. The finding that lower synaptic protein levels related to better memory in controls, but to worse memory in preclinical AD suggests that synaptic protein levels may reflect different biological processes in these groups.
Psycholinguistic properties of words on fluency testing relate to different aspects of subjective cognitive decline
Authors: Barker Megan S. , Chapman Silvia , Mejia Arlene , Joyce Jillian L. , Sunderaraman Preeti , Idnay Betina R.S. , Kreisl William Charles , Cosentino Stephanie
Published: December 2020

Background

Subjective Cognitive Decline (SCD) is posited as a marker of preclinical Alzheimer’s disease. However, the nature of SCD and its relationship with objective cognition remain the subject of debate. More sensitive markers of objective cognition are likely needed to capture variability in SCD; one candidate is the psycholinguistic information embedded in language tasks, such as lexical frequency and concreteness, which is rich in cognitive information. In addition, attention to the nature of SCD is important for advancing our understanding of its relationship with objective cognition. Here we investigate how psycholinguistic information (lexical frequency and concreteness) relate to different sets of items on an SCD scale.

Method

Participants included 74 cognitively healthy older adults (mean age = 73.76 (7.20), education =16.91 (2.20), 66% female, 85% Caucasian, 10% African American, 4% Asian and 1% other). SCD was measured with a 20‐item questionnaire, using a 7‐point Likert scale to rate difficulty on each item compared with others their age. Principal Component Analysis (PCA) was conducted to derive underlying SCD factors. Participants also completed semantic fluency (animals) and phonemic fluency (CFL) tasks. Lexical frequency values were computed for each word generated on fluency tasks. Concreteness was computed for CFL only; this value would not vary within a semantic task. Nonparametric partial correlations between psycholinguistic measures and SCD factors were conducted, controlling for age, sex and education.

Results

PCA identified three SCD factors with Eigen values >1 that together explained 63% of the total variance. Factor 1 loaded primarily on memory, Factor 2 was a combination of memory and language, and Factor 3 related to attention/executive function. Lexical frequency (animals) was correlated with Factor 1 only; higher SCD related to higher frequency (more common) animals (r=.27, p=.025). Concreteness (CFL) was correlated with Factor 2 only; higher SCD was associated with more concrete, less abstract, words (r=.25, p=.035).

Conclusion

Two measures of psycholinguistic information were uniquely related to different SCD items. This double dissociation reinforces the idea that mapping SCD to objective cognition requires a carefully refined measurement approach with regard to subjective experiences and the information collected from objective measures.
Evaluation of the neurocognitive and neuroprotective potentials of selected Nigerian medicinal plants in preclinical models of learning and memory
Authors: Atunwa Soliu Abiola
Published: December 2020

Background

Dementia is one of the most common forms of neurocognitive disorders with increasing global prevalence and attendant huge socio‐economic burden on the existing healthcare systems. The pathophysiology of amnesia which is unarguably common to all stages in dementia is poorly understood. Meanwhile, the inhabitants of Ibarapa Area of Oyo State, South‐West, Nigeria have long been using certain medicinal plants as memory‐enhancers and neuroprotective remedies. These ethnomedicinal claims however have not been scientifically evaluated, hence, this study.

Method

Ethno‐pharmacological survey of medicinal plants used in the management of neurocognitive disorders in Ibarapa Area of Oyo State, South‐West, Nigeria was carried out among the relevant study groups of the inhabitants through semi‐structured questionnaires and interviews in local language. Informed consent was obtained orally from all respondents before the administration of research tools. The Use Mention Index (UMI), frequency and percentage of occurrence as well as literature search were used as selection criteria for choosing medicinal plants to be screened for possible neurocognitive activities. Data will be expressed as mean ± standard error of mean (SEM) and evaluated using one‐way analysis of variance (ANOVA) followed by post‐hoc test (student‐newman‐keuls test) to determine the source of significant effect or interaction. Graphpad prism version 6 (Graphpad Prism Inc., CA, U. S. A.) will be used as a statistical tool.

Result

data obtained from the ethnomedicinal survey revealed that about 105 medicinal plants are being used as memory enhancers and anti‐aging remedies in Ibarapa Area of Oyo State. They are called different local names as: “marugbo takebe”, ”oogun isoye,”, ”ajidewe”, ”sagba dewe”, “sarugbo domidan” among others. Basic information about geographical distribution; scientific, common and local names; identification, collection/harvesting, part(s) used; method(s) of preparation/processing of herbal remedies; formulations; mode of administration and posology; duration and frequency of use; potency/efficacy, toxicity, conservation and economic issues; poly‐pharmacy; peculiarities of each remedies; and other ethno‐medicinal uses were recorded.

Conclusion

preliminary results obtained so far showed that some of the medicinal plants have central activities thus, scientifically suggesting the rationale for their potential use in the management of memory disorders.
Evaluation of 18F‐MK‐6240 and 18F‐AV‐1451 tau PET tracers in Alzheimer disease
Authors: Mansor Syahir , Zhou Yun , Flores Shaney E. , Hornbeck Russ C. , Dincer Aylin , Gordon Brian A. , Cash Lisa , Swisher Laura , Ances Beau M , Tu Zhude , LaForest Richard , Morris John C. , McDade Eric , Bateman Randall J , Benzinger Tammie L.S. ,   Dominantly Inherited Alzheimer Network
Published: December 2020

Background

Two tau tracers, 18F‐MK‐6240 and 18F‐AV‐1451, have recently been introduced into many studies of Alzheimer disease (AD) but it remains unclear how each tracer evaluates heterogenous tau pathology. In this study we compared the binding of two tau‐specific PET tracers in asymptomatic control (AC) and (AD) participants enrolled in DIAN.

Method

Nine AC and three AD participants were recruited from DIAN underwent PET/CT imaging twice, one with 18F‐MK‐6240 and the other one with 18F‐AV‐1451 on consecutive days. AC participants were scanned with full dynamic scan (0‐110 min for 18F‐MK‐6240 and 0‐105 min for 18F‐AV‐1451) while 20 min (90‐110 for 18F‐MK‐6240 and 80‐100 min for 18F‐AV‐1451) scan for AD participants. Data were analysed using standardized uptake ratios (SUVr) with whole cerebellum used as a reference tissue from an early frame duration (SUVr0.75‐2.5 min) for all nine AC participants and late SUVr (SUVr20min) for all twelve participants. In addition, centrum semiovale was tested as reference region for SUVr20min. Relative delivery (R1) and distribution volume ratio (DVR = BPND+1) were generated using SRTM2 methods from nine AC dynamic data with cerebellum as reference. Bland–Altman analyses were used to evaluate an agreement between two tracers both for AC and AD participants.

Result

Both tracers show an agreement for relative flow and binding in AC participants as shown in Figure 1. In AD participants, 18F‐MK‐6240 shows a proportionally higher tracer specific binding compare to 18F‐AV‐1451 for regions with an average SUVr value higher than 1.5 as seen in Figure 2. 18F‐MK‐6240 shows relatively lower uptake compared to 18F‐AV‐1451 in AC and significantly higher in AD as in Figure 3. The SUVr attain stable after 80 min post injection for both tracers, but the centrum semiovale reference tissue‐based SUVr shows higher contrast between both tracers than the ones using cerebellum reference tissue (Fig 4).

Conclusion

Both tracers show an agreement in AC participants. 18F‐MK‐6240 demonstrates higher SUVr compared to 18F‐AV‐1451 for participants with significant tau deposition in AD. Centrum semiovale is suggested for reference region for both tracers and will be evaluated carefully by the ongoing evaluation study.
Early‐mid adulthood measures of HDL, triglycerides and fasting glucose are associated with late‐onset Alzheimer disease
Authors: Zhang Xiaoling , Tong Tong , Chang Andrew , Ang Ting Fang Alvin , Tao Qiushan , Auerbach Sandford H , Devine Sherral , Qiu Wendy , Mez Jesse , Massaro Joseph , Lunetta Kathryn L , Au Rhoda , Farrer Lindsay A
Published: December 2020

Background

Measures of cardiovascular and metabolic disease are well‐established risk factors for late‐onset Alzheimer disease (AD). However, it is poorly understood whether exposure to these risk factors in early adulthood is associated with AD incidence in late‐life.

Method

Association of incident AD occurring after age 60 with measures of lipid fractions, hypertension, diabetes, blood glucose, BMI and smoking obtained prospectively across multiple exams starting in early adulthood was evaluated in the Framingham Heart Study (FHS) Offspring cohort (n = 5,100) using Cox proportional hazard models. Three models were tested for each risk factor measured at each exam with progressive adjustment for the following covariates: Model 1 ‐ age and sex; Model 2 – age, sex, and risk factor‐specific treatment; and Model 3 – age, sex, and other vascular risk factors. Hazard ratio (HR) was calculated for a 10 mg/dL unit increase of risk factor.

Result

During a mean follow‐up period of 31.7 ± 6.7 years, a consensus diagnosis of incident AD was established for 261 participants. Higher high‐density lipoprotein (HDL) measured at early (mean age =36) and midlife (mean age = 59) were associated with a decreased risk of AD (HR=0.90 [95%CI 0.83, 0.98], p=0.020 and HR=0.90 [0.79, 0.98], p=0.020, respectively). These associations remained significant after adjusting for lipid treatment. Higher triglyceride (TG) measured at these exams were associated with an increased risk of AD (HR=1.015 [1.003, 1.03], p=0.0013 and HR=1.02 [1.004, 1.04], p=0.0035, respectively). Of note, higher fasting blood glucose (FBG) measured at early, midlife and late life were associated with an increased risk of AD (HR=1.06 [1.01, 1.11], p=0.03; HR=1.08 [1.03, 1.13], p=0.0006; and HR=1.24 [1.02, 1.52], p=0.03, respectively), with attenuated associations after adjusting for diabetes treatment. In the model adjusting for other vascular risk factors, FBG at early, middle and late life remained significant.

Conclusion

HDL, TG and Blood Glucose levels measured at approximately age 36 years are significantly associated with incident AD several decades later. To our knowledge this is the first evidence of the association of AD with decreased HDL level and increased TG and fasting glucose levels measured in cognitively normal individuals during early to middle adulthood.
Plasma biomarkers of neuroinflammation and vascular injury predict cognitive decline in patients with mild cognitive impairment
Authors: Trombetta Bianca A. , Kivisäkk Pia , Carlyle Becky C. , Magdamo Colin , Merrill Emily , Chibnik Lori B. , Serrano‐Pozo Alberto , Hyman Bradley T. , Das Sudeshna , Arnold Steven E.
Published: December 2020

Background

The development of robust blood‐based biomarkers for pathological and clinical characterization of Alzheimer’s disease (AD) is necessary, particularly as therapeutic approaches shift towards early intervention. Novel, ultra‐sensitive OlinkTM technology allows for high‐throughput quantification of protein signatures in biofluids. In this study, we examined the utility of this technology to identify plasma biomarkers associated with longitudinal cognitive performance in individuals presenting with mild cognitive impairment (MCI).

Methods

60 participants from the Massachusetts ADRC Longitudinal Cohort with a clinical diagnosis of MCI, baseline global CDR of 0.5, and at least five annual follow‐up evaluations were classified into two groups based on their global CDR trajectory: MCI‐decline (an increase in global CDR from 0.5 to 1) and MCI‐stable (no change in global CDR). Five OlinkTM Proximity Extension Assay (PEA) panels were assessed for technical reliability and used to quantify 460 plasma proteins at baseline visit. We built statistical models to identify proteins whose plasma levels were predictive of future cognitive decline, and used machine‐learning to evaluate the utility of these proteins for predicting conversion from MCI to dementia, relative to clinical and demographic predictors.

Result

OlinkTM panels exhibited excellent technical precision and plate‐to‐plate replication. Of the 460 proteins measured, 60 did not pass quality control thresholds. A final model adjusting for age and sex identified 14 proteins with a significant fold‐change in MCI‐decline compared to MCI‐stable (p<0.05), including NfL, CX3CL1, M‐CSF, VEGF‐A, IL‐8, NOS3, TNFRSF12A, and PHOSPHO1. An additional 10 proteins approached significance (p<0.1), primarily representative of inflammatory and vascular processes. Addition of these proteins to a supervised classification model informed by baseline cognitive measured substantially improved the overall accuracy from 63% to 83.3% (AUC: 0.88, sensitivity: 0.76, specificity: 0.87).

Conclusion

Our findings suggest that plasma biomarkers of neuroinflammation and vascular injury have value as predictors of MCI‐to‐dementia progression. These circulating biomarkers may reflect CNS processes, blood‐brain barrier dysfunction, and/or systemic inflammation that drive AD associated pathophysiologies, or represent comorbid vascular pathologies. Developing a plasma biomarker panel could aid in prognostic deliberations by identifying MCI individuals at higher risk of progressing to dementia in clinical practice.
The relationships of grip strength and gait speed with cognitive function in a diverse cohort: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: George Kristen M. , Gilsanz Paola , Peterson Rachel , Glymour M. Maria , Mayeda Elizabeth Rose , Mungas Dan M. , Whitmer Rachel A.
Published: December 2020

Background

Grip strength and gait speed, indicators of frailty, have been associated with poor cognitive outcomes. Whether there are differences in these associations by race/ethnicity is unknown. In the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study, we examined the cross‐sectional associations of grip strength and gait speed with cognition.

Method

KHANDLE aimed to evaluate how race/ethnicity and life‐course health influence late‐life brain health among community‐dwelling adults ages 65+ living in Northern California. Analysis included 1,353 Asian (24%), Black (26%), Latino (18%), and White (32%) participants. Grip strength (kg) was measured using a hand‐held dynamometer and gait speed measured a timed 4‐meter walk (m/s). Cognitive domains of verbal episodic memory, semantic memory, and executive function were measured using the Spanish and English Neuropsychological Assessment Scales (SENAS). Z‐standardized test scores were averaged for a global z‐score. Linear regression was used to assess the associations of grip strength and gait speed with cognition. Models were adjusted for demographic (age, education, income), physical (waist circumference), and behavioral risk factors (physical activity, smoking status, alcohol consumption). Gender and race/ethnicity interactions were tested separately.

Result

Participants had a mean age of 76 (SD=7) years and 58% were women. The associations of grip strength and gait speed with cognition did not differ by gender. A standard deviation (SD) increase in grip strength was associated with better global cognition [β=0.11(0.06, 0.15)]. This association did not differ by race/ethnicity and was similar across cognitive domains [executive β=0.07(0.03, 0.12); semantic β=0.12(0.07, 0.17); verbal β=0.06(0.01, 0.11)]. A SD decrease in gait speed was associated with worse global cognition [β=‐0.09(‐0.12, ‐0.06)] and associations were consistent across domains [executive β=‐0.08(‐0.11, ‐0.05); semantic β=‐0.08(‐0.11, ‐0.05); verbal β=‐0.06(‐0.09, ‐0.02)]. There were significant race/ethnicity interactions on the associations of gait speed with global cognition (p=0.001), executive function (p=0.02), and semantic memory (p=0.0004). Decreased gait speed was associated with worse cognition in these domains for Asians, Latinos, and Whites, but not associated in Blacks.

Conclusion

Grip strength and gait speed were cross‐sectionally associated with cognition. There were race/ethnicity differences in the association of gait speed with executive function, semantic memory, as well as global cognition.
Early adulthood and midlife cardiovascular risk factors and late‐life cognition in KHANDLE: A lifecourse study of a diverse cohort
Authors: Peterson Rachel , George Kristen M. , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M. Maria , Mungas Dan M. , DeCarli Charles , Whitmer Rachel A.
Published: December 2020

Background

Midlife cardiovascular risks (CVR) are associated with late‐life cognition and dementia. Prior studies that examine early and midlife CVR on cognitive aging in Asians, Blacks, and Latinos are limited.

Methods

The Kaiser Healthy Aging and Diverse Life Experiences Study (KHANDLE) is a cohort of community‐dwelling Kaiser Permanente members residing in Northern California (Asians (26%), Blacks (29%), Latinos (20%) and Whites (24%)) who completed a multiphasic health checkup (MHC) from 1977‐1985 (n=1,207; mean age=37.6). KHANDLE aims to evaluate how lifecourse factors influence late‐life brain health and cognitive decline and may impact race/ethnic disparities. Using linear regression, we examined the association between late‐life cognition and early/midlife hypertension, hyperlipidemia and overweight/obesity collected at MHC. Executive function, semantic memory and verbal episodic memory measured using the Spanish and English Neuropsychological Assessment Scales (SENAS) were z‐standardized and combined for a composite measure of overall cognition. We tested for effect modification by race/ethnicity. Models controlled for age at KHANDLE, age at MHC, gender, and education.

Results

At KHANDLE baseline, mean age was 75.4(6.7). At MHC, 46% of participants were ages 26‐35, 47% ages 36‐49 and 7% ages 50‐65. Prevalence of 2+ CVR was highest in Blacks (24%), followed by Latinos (24%), Asians (15%), and Whites (13%). Across race/ethnicity, having 2+ risk factors was associated with lower cognition in all domains: Overall cognition β=‐0.35 (‐0.47, ‐0.23). Having hypertension, hyperlipidemia or being overweight/obese was associated with worse cognition in all race/ethnic groups and across all cognitive domains (see table). Effect estimates varied by race/ethnicity, but interactions were not statistically significant: Blacks with hypertension (n=108) had lower late‐life cognition than other groups, especially for semantic memory and verbal episodic memory; Latinos with hyperlipidemia (n=49) had worse verbal memory than other groups; whites who were overweight/obese (n=84) had lower late‐life cognition across all domains, while Asians who were overweight/obese (n=50) had better late‐life cognition than non‐Asian participants who were overweight/obese.

Conclusions

Early/midlife cardiovascular risk factors are associated with lower late‐life cognition in all race/ethnic groups. The association between specific cardiovascular risk factors and late‐life cognition may vary by race/ethnicity, but differences were not significant.
Transcriptomic profiles underlying functional brain networks at different stages of Alzheimer’s disease
Authors: Yu Meichen , Nho Kwangsik , Risacher Shannon L. , Chumin Evgeny J. , West John D. , Tharp Matt , Zhu Jian , Wen Qiuting , Eastman Bobi , Shen Li , Apostolova Liana G. , Wu Yu‐Chien , Sporns Olaf , Saykin Andrew J.
Published: December 2020

Background

Specific functional network connectivity patterns have been shown at different stages along the Alzheimer’s disease (AD) continuum, but the contribution of regional gene expression to molecular mechanisms remains unknown.

Method

We used resting‐state functional MRI to construct functional brain networks in 47 cognitively normal (CN), 46 subjective cognitive decline (SCD), 34 mild cognitive impairment (MCI) and 22 AD participants. Regional gene expression profiles for 20736 protein‐coding genes were derived from brain‐wide microarray‐based transcriptome data from the Allen Human Brain Atlas. We performed one hypothesis‐driven (using pre‐selected AD susceptibility genes) and two data‐driven analyses (using all 20736 genes) to uncover the spatial associations between brain‐wide gene expression levels and connectivity strength (gene‐to‐connectivity associations). In the hypothesis‐driven analysis, we computed the spatial gene‐to‐connectivity associations for 51 AD susceptibility genes selected from large‐scale GWAS for the four clinical groups, separately. In a data‐driven analysis, we determined the gene‐to‐connectivity associations for average gene expression levels of co‐expressed gene modules in the gene co‐expression network. We also performed gene‐set enrichment analysis (GSEA) to identify biochemical pathways associated with the connectivity patterns in AD (1000 permutations; PFDR < 0.05; gene sets from the Gene Ontology). Finally, we analyzed commonalities among the most relevant genes of the identified pathways.

Result

We identified 15 AD susceptibility genes showing significant gene‐to‐connectivity associations after multiple testing adjustment (PFDR < 0.05). In particular, ECHDC3 and HS3ST1 showed the strongest positive and negative gene‐to‐connectivity associations, respectively, and the strength of the correlations increased as a function of disease stage (CN < SCD < MCI < AD). In addition, two of five gene co‐expression modules showed consistently significant gene‐to‐connectivity associations across the four clinical groups. GSEA identified 31 positively enriched pathways including cellular response to metal ion and fatty acid binding, and 11 negatively enriched pathways including enzyme activity and cellular metabolism.

Conclusion

Our findings may open novel avenues for improving the interpretation of genetic and imaging biomarkers, for facilitating the detectability of AD trajectories, and for developing effective therapeutic strategies at earlier stages of the disease spectrum when connectivity changes may be among the earliest features.
Dementia knowledge and associated demographic factors within a registry sample
Authors: Reynolds Gretchen O , Manning Lyssa K , Kirn Dylan , Burke Orett , Klein Hannah , Rentz Dorene , Sperling Reisa A. , Marshall Gad A , Amariglio Rebecca
Published: December 2020

Background

Research on Alzheimer’s disease (AD) and related dementias is increasingly focused on prevention and identification of risk factors. In order to effectively disseminate knowledge about dementia risk, there is need to understand gaps in dementia knowledge (Carpenter et al., 2011, Cations et al., 2018). For example, education level, among other factors, may be associated with reduced knowledge about AD, which could impact engagement in early prevention strategies (Ayalon & Arean, 2004). We explored dementia knowledge and demographic variables in a community‐based registry sample to inform approaches to psychoeducation and intervention.

Method

We administered surveys via REDCap to participants enrolled in an online registry. Surveys included measures of dementia knowledge (subset of 13 questions from the Dementia Knowledge Assessment Scale (DKAS)), personality (Ten‐Item Personality Inventory), and demographic variables. Response rate was 42%. Participants were 292 clinically normal adults (mean age=67.4 (range: 50‐87); 65% women; 98% non‐Hispanic or Latino; 94% Caucasian; 81% with a bachelor’s degree or higher).

Result

Most participants (77%) reported knowing “some” to “a good amount” about dementia, learned primarily via family/friends (27%), doctors (21%), and the internet (22%). Mean dementia knowledge on the DKAS was 14.4 (range=1‐26, out of 26 possible points). Dementia knowledge was weakly associated with age (r=‐.12, p=.045), with younger individuals showing higher knowledge. Controlling for age, self‐reported dementia knowledge correlated with objective dementia knowledge on the DKAS (r=.46, p<.01). Also controlling for age, dementia knowledge was higher among individuals with more education (F(1, 287)=8.6, p=.004) and among women (F(1, 285)=5.9, p=.016). Dementia knowledge was not associated with aspects of personality (ps>.08).

Conclusion

Dementia knowledge was higher among younger individuals, as well as those with more education and among women, but did not relate to personality. Self‐reported dementia knowledge correlated with objective dementia knowledge, suggesting that participants accurately judged their own knowledge. Future work should examine these questions within a more diverse registry sample. Findings underscore the value of registries to examine dementia knowledge and inform dissemination and intervention strategies. By increasing psychoeducation about dementia among adults with lower baseline knowledge, we may facilitate early engagement in preventative strategies to reduce dementia risk.
Racial/ethnic differences in the association of high school quality with later life cognitive function
Authors: Seblova Dominika
Published: December 2020

Background

Longer education predicts better cognitive health, but it is unclear whether other attributes of schooling matter, or whether educational opportunities confer equal benefits across our society. We examined racial/ethnic differences in the association of high school quality with later life cognition among a unique cohort of older adults followed since high school.

Method

In 1960, about 5% of US high schools participated in Project Talent (PT). PT measured demographics and aptitude in students and gathered objective information about school characteristics. In 2018‐2019, a total of 2,353 PT participants (mean age=74.6) responded to a telephone interview, which included neuropsychological tests. Language ability was measured with animal (semantic) and letter F (phonemic) fluency. Memory was measured with the CERAD learning list and delayed recall savings. A school quality factor score, capturing term length, class size, and teacher qualifications, was used as a predictor of individual test scores. We examined differences in the association between school quality and cognitive function by self‐reported race/ethnicity. For each outcome, we estimated two linear regression models. We first estimated the main effects of school quality and race/ethnicity, adjusting for 1960 cognitive aptitude, sex/gender, age, and a composite measure of parental socioeconomic status, then we added an interaction term for school quality and race/ethnicity.

Result

Respondents were mostly non‐Hispanic White (76%), 10% non‐Hispanic Black, 4% Hispanic (of any race) and 9% self‐identified as Asian, Pacific Islander, Middle Eastern/North African, American Indian/Alaska Native, or more than one race. School quality was highest for Hispanic respondents and lowest for Blacks. Higher school quality was associated with higher cognitive scores 58 years later, reaching statistical significance for CERAD learning (0.05 SD; 95%CI: 0.01;0.09) and letter fluency 0.07 SD (95%CI 0.03;0.1). Whites, Hispanics, and other racial/ethnic groups benefited more from higher school quality compared to Blacks, and this was reliably different for phonemic fluency.

Conclusion

Attending higher quality high schools was associated with better scores on neurocognitive tests 58 years later. Future work will examine the structural and social inequalities to address why non‐Hispanic Black students had lower cognitive benefits from higher school quality than other racial/ethnic groups.
Practice effect of repeated cognitive tests among older adults: Associations with brain amyloid status and other influencing factors
Authors: Zheng Bang , Udeh‐Momoh Chinedu T. , Price Geraint J , Watermeyer Tam J. , Jager Celeste A. , Ford Jamie , Robb Catherine , Giannakopoulou Parthenia , Fogle Michael , Saad Ziad , Ahmadi‐Abhari Sara , Ritchie Craig W. , Baker David , Novak Gerald P. , Middleton Lefkos T.
Published: December 2020

Background

Practice effects (PE), after repeated cognitive measurements, may mask cognitive decline and remain a major issue in clinical and research settings. However, an attenuated practice effect may indicate cognitive decline or the presence of brain pathologies. Exploring factors that influence PE can inform strategies to distinguish true signal from bias in future research. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status in a cohort of older adults enrolled in the Cognitive Health in Ageing Register: Investigational, Observational, and Trial Studies: Prospective Readiness cOhort Study (CHARIOT‐PRO) Sub‐study.

Method

502 cognitively healthy participants aged 60‐85 years were assessed with RBANS in both screening and baseline clinic visits (median time gap of 3.5 months). We assessed the reliability of the RBANS scale and tested PE based on differences between test and retest scores in total scale and domain‐specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, educational attainment, and APOE‐ε4 carriage. PE and the initial RBANS score were also examined as predictors for amyloid positivity status based on defined thresholds, using logistic regression.

Result

The internal consistency (Cronbach's α=0.64) and test‐retest reliability (r=0.79) of RBANS were good. Participants’ Total Scale, Immediate Memory and Delayed Memory indices were significantly higher in the second test than in the initial test (d=3.8, 7.6 and 3.2, P<0.001). On the Immediate Memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group (d=6.5 vs 8.6, P=0.028). Older participants (≥70 years), women, non‐APOE‐ε4 carriers, and those with worse initial RBANS test performance had larger PE. In addition, worse performance and lower practice effects in immediate or delayed memory index were independent predictors for amyloid positivity (OR=0.97, P<0.05).

Conclusion

Significant practice effects on RBANS total scale and memory indices were influenced by age, sex, APOE‐ε4, initial RBANS scores and amyloid status. The association with amyloid suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology.
In‐out‐test and inverse translational medicine: When a new clinical paradigm is needed to find new biomarker perspectives
Authors: Torrealba Eduardo , Garcia‐Morales Pilar , Rodriguez‐Esparragon Francisco
Published: December 2020

Background

PROA project is based in the Neurology Service and the Investigation Unit at the Hospital Dr. Negrin (Canary Islands, Spain). PROA aims to find new ways to a better understanding of cognitive and biological mechanisms of normal aging and Alzheimer's disease (AD). This study shows previous, preliminary and ongoing PROA project data about the relationship between clinical assessment and biomarkers in Alzheimer’s disease research. It is considered the contribution of In‐out test, a paradigm hypothesized to avoid reliance on executive function, which may compensate damaged memory networks. Unlike other tests using the hippocampal amnesia paradigm, that assess memory after effective encoding of information, the In‐out‐test provokes an interference during encoding by means of a simultaneous executive task. According to this model the memory deficit in prodromal AD can be unmasked when those compensatory networks are saturated by an executive activity without being able to compensate the already damaged mnemonic activity.

Method

Neuropsychological assessment: Neuropsychological battery: episodic (Free and cued Selective Reminding Test‐ FCSRT), shot‐term, visual memory, visuospacial and constructive praxis; executive functions; Daily living and instrumental activities. In‐out‐test: Assesses episodic memory after the patient performs a categorization task and memorizes 6 words simultaneously. The time taken to complete this test was 5 to 12 minutes.

Result

Cross‐sectional study: ICC (Intraclass correlation) between the In‐out‐test and FCSRT r= 0.87 (p=0.001). ICC between the In‐out‐test and Aβ42 and P‐tau/Aβ42 for controls: 0.73 and 0.75 respectively; P‐tau for MCI: 0.77 and total sample: 0.70; Aβ42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤ 0.264. Sensitivity: 0.93; specificity: 0.77. Predictive value for In‐out‐tet, Positive:0.89; negative: 0.83. Conversion study: Agreement (Kappa): In‐out‐test: 0.67/0.61 (memory/learning); FCSRT: 0.57; P‐tau/Aβ42: 0.126. P‐tau(50ng/ml): 0.40. Aβ42 (500 ng/ml): 0.07

Conclusion

Compensatory mechanisms in prodromal AD might be a confounding factor in the early detection by classical hippocampal amnesia paradigm and even by csf biomarkers. In‐out‐test may play a roll unmasking the memory deficit in the early stages of AD. In orfer to find new reliable biomarkers for aging and AD, PROA project will focused on new targets such as oxidative stress, phosphorilation, microbiota and telomers.