bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perivascular space volumes relate to arterial stiffness and cognition
Authors: Bown Corey W. , Khan Omair A. , Liu Dandan , Remedios Samuel , Pechman Kimberly R. , Schrag Matthew , Davis L. Taylor , Terry James G. , Nair Sangeeta , Carr J. Jeffrey , Gifford Katherine A. , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2021

AbstractBackgroundEnlarged perivascular spaces (PVS) are a marker of small vessel disease (SVD). PVS in the basal ganglia are associated with hypertensive damage to arteries and arterioles; however, prior work relating arterial stiffness to changes in PVS have been inconclusive. Additionally, clinical consequences of PVS are poorly understood, possibly due to reliance on manual rating systems that lack precision. This study used an automated process to measure basal ganglia PVS count and volume and cross‐sectionally assess their associations with central arterial stiffness and cognition.MethodVanderbilt Memory and Aging Project participants free of clinical stroke and dementia (n=327, 73±7 years, 41% female) completed T1‐weighted brain MRI to measure PVS burden, neuropsychological assessment, and cardiac MR to quantify pulse wave velocity (PWV) in the thoracic aorta, a marker of central arterial stiffness. PVS volume and count were quantified using an automated approach. Basal ganglia volume and count measures were log‐transformed. Linear regression models related PWV separately to PVS volume and count adjusting for demographic and health variables, apolipoprotein E‐e4 status, and intracranial volume. Models were repeated separately relating PVS volume and count to neuropsychological performance with identical covariates.ResultHigher PWV related to greater basal ganglia PVS volume (b=7.0e‐5, p=0.04) and count (b=0.02, p=0.03). When excluding outliers, PVS volume results were attenuated (p=0.17) but count results persisted (p=0.03). Higher PVS volume was associated with worse sequencing (b=1560, p=0.002), digit symbol (b=‐979, p=0.003), executive function (b=‐82.3, p<0.001), and visuospatial performances (b=‐193, p=0.02). Cognitive results were comparable for models using PVS count as the predictor.ConclusionCentral arterial stiffness is associated with greater PVS burden in the basal ganglia. Findings support the hypothesis that increased aortic stiffness and resulting changes in hemodynamics essential for maintaining perfusion pressure may result in PVS damage. Greater PVS burden is associated with worse cognitive performance, primarily on tests of executive function and information processing, aligning with our prior findings relying on a manual PVS rating system. PVS may account for damage to frontal subcortical networks which integrate the basal ganglia and play an important role in executive function and information processing. Funding: F31‐AG066358, T32‐AG058524, Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082
Biomarker driven enrichment strategies for tau pathology in AD clinical trials
Authors: Leuzy Antoine , Smith Ruben , Cullen Nicholas , Strandberg Olof , Janelidze Shorena , Ohlsson Tomas , Jögi Jonas , Borroni Edilio , Klein Gregory , Dage Jeffrey L , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Stomrud Erik , Hansson Oskar 
Published: December 2021

AbstractBackgroundTau‐PET has great potential in Alzheimer’s disease (AD) clinical trials as pre‐trial inclusion biomarker and as trial endpoint. However, it is unclear which Tau‐PET ROI is optimal for tracking treatment response in relevant trial populations, and how best to enrich trials if using Tau‐PET as an endpoint. We aimed to determine the sample required to achieve 80% power to observe a reduction in Tau‐PET increase when using different combinations of A/T/N biomarkers as trial inclusion measures. Tau‐PET outcome variables were selected based on ROIs that showed greatest increases using longitudinal data.MethodsWe included 179 cognitively unimpaired (CU) individuals (39% Aβ‐positive) and 103 MCI (62% Aβ‐positive) with longitudinal Tau‐PET ([18F]RO948;baseline and after ∼18‐months [mean 18.81±4.02]) from BioFINDER‐2. Annual change in Tau‐PET SUVR was calculated across event‐based modelling (EBM) (Figure 1) ROIs. For the power analysis, linear models were fit with the best ROI identified in the first step as outcome and different combinations of A (Amyloid‐PET), T (CSF/plasma P‐tau217, baseline Tau‐PET in outcome ROI), and N (CSF/plasma NfL, hippocampal volume) biomarkers as predictors. Model fit was assessed using change in AIC relative to no enrichment (i.e. all subjects).ResultsIn CU, annual Tau‐PET increase was highest in EBM stage‐I (1.26%,95%CI [0.82‐1.70%]) (Figure 2); in MCI, the greatest change was seen in EBM stage‐II (1.89%, 95%CI[1.22‐2.56%]). Using these ROIs as outcome variables (assuming selection of top 50% of individuals), regression models showed that plasma P‐tau217 provided the best model fit in CU (44% fewer participants,∆AIC=‐5,P<0.01), followed by CSF P‐tau217 (‐32%, ∆AIC=‐3,P<0.05). In MCI, Amyloid‐PET provided the best model fit (‐71%,∆AIC=‐8, P<0.01), followed by plasma P‐tau217 (‐69%,∆AIC=‐6,P<0.01) and CSF P‐tau217 (‐71%,∆AIC=‐6,P<0.01). When combining biomarkers (Figure 3), plasma P‐tau217, CSF P‐tau217 and Amyloid‐PET proved the best model in CU (‐74%,∆AIC=‐3,P<0.0001). In MCI, Amyloid‐PET with EBM‐II baseline Tau‐PET and plasma P‐tau217 proved the best model (‐92%,∆AIC=‐3,P<0.0001). Combining plasma P‐tau217 with Amyloid‐PET (CU) or baseline Tau‐PET (MCI) provided similar results, however (69%,∆AIC=‐4,P<0.0001; 87%,∆AIC=‐6,P<0.0001, respectively).ConclusionPlasma P‐tau217 combined with either Amyloid‐PET (preclinical AD) and baseline Tau‐PET (prodromal AD) may prove optimal and feasible enrichment strategies for trials with Tau‐PET as endpoint.
Sexually dimorphic association of circulating leptin levels with early amyloid‐beta pathology assessed by amyloid PET
Authors: Ishii Makoto , Iadecola Costantino , Sanjay Apoorva Bharthur , Apostolova Liana G. 
Published: December 2021

AbstractBackgroundWeight loss can precede the cognitive decline in Alzheimer’s Disease (AD), suggesting that mechanisms regulating body weight such as the adipocyte hormone leptin are an early target of AD pathology (Cell Metabolism 22:761,2015). In mouse models, we previously found that amyloid‐beta pathology can cause hypothalamic dysfunction that was associated with low body adiposity and low plasma leptin levels prior to significant memory impairment (J Neuroscience 34:9096,2014). In this study, we sought to determine if circulating leptin levels are associated with brain amyloid‐beta pathology, assessed by amyloid PET, in individuals with normal cognition or mild cognitive impairment (MCI).MethodThis cross‐sectional study involved community dwelling volunteers originally recruited for the Imaging and Genetic Biomarkers for AD (ImaGene) study. All subjects were age ≥ 50 years, normal cognition or MCI as defined by Clinical Dementia Rating (CDR) score of 0 or 0.5 respectively, and underwent PET scan using the amyloid‐beta tracer 18F‐flutemetamol. Subjects were classified as positive for amyloid‐beta pathology if standard uptake value ratios (SUVr) ≥ 1.27. Serum leptin levels were measured by enzyme linked immunosorbent assay and log transformed. Multiple linear regression analysis was used to examine correlations between serum leptin levels and amyloid PET SUVr.ResultIn men, body mass index (BMI) and serum leptin levels were significantly lower in amyloid PET positive subjects (n = 12) compared to control subjects (n = 8). Furthermore, BMI and serum leptin levels were significantly associated with amyloid PET SUVr (BMI: age‐adjusted β coefficient = ‐0.53, p = 0.018; leptin: age‐adjusted β coefficient = ‐0.69, p = 0.002). However, in women, BMI and serum leptin levels were not significantly different between control and amyloid PET positive subjects and were not associated with amyloid PET SUVr (12 control and 5 amyloid PET positive subjects, all p > 0.05).ConclusionThese studies raise the possibility that, in men, amyloid‐beta pathology causes alterations in leptin signaling and metabolic dysfunction early in AD. Studies in larger cohorts will be needed to confirm these observations and to help determine their clinical utility as well as the underlying mechanisms of the sex differences.
Baseline plasma total tau predicts longitudinal cognitive and functional decline in aging adults
Authors: Bolton Corey J. , Khan Omair A. , Liu Dandan , Moore Elizabeth E. , Pechman Kimberly R. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Gifford Katherine A. , Jefferson Angela L. 
Published: December 2021

AbstractBackgroundPlasma total‐tau (t‐tau) is an emerging biomarker of neurodegeneration and cognitive decline; however, findings are mixed regarding what specific cognitive domains are affected and it is unknown whether plasma t‐tau predicts early functional changes in aging adults at risk for dementia. This study examined baseline plasma t‐tau in relation to longitudinal cognitive and functional trajectories among community‐dwelling older adults.MethodVanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=332, 73±8 years, 40% mild cognitive impairment (MCI)) underwent baseline fasting venous blood draw and serially completed a comprehensive neuropsychological protocol and a 50‐item informant functional abilities questionnaire at study entry, 18‐month, 3‐year, and 5‐year intervals (mean 4.5±1.2 year follow‐up). Plasma t‐tau concentration was measured using single molecule array technology. Linear mixed effects models related baseline t‐tau to cognitive and functional trajectories through interaction with follow‐up time adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE) ∑4 status, modified Framingham Stroke Risk Profile, and cognitive diagnosis. Subsequent models assessed t‐tau x cognitive diagnosis and t‐tau x APOE‐∑4 interactions on cognitive and functional trajectories.ResultA higher baseline concentration of t‐tau was associated with faster decline in processing speed (p<.05). Baseline t‐tau concentration interacted with diagnosis on longitudinal trajectories of processing speed (p‐values<.03). After excluding outliers, higher baseline t‐tau was associated with faster decline in language, processing speed, and functional abilities (p‐values<.05) with t‐tau interacting with diagnosis on each of these measures (p‐values<.05). Baseline t‐tau interacted with APOE‐∑4 status on longitudinal trajectories of language after outlier exclusion (p‐values<.04). Associations linking baseline t‐tau with faster decline were largely driven by participants with MCI (p‐values<.05) and APOE‐∑4 carriers (p‐values<.04).ConclusionAmong community‐dwelling aging adults free of clinical dementia, higher baseline plasma t‐tau concentration was associated with faster cognitive and functional decline over a mean 4.5‐year follow‐up. Processing speed was consistently implicated, especially in individuals with MCI. T‐tau may reflect non‐specific brain changes involving widely distributed neuronal networks, leading to slowed processing, a common complaint in aging adults. Taken together, results suggest that plasma t‐tau may be a useful biomarker for cognitive and functional decline in at‐risk individuals.
Automated vehicles as a tool to extend the safe driving of people with dementia: Family caregivers’ perspectives
Authors: Haghzare Shabnam , Delfi Ghazaleh , Mohamud Hodan , Stasiulis Elaine , Rapoport Mark , Naglie Gary , Mihailidis Alex , Campos Jennifer L. 
Published: December 2021

AbstractBackgroundThe progression of dementia often leads to complete driving cessation, which poses major challenges for persons with dementia (PwD) and their caregivers. In response to these challenges, the use of Automated Vehicles (AV) by PwD has been considered as a way of prolonging PwD’s safe driving. AVs can either be used to assist PwD with certain driving tasks, such as steering or braking (Partially Automated Vehicles; PAVs), or by performing all driving tasks (Fully Automated Vehicles; FAVs). There are unique considerations regarding the use of AVs by PwD that are currently not well‐understood. This study examined caregivers’ perspective on the usefulness of AVs in addressing the driving‐related challenges faced by PwD.MethodSemi‐structured interviews were conducted with 20 primary family caregivers of PwD. Both in the interviews and using a Likert scale questionnaire, participants were asked about their attitude towards PAV and FAV use by themselves and the PwD in their care. Thematic analysis with inductive coding was used to analyse the transcribed interview data.ResultCaregivers reported significantly more negative attitudes towards PAV/FAV use by the PwD in their care compared to use by themselves (Table 1). The thematic analysis yielded two overarching types of caregiver concerns. (1) unresolved concerns about PwD’s mobility that persist after PAV/FAV use: difficulty navigating tasks at the destination; AVs not providing the same sense of freedom as driving; need for caregivers’ presence in the vehicle; caregivers’ unawareness of PwDs’ driving ability decline until a traffic incident. (2) emerging concerns specific to PAV/FAV use by PwD: PwD’s confusion caused by lack of exposure to AVs; PwD’s possible distress/agitation in AVs; PwD’s possible inability to navigate tasks required by the AV (e.g., response to system failures, negotiating pick‐up/drop‐off locations); PwD’s manual driving skill degradation upon constant use of AVs; AVs enabling PWD to wander to distant locations.ConclusionThis study helps to identify AV design targets specific to PwD. In addition, study results outline caregivers’ concerns around AV use by PwD that extend beyond PwD’s driving, which highlights the importance of considering a holistic perspective when addressing mobility‐related needs of PwD by introducing AVs.
Measuring synaptic loss in early AD stages: Trajectories of SNAP25 and SYT1 using serial CSF sampling
Authors: Duits Flora H. , Brinkmalm Ann , Scheltens Philip , Blennow Kaj , Zetterberg Henrik , van der Flier Wiesje M. , Teunissen Charlotte E. 
Published: December 2021

AbstractBackgroundIt is increasingly recognized that synaptic dysfunction plays an important role in Alzheimer pathology, already in an early phase. In this study we investigated the presynaptic biomarkers SNAP25 and SYT1 in early stages of AD. Using serial CSF samples in a cohort of memory clinic patients with detailed clinical follow‐up, we studied prognostic value, the association with cognitive decline and longitudinal trajectories of these biomarkers.MethodWe included 150 subjects with subjective cognitive decline (SCD; 62±7 years), mild cognitive impairment (MCI; 66±8 years) and AD dementia (64±7 years) from the Amsterdam dementia cohort, based on availability of CSF at two time points (median[IQR] 2.1[1.4‐2.7] years) and clinical follow‐up of at least one year. CSF SNAP25 and SYT1 were analyzed using immunoprecipitation mass spectrometry. To assess differences in SNAP25 and SYT1 levels between diagnostic groups at baseline, change in biomarker levels over time and association with cognitive decline we used linear mixed models. We used Cox regression models to assess predictive value of baseline biomarker level for disease progression. Analyses were adjusted for age and gender, Cox models also for ATN biomarker status.ResultTable 1 shows the results of the linear mixed models. Baseline levels of SNAP25 were higher in AD dementia compared to SCD and MCI, SYT1 levels were similar between groups. Over time SNAP25 increased in SCD subjects (B[SE] 0.24[0.10], p<0.05), SYT1 decreased in AD dementia patients (B[SE] ‐2.6[0.8], p<0.01). In SCD and MCI subjects higher SNAP25 was associated with faster decline in MMSE over time (st.B[SE] ‐0.24[0.12], p<0.01 for SCD; ‐0.39[0.16], p<0.05 for MCI). For SYT1 there was an effect only for SCD subjects (st.B[SE] ‐0.18[0.07], p<0.01). Baseline SNAP25 was a significant predictor for conversion to MCI or AD in non‐demented subjects (HR[95%CI] 4.4 [2.1‐9.1]), even after addition of ATN status (HR[95%CI] 2.8 [1.1‐7.3]; table 2, figure 1).ConclusionSNAP25 levels increased over time in SCD subjects, and both SNAP25 and SYT1 were associated with cognitive decline in early stages of AD. High levels of SNAP25 predicted conversion to AD dementia. Hence, they may have potential to be used for disease monitoring or as amyloid‐independent outcome measure in clinical trials.
Effects of fitness and sedentarism on a biomarker of early AD progression
Authors: Carrasco‐Gómez Martín , García‐Colomo Alejandra , Nebreda Alberto , de Frutos Jaisalmer , Salas‐González María Dolores , Lorenzo‐Mora Ana María , Pedrero‐Chamizo Raquel , Sobaler Ana Maria Lopez , Higes Ramón López , Dolado Alberto Marcos , Losada María Luisa Delgado , González‐Gross Marcela , Maestú Fernando 
Published: December 2021

AbstractBackgroundGiven the lack of an effective treatment for Alzheimer’s Disease (AD), research on factors that might prevent it or delay its symptoms is needed. Physical activity (PA) stands as a means for favourably altering cognitive performance and neuropathologic processes and has been identified as a relevant and easily modifiable lifestyle factor against AD progression. This study thrives to understand the effects of both cardiorespiratory fitness (CRF) and sedentary behaviours (SB) in adult controls through the assessment of magnetoencephalography (MEG).Method30 healthy adults (age between 50 and 70 years) participated in the study. The sample underwent a five minutes of eyes‐closed resting MEG recording (NMEG = 24), a cycloergometer incremental exercise test to evaluate CRF through VO2peak (Nstress = 17), and carried an accelerometer for one week to estimate SB (NACC = 26). The alpha peak frequency at posterior brain areas was extracted, and then its partial correlation to VOpeak and the relative sedentary time from the accelerometer data were calculated, respectively, while also controlling for age. Partial correlation between VO2max and relative sedentary time was calculated as well.ResultStatistical analysis yielded a significant direct correlation between VO2peak and Alpha peak frequency (N=17, rho = 0.504, p‐value = 0.023), while relative sedentary time and Alpha peak frequency showed a significant inverse correlation (N = 20, rho = ‐0.435, p‐value = 0.032). Partial correlation between VO2peak and relative sedentary time was not significant (N = 17, rho = ‐0.404, p‐value = 0.120).ConclusionDespite the small cohort, results pinpoint a strong influence of both CRF and SB. Greater CRF, described as higher VO2peak, appears associated with increased alpha frequency in posterior brain regions, a robust biomarker of brain health which is negatively affected in AD. At the same time, higher levels of sedentarism show a strong relation to decreased alpha peak frequency, indicating that low levels of PA might put subjects entering old age at risk.
Statin therapies reduce risk of Alzheimer’s disease and dementia with increased protective therapeutic effect with increasing age
Authors: Torrandell‐Haro Georgina , Branigan Gregory L , Vitali Francesca , Brinton Roberta Diaz 
Published: December 2021

AbstractBackgroundA previous peer‐reviewed publication (Torrandell‐Haro et al. 2020, Alzheimer’s & Dementia: TRCI) reported that statin therapy was associated with risk reduction of Alzheimer’s disease. Herein we sought to determine the replication validity of statin therapy on the incidence of Alzheimer’s disease and dementia in a larger dataset with a clinical population of 15 million participants.MethodThis retrospective cohort study used the Mariner claims dataset, which includes prescription and records of 15 million patients from private‐payer and Medicare insurance from across the United States. Patient records surveyed for a diagnosis of Alzheimer’s or dementia starting 1 year after statin exposure. 304,662 participants aged 45 years and older, without prior history of neurodegenerative diseases or brain surgery, were included in the study. In this study, patients with and without exposure to statins were categorized by age groups (60‐65, 70‐75, 80‐85) to determine an association between age and Alzheimer’s outcomes.ResultOf the 304,662 participants included in the study, 152,331 patients (mean [SD] age, 61.75 [3.4] years) were exposed to statin therapy, and 152,331 patients (59.76 [2.6] years) were not treated with statins. Statin exposure was associated with a lower incidence of Alzheimer’s (relative risk, 0.51; 95%CI, 0.46‐0.57; P < .001) and dementia (relative risk, 0.61; 95%CI, 0.58‐0.61; P < .001). The incidence of Alzheimer’s and dementia was reduced by all statins with variances in individual risk profiles. Increasing age was associated with a greater risk reduction of Alzheimer’s disease in patients with statin exposure compared to non‐statin controls.ConclusionOutcomes of these analyses validated previous findings that statin therapy is associated with decreased risk of Alzheimer’s and dementia using a larger database than the previously reported. Further, statin exposure was associated with age‐dependent reduction in risk of Alzheimer’s disease diagnosis.This work was supported by the National Institute on Aging (grants P01AG026572 [Perimenopause in Brain Aging and Alzheimer's Disease], the Sex Differences in the Molecular Determinants of Alzheimer’s Disease Risk: Prodromal Endophenotype (grant 5R01AG057931‐02), the Women's Alzheimer's Movement and the Center for Innovation in Brain Science to Dr Brinton.
Cardio‐autonomic control during exercise and risk for incident delirium
Authors: Gao Lei , Ulsa Ma Cherrysse , Zheng Xi , Yang Hui‐Wen , Li Peng , Hu Kun 
Published: December 2021

AbstractBackgroundDelirium is associated with increased risk for Alzheimer’s disease (AD) and mortality; it is characterized by acute confusion commonly after stressors of illness during hospitalization. Integration between the heart and brain via the autonomic nervous system, or cardio‐autonomic control (CAC) is thought to be potentially protective during such stressors. Related to CAC, heart rate (HR) fluctuations display fractal correlations (similar temporal autocorrelation across different time scales) that reflect a dynamic interplay between sympathetic and vagal outflows, where disruption is thought to contribute to neuronal damage. We hypothesized that fractal correlations in HR fluctuations can serve as a novel physiological biomarker for predicting incident delirium.MethodWe derived fractal correlations (α) using ECG data from 37,978 participants (mean age 57.4) free from delirium and AD within the UK Biobank who underwent a 7‐minute stationary bike stress test between 2009‐2010, and had ≥1 inpatient hospitalization episode through to August 2020. Cox proportional hazards models were used to examine the association between α and incident delirium. We adjusted for demographics, physical activity levels, BMI, smoking, alcohol, cholesterol, diabetes, hypertension, ischemic heart disease, stroke, as well as test‐specific peak exercise load and mean heart rate achieved.ResultIncident delirium was newly diagnosed in 247 cases (6.5/1,000) during a median follow‐up time of 8.1 years (SD: 2.0, range: 0.2‐10.2) following ECG assessment. α showed a normal distribution with mean of 1.27±0.3 (SD). Negative association between α and incident delirium was observed. The fully adjusted hazard ratio was 1.26 (95% confidence interval: 1.10‐1.45; p=0.001) for each 1‐SD decrease in α. Putting this into context, a subject with a lower α at the 10thpercentile (vs. 90th) showed a 59% increased risk of developing incident delirium, equivalent to the additional risk of being 5‐years older or a current smoker in this cohort.ConclusionFractal correlation of heartbeat fluctuations during an exercise ECG recording was independently associated with incident delirium, and may be a hidden measure of brain‐heart resilience. As this cohort ages, future work will be able to answer the crucial question of whether this is a shared marker of vulnerability between delirium and AD.