bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does playing a musical instrument prevent dementia?
Authors: Walsh Sebastian , Brayne Carol E 
Published: December 2021

AbstractBackgroundMusical instrument playing provides intellectual stimulation, which is hypothesised to generate cognitive reserve that protects against cognitive impairment.MethodA systematic review and meta‐analysis of all studies with musical instrument playing as the exposure, and cognitive impairment and/or dementia as the outcome. This was followed by a primary analysis drawing on data from the EPIC‐Norfolk population cohort, attesting for a dose‐response relationship between mid‐life musical instrument playing and late‐life cognition, after adjusting for relevant health and social confounders.ResultOf 1211 articles identified from literature searching, three met inclusion criteria. All were of good methodological quality, and reported large protective effects of musical instrument playing. A twin study reported that musicians were 64% less likely to develop mild cognitive impairment or dementia, after additionally adjusting for sex, education and physical activity. A meta‐analysis of two cohort studies found a 59% reduction in the risk of developing dementia within the study follow up.In EPIC‐Norfolk, data were available from 5693 participants (745 musicians) on music playing, cognition, and all covariables. Classification of musicianship by frequency of playing demonstrated key differences in socio‐demographic factors. Musicians outperformed non‐musicians in cognition generally. Compared to non‐musicians, frequent musicians had 80% higher odds of being in the top cognitive decile (OR 1.80 [95%CI 1.19‐2.73]), whilst musicians playing at any frequency had 29% higher odds (95% CI 1.03‐1.62), compared to non‐musicians. There was evidence of a threshold effect, rather than a linear dose‐response relationship.ConclusionThe existing evidence base suggests a substantial protective effect of musical instrument playing on cognition, but is limited by size and the risk of reverse causality. Our primary EPIC‐Norfolk analysis also supports a positive association between mid‐life musical instrument playing and late‐life cognition. ‘Musicians’ are a heterogeneous group, and those playing frequently demonstrated the best cognition. Larger, more focused studies are required to further explore this association, with a particular need to consider the cumulative lifetime quantity of music playing. Studies investigating the association between lifestyle factors (e.g. music playing) and cognitive decline should consider the heterogeneous nature of participants, rather than simply adopting a binary classification.
Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve
Authors: Illán‐Gala Ignacio , Casaletto Kaitlin B. , Borrego‐Écija Sergi , Arenaza‐Urquijo Eider M , Wolf Amy , Cobigo Yann , Goh Sheng‐Yang Matthew , Staffaroni Adam M. , Alcolea Daniel , Fortea Juan , Blesa Rafael , Clarimon Jordi , Iulita M. Florencia , Brugulat‐Serrat Anna , Lladó Albert , Grinberg Lea T. , Possin Kate L , Rankin Katherine P , Kramer Joel H , Rabinovici Gil D. , Boxer Adam L. , Seeley William W. , Sturm Virginia , Tempini Maria Luisa Gorno , Miller Bruce L. , Sanchez‐Valle Raquel , Perry David C. , Lleó Alberto , Rosen Howard J. 
Published: December 2021

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive behavioral change along with social, cognitive, and functional deterioration. In contrast Alzheimer´s disease, patients with bvFTD show an anterior pattern of neurodegeneration with selective involvement of the frontotemporal cortex. Biological sex is an increasingly recognized factor driving clinical heterogeneity in Alzheimer's disease, but its role in bvFTD is unknown.MethodIn this multicenter study, we aimed to characterize the impact of sex on clinical presentation, longitudinal decline, and cortical thickness in bvFTD. We included 216 patients with bvFTD and 235 controls with MRI. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We further explored the existence of sex differences in cognitive reserve by following the residuals approach to operationalize reserve as having better cognition and fewer behavioral changes than predicted by cortical thickness (a proxy of pathology). To do this, we modeled the relationship between cognition or behavior with cortical thickness and used each individual's residual as a proxy of their reserve.ResultAt diagnosis, women with bvFTD showed greater atrophy burden in frontotemporal regions compared to men despite very subtle differences in cognitive and functional impairment, progression, and survival. For a similar amount of atrophy, women demonstrated better‐than‐expected scores on executive function and less apathy, sleep, and appetite changes than men.ConclusionOur findings suggest that women might have greater behavioral and executive reserve than men. Future studies should examine the specific mechanisms underlying the observed differences and consider biological sex for the design of research studies and clinical trials in bvFTD and other frontotemporal lobar degeneration syndromes.
Blood and digital markers: Novel findings and its implication on dementia care in China
Authors: Jia Jianping , Jia Longfei , Li Tingting , Yang Jianwei , Song Yang 
Published: December 2021

AbstractBackgroundAs an aging country with a large population, China has the largest population of patients with dementia in the world (10‐11million patients aged 60 years or older), accounting for approximately 25% of the entire population with dementia worldwide. Currently in China, due to the differences between tier 1, 2, and 3 hospitals (Fig 1), only at academic hospitals affiliated to medical university, the diagnosis of dementia is determined to standard procedures, while more patients with cognitive impairment are diagnosed by neurologists or internists without specialized training in dementia. Exosomes are an attractive source of biomarkers in AD, with its accessibility, generalizability and availability advantages over CSF or PET gold standard.MethodWe will present two of our latest findings based on two multicenter studies and explore the impact of novel blood and digital markers on dementia care in China.ResultOur latest findings indicated that exosomal biomarkers ‐ in particular, Aβ42, T‐tau, P‐T181‐tau, growth associated protein 43 (GAP43), neurogranin, synaptosome associated protein 25 (SNAP25), and synaptotagmin 1 ‐ had the same diagnostic power as the CSF biomarkers. Moreover, the combination of exosomal GAP43, neurogranin, SNAP25, and synaptotagmin 1 detected AD 5 to 7 years before cognitive impairment.ConclusionAccording to our latest results, exosomal biomarkers could predict AD at asymptomatic stage, making an effective intervention to slow or halt the progression of AD possible. Provided that diagnosis of dementia depends on validated plasma biomarkers, AD would be easily diagnosed in tier 1 or tier 2 hospitals in China. Then, tier1 or tier 2 hospital will play more important role in AD diagnosis, monitoring and patients’ enrolment in clinical trials. Tier 3 hospitals will focus on the diagnosis and treatment of difficult and complicated cases transferred from tier 1 or tier 2 hospitals as well as treatment decision. They will have more time and resources for exploring new mechanism, interventions, translational research and clinical trials.
Automated speech analysis for detection of cognitive and emotional changes
Authors: König Alexandra , Ramakers Inez H.G.B. , Linz Nicklas , Zeghari Radia , Robert Philippe 
Published: December 2021

AbstractBackgroundMany aspects of language and speech seem affected with increased dementia risk. Recently speech analysis has become mature enough to provide completely automatically extracted fine‐grained features highly sensitive to early cognitive and affective changes.MethodSeveral studies were performed during which over 150 speech samples of patients at different stages (controls, Mild Cognitive Impairment, Dementia) were collected at the clinic as well as remotely (over the phone and video‐conference system). Subsamples of patients with apathy and depression were included. The spoken features extracted from the recordings were compared against data from classical assessment tools and manual annotations.ResultComparison to reference measures show firstly, highly accuracies in demonstrating speech differences based on clinical diagnosis (up to 90%) and secondly, significant correlations between automatically extracted and manually annotated measures (r = 0.9).ConclusionSpeech and language features represent a promising biomarker candidate as they can be automatically and remotely extracted even over the telephone. With the help of advanced machine learning and different computational techniques the most significant markers can be identified as early indicator for screening.
Socioeconomic inequalities in dementia diagnostic process and medication prescription: Experience from the Swedish Dementia Registry
Authors: Hoang Minh Tuan , Kåreholt Ingemar , von Koch Lena , Xu Hong , Secnik Juraj , Religa Dorota , Tan Edwin CK , Johnell Kristina , Garcia‐Ptacek Sara 
Published: December 2021

AbstractBackgroundLower socioeconomic position (SEP) was associated with higher risk of morbidity and mortality. However, the influence of SEP on diagnosis and medication use in dementia is understudied. Our study aimed to explore the impact of patients’ SEP on dementia diagnostic process and medications.MethodIn this longitudinal cohort study, data from 74,414 dementia patients registered in the Swedish Dementia Registry (2007‐2018) were linked with the Swedish Longitudinal Integrated Database for Health Insurance and Labor Market Studies (2006‐2017). SEP was expressed through education and disposable individual income. Outcomes included performance of the dementia diagnostic examinations and prescription of anti‐dementia drugs. The complete basic diagnostic work‐up comprising blood testing, neuroimaging, clock‐test and Mini‐Mental State Examination (MMSE) was suggested by the diagnostic guidelines for dementia from the Swedish National Board of Health and Welfare and was the main study outcome.ResultIn comparison with patients who completed compulsory education < 9 years, patients with university ≥3 years had higher probability of receiving the basic diagnostic work‐up (odds ratio (OR) 1.19; 95% confidence interval (CI) 1.10‐1.29), clock test (OR 1.12; 95%CI 1.02‐1.24) and CT‐MRI (OR 1.23; 95%CI 1.09‐1.39). Compared with people in the lowest income quintile, patients in the highest income quintile presented higher chance of receiving the basic diagnostic work‐up (OR 1.35; 95%CI 1.26‐1.46), clock test (OR 1.40; 95%CI 1.28‐1.52), blood analysis (OR 1.21; 95%CI 1.06‐1.39), MMSE (OR 1.47; 95%CI 1.26‐1.70) and CT‐MRI (OR 1.30; 95%CI 1.18‐1.44). Higher SEP was significantly associated with higher chance of being diagnosed at a specialist care. People with higher income were more likely to receive a specific dementia diagnosis, as opposed to “unspecified” dementia. SEP presented no association with prescription of anti‐dementia medication, except for the association between education and the use of memantine.ConclusionInequalities in dementia diagnostic process and prescription of anti‐dementia medications occur among people with different education or income levels. Income was more decisive than education in the relation to dementia diagnostic process.
Prodromal markers of neurodegenerative disease: Insights from the UK Biobank dataset
Authors: Street Duncan , Whiteside David , Rittman Timothy , Rowe James B. 
Published: December 2021

AbstractBackgroundAbnormal quantitative motor testing and subtle cognitive deficits are associated with increased neurodegenerative disease risk although assessment methods and outcomes vary. Understanding how and when these deficits develop will improve early detection and clarify prodromal disease course. We set out to determine markers predictive of two common neurodegenerative diseases, Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), in a prospective cohort study.MethodThe UK Biobank dataset includes demographics, medical history, cognitive function tests and physical measures collected from 500,000 adults aged 40‐69 between 2006‐2010. Ongoing follow‐up includes repeat testing, death registry and hospital diagnostic coding. Cases were identified from hospital coding data and death registry and were matched with age and gender‐similar controls (2:1). Those with a known diagnosis at baseline were excluded.Result2248 AD cases (male=48%, mean age 65.3±4.2 years, mean time to diagnosis 8.4±2.5 years) and 2212 PD cases (male=62%, mean age 63.8±5.2 years, mean time to diagnosis 7.7±2.7 years) were identified. 537/2248 (male=51%) AD cases had died by June 2020 (mean assessment to death 9.8±2.0 years) and 357/2212 (male=70%) PD cases (mean assessment to death 9.4±2.2 years). The AD group had shown poorer performance on tasks of fluid intelligence (p<0.0001) and numeric memory (p<0.0001) at baseline than both controls and the PD group. Both AD and PD groups had had slower reaction times (p<0.0001) and weaker hand grip strength at baseline (p<0.0001) than controls. There were no significant effects of age or sex.ConclusionPoor performance on tasks of cognitive function are established features of AD at diagnosis, however it is unknown when during the prodromal disease course they begin. Our data demonstrate subtle changes in markers of these features many years prior to diagnosis in a large, prospective cohort.
Domain‐specific cognitive trajectory among patients with minor stroke or transient ischemic attack in a 6‐year Asian cohort: Temporal patterns and indicators
Authors: Zhao Xuhao 
Published: December 2021

AbstractBackgroundThis study aimed to assess the 6‐year domain‐specific patterns of cognitive trajectory among survivors of minor stroke or transient ischemic attack (TIA) in a multi‐ethnic clinical cohort in Singapore, and to identify possible demographic, clinical and vascular indicators of different trajectory patterns.MethodElderly participants completed cognitive and clinical assessments at 2 weeks, 3‐6 months, 1 year, 3/4 years, 5 years and 6 years post‐stroke. Global and domain‐specific cognition was transformed to standardized z‐scores. Generalized estimating equation and mixed linear model were used to examine baseline predictors of long‐term cognitive impairment and domain‐specific cognitive trajectory. Survival analysis was performed for incident cognitive impairment during the 6‐year study duration.ResultA total of 244 participants were included in the analysis. A fluctuating yet stable pattern was observed in all cognitive domains, except for visual memory, which showed a significant improvement across the six‐year follow‐up. Regardless of baseline characteristics, baseline MoCA was associated with lower odds of long‐term cognitive impairment (0.67, 95%CI= (0.60, 0.75)), whilst both MoCA improvement from baseline to 3‐6 months, and from baseline to 1 year were associated with lower risk of cognitive impairment (OR 0.80, 95%CI= (0.71, 0.90) and 0.86, 95%CI= (0.77, 0.97) respectively) after controlling for covariates.ConclusionPost‐stroke cognitive trajectory showed varying patterns across different cognitive domains. Our findings provide evidence on practice effects of the MoCA which can be used for identifying patients with higher risk of long‐term cognitive impairment.
Evidence of significant cognitive improvement over baseline in advanced Alzheimer’s disease (AD) patients: A regenerative therapeutic strategy
Authors: Alkon Daniel , Sun Miao‐Kun , Thompson Richard 
Published: December 2021

AbstractBackgroundSynaptogenix scientists have pioneered a regenerative therapeutic strategy designed to reduce (1.) a beta‐oligomers and hyperphosphorylated tau, but importantly, (2.) also restores the AD – induced loss of synaptic networks and neurons. In pre‐clinical studies (Sun and Alkon, TIPS, 2019), increased numbers of mature, mushroom spine synapses were measured with serial electron micrographs of the hippocampus with the rat spatial maze memory task, and were further significantly increased by the Bryostatin‐induced activation of the PKC epsilon‐BDNF cascade (Hongpaisan and Alkon, PNAS, 2007). Similarly, Bryostatin increased the numbers of mature synapses, normalized cognitive deficits, and prevented neuronal death in pre‐clinical models of neurodegeneration including AD (p<.01, 2‐tailed), stroke, Fragile X syndrome, and traumatic brain injury. Subsequently, compassionate use trials showed marked improvements in advanced AD patients (Nelson et al., JAD, 2017).MethodThereafter, an initial pilot (13 weeks, N=150) trial of Bryostatin to treat AD, Study #202, and a 2nd (13 weeks, N=100) pilot trial, Study #203, included identical protocols: 7 i.v. doses of 20 mcg / kg Bryostatin over 11 weeks with Placebo groups in each.ResultsBryostatin Treatment (at Week #13) in the 1st trial improved Severe Impairment Battery (SIB) scores over baseline (+4.5 over baseline, p<.04, 2‐tailed, pre‐specified exploratory analyses of AD patients, MMSE 14 – 4, vs. placebo, without chronic Namenda, Farlow et al., J. Alz. Dis., 2019). In a second pilot trial, Bryostatin caused significant SIB improvement (+4.12 over baseline) in the pre‐specified Moderate Stratum (MMSE 10 – 14) of advanced AD patients without Namenda (p < .005, 2‐tailed). In both trials, trend analyses demonstrated increased drug benefit with increasing dosing number. In a pooled trend analysis of Studies #202, 203, Bryostatin caused highly significant benefit (p<.001) and Placebo was NS.ConclusionWhile issues such as baseline imbalance (Study #203) and Namenda blockade of Bryostatin efficacy (Study #202) prevented reaching primary endpoints, these pre‐specified exploratory analyses (see above) revealed clear evidence of Bryostatin therapeutic efficacy, now being tested in an NIH‐sponsored, 6‐month trial, incorporating lessons learned from these pilot studies. This potential efficacy involved significant improvement over baseline, not only reduction in the rate of cognitive decline.
Towards a fully automatic AI framework to calculate voxel‐wise atrophy in the human brain
Authors: Reinwald Michael , Joules Richard , Papoutsi Marina , Weatheritt Jack , Wolz Robin 
Published: December 2021

AbstractBackgroundLongitudinal changes in volume using co‐registration of two serial T1W MRI scans are used as biomarkers to track the development of Alzheimer’s Disease and monitor potential treatment effects. Current methods (e.g., the boundary shift integral, BSI) may be restricted to certain regions or are computationally intensive and slow (e.g., the Advanced Normalization Tools, ANTs).MethodWe present an AI‐based framework to calculate voxel‐wise atrophy in the human brain. Our method features convolutional neural networks for cross‐sectional semantic segmentation and longitudinal pairwise non‐linear registration which does not require subject‐specific optimization. It warps one image to another by minimizing their difference, while preserving topology. Voxel‐wise volume change is estimated using the Jacobian determinant of the warp field, summed within a specified and automatically segmented region of interest in the baseline image. We evaluate our framework in ADNI (40 HC and 40 MCI) and OASIS3 (100 HC and 100 MCI) participants and assess the method’s measures of annualized atrophy in whole brain, ventricles, and hippocampus using common language effect sizes (CLES) and a Mann‐Whitney U‐test. Retest variability is measured in 30 OASIS3 participants with two serial MR scans not more than 13 days apart. We compare results to BSI as well as the same framework but substituting the non‐linear registration part with ANTs.ResultOur algorithm outperforms ANTs in non‐linear registration accuracy with mean (SD) normalized mutual information of 0.746 (0.055) compared to 0.651 (0.052) for ANTs and 0.646 (0.049) with affine registration only. It also has lower retest variability than ANTs (mean variability range is 0.08%‐0.12% and 0.15%‐0.34% for our algorithm and ANTs respectively). Finally, both BSI and our method show significant group difference for whole brain, ventricles, and hippocampus (all p < 0.002, CLES > 0.69) in both datasets, whereas in ANTs there is no significant group effect for hippocampus (p = 0.12) (see Table 1 for all results).ConclusionOur framework produces fast (seconds) and accurate non‐linear registration and voxel‐wise atrophy calculation for two serial MR images. Our calculated atrophy values show sensitivity to clinical diagnosis in cognitively impaired patients, comparable to current state‐of‐the‐art methods.
Mid‐life epigenetic age, neuroimaging brain age, and cognitive decline: Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Zheng Yinan , Habes Mohamad , Gonzales Mitzi M. , Pomponio Raymond , Nasrallah Ilya M. , Davatzikos Christos , Seshadri Sudha , Launer Lenore J. , Sorond Farzaneh , Sedaghat Sanaz , Bryan Nick , Sidney Stephen , Yaffe Kristine , Baccarelli Andrea , Hou Lifang 
Published: December 2021

AbstractBackgroundEstablishing biological aging markers that predict cognitive performance may aid early identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal cognitive function across the lifespan. We investigated two distinct classes of biological aging markers, 1) epigenetic aging, an emerging class of blood‐derived DNA methylation markers that aggregate aging‐related DNA methylation information; and 2) Spatial Patterns of Abnormality for Recognition of Brain Aging (SPARE‐BA), a composite magnetic resonance imaging (MRI) index of brain aging.MethodWe evaluated the cross‐sectional and prospective associations between both classes of aging markers and cognitive performance across a 15‐year follow‐up in the biracial CARDIA cohort of approximately 1,000 middle‐aged adults, using multiple linear regression and logistic regression. We compared the diagnostic performance of both aging markers using receiver operating characteristic (ROC) curve analysis.ResultWe found that accelerated epigenetic aging and brain aging were both cross‐sectionally and prospectively associated with worse cognitive outcomes. Specifically, every 5‐year faster epigenetic/brain aging is on average associated with 9.7% standard deviation (SD) higher in Stroop Test score, 7.7% SD lower in Rey Auditory Verbal Learning Test score, and 10.3% SD lower in Digital Symbol Substitution Test (all false‐discovery‐rate‐adjusted p <0.05). ROC analysis showed that a combined model with both epigenetic aging and brain aging markers optimized discriminability of individuals with lower cognitive performance 5 to 10 years later (area under the ROC curve: 0.70; 95% confident interval: 0.63‐0.77, Figure). Epigenetic and brain aging markers were weakly correlated with one another (Person’s r =0.17) and not statistically significant.ConclusionOur results showcase the significance of novel biological aging markers for cognitive health. Accelerated epigenetic aging and brain aging may capture distinct facets of biological aging and may jointly serve as early indicators of future cognitive decline and inform early interventions to prevent or delay cognitive impairment.