bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal imaging markers of tau, neuroinflammation and atrophy to predict clinical progression in progressive supranuclear palsy
Authors: Malpetti Maura , Passamonti Luca , Jones P Simon , Rittman Timothy , Fryer Tim D , Hong Young T , Street Duncan , Rodríguez Patricia Vázquez , Bevan‐Jones W Richard , Aigbirhio Franklin I , O'Brien John T , Rowe James B 
Published: December 2020

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is associated with tau pathology and neurodegeneration, particularly in basal ganglia, diencephalon, and brainstem. Recently, neuroinflammation has been recognized as another key aspect in the pathophysiology of PSP. Understanding whether these three pathological features predict the clinical progression is crucial to develop new prognostic measures. Here, we studied how baseline assessments of in vivo tau pathology (measured by [18F]AV‐1451 PET), neuroinflammation ([11C]PK11195 PET), and atrophy (structural MRI) predicted longitudinal clinical changes in n=17 patients with PSP‐Richardson’s syndrome.MethodAll patients underwent a baseline multi‐modal assessment with [18F]AV‐1451 PET, [11C]PK11195 PET, and structural MRI. They were clinically assessed up to 4 years, with the PSP rating scale. Regional PET binding potentials and grey‐matter volumes across all brain regions were summarised by method‐specific Principal Component Analyses (PCAs). A linear mixed model was applied to the longitudinal PSP rating scale scores to estimate the rate of annual decline in each participant. We regressed the individuals’ estimated rate of clinical progression on neuroimaging components, to identify the prognostic value of PET and MRI markers in different clusters of regions, with age and time between scan and the first clinical assessment as covariates.ResultPCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions, and seven components of grey‐matter volumes. Patients showed an average increase of 6.15 points (p<0.0001) per year on the PSP rating scale. PCA‐derived components reflecting tau burden (r=0.639, p=0.010) and neuroinflammation (r=0.596, p=0.019) in PSP‐related subcortical areas were linked to the annual rate of change of disease severity. These pathology markers components were associated with atrophy of the same regions (tau: r=‐0.626, p=0.007; neuroinflammation: r=‐0.584, p=0.014) but atrophy did not correlate with clinical progression (r=‐0.474, p=0.074).ConclusionIn vivo PET markers of both tau pathology and neuroinflammation in subcortical regions predicted clinical progression in PSP patients. Our results encourage the application of [18F]AV‐1451 and [11C]PK11195 PET in PSP as stratification measures that inform prognosis, to develop new targeting disease‐modifying therapies and empower clinical trials.
Multiple biological pathways associate with cerebral amyloid load in the early Alzheimer's continuum
Authors: Salvadó Gemma , Molinuevo Jose Luis , Milà‐Alomà Marta , Falcon Carles , Operto Greg , Cacciaglia Raffaele , Arenaza‐Urquijo Eider M , Vilor‐Tejedor Natalia , Shekari Mahnaz , Minguillón Carolina , Fauria Karine , Battle Mark R , Buckley Chris J , Farrar Gill , Simon Maryline , Kollmorgen Gwendlyn , Blennow Kaj , Zetterberg Henrik , Suárez‐Calvet Marc , Gispert Juan Domingo 
Published: December 2020

AbstractBackgroundThe pathophysiological events associated with the earliest cerebral amyloid deposition are not fully understood. Here, we describe, in cognitively unimpaired individuals, the association between amyloid load and cerebrospinal fluid (CSF) biomarkers of the pathogenic events described in Alzheimer’s disease (AD): core AD biomarkers (Aβ42/40 and pTau), synaptic dysfunction (neurogranin), neurodegeneration (neurofilament light [NfL]), microglial and astroglial‐related response (sTREM2, YKL‐40, GFAP, S100b), neuroinflammation (IL‐6) and α‐synuclein.MethodThe first consecutive 293 participants of the ALFA+ study with both valid CSF biomarker determination and [18F]flutemetamol amyloid PET scans acquired within one year time were included. We measured the CSF biomarkers using the Roche NeuroToolkit robust prototype assays and the commercially available Elecsys® Phospho‐Tau CSF assay. Centiloid (CL) values and SUVr images were derived from [18F]flutemetamol scans using the whole cerebellum as reference region. We sought for correlations between CSF biomarkers and cerebral amyloid deposition both globally, using the Centiloids as outcome variable, and regionally, using a voxel‐wise approach. The final model used for both analyses included: main effects of all CSF biomarkers and also interaction effects between CSF biomarkers with age, sex and APOE‐ε4 status. Interactions were only included if they showed a trend effect (p<0.10) in the global analysis. Neurogranin and pTau were included in the model as a unique vector due to their high collinearity (r>0.9).ResultIn the global analysis, pTau‐neurogranin, NfL, GFAP and YKL‐40 showed a positive correlation with global amyloid burden (Table 1). Significant interaction effects were found between: age*pTau‐neurogranin (older participants show higher amyloid deposition with higher pTau‐neurogranin); sex*sTREM2 (women with higher sTREM2 had higher amyloid deposition); APOE‐ε4*NfL (carriers with higher NfL had higher amyloid deposition) and APOE‐ε4*α‐synuclein (carriers with higher α‐synuclein had lower amyloid deposition), which are shown in Table 1 and Figure 1. Regional main effects are shown in Figure 2 while interactions are shown in Figure 3.ConclusionNeurodegeneration and inflammation pathways are associated to early amyloid deposition. The fact that biomarkers of these pathways show interactive effects with the main AD risk factors (age, sex and APOE‐ε4) also suggests that they play different roles in the early stage of the Alzheimer’s continuum.
Do call it screening: How the conceptualisation of dementia screening is intertwined with its practice
Authors: Kapeller Alexandra , Zeiler Kristin , Gunnarson Martin 
Published: December 2020

AbstractBackgroundWhile the value of early detection of dementia is largely agreed upon, the value of population‐based screening as a means to early detection is controversial. Due to this controversial status, population‐based screening is not recommended in the majority of national dementia plans. Some current practices, though, resemble screening but are called 'active case‐finding' or 'opportunistic screening'. Labelled them as such could help to avoid the ethical scrutiny of screening criteria.MethodTwo practices, the Annual Wellness Visit in the USA and the UK hospital 'case‐finding' scheme, are analysed with different conceptualisations of screening and case‐finding from the literature.ResultBased on this literature, both practices could be called 'opportunistic screening', which, so we argue, should fulfill the same criteria as population‐based screening. Factors distinguishing the practices are the application of clinical judgement, the way the practice is offered, and whether it targets a predefined population.ConclusionNo matter how a practice is conceptualised, conforming to the ethical standards should always be ensured. We propose a distinction between population‐based screening, opportunistic screening, and case‐finding. A distinction between active and passive case‐finding is deemed unhelpful.
Dementia knowledge among older Chinese adults: A cross‐national comparison between Melbourne and Beijing
Authors: Zhao Mei , Lv Xiaozhen , Lin Xiaoping , You Emily , Zhang Haifeng , Ellis Kathryn A , Yu Xin , Wang Huali , Lautenschlager Nicola T 
Published: December 2020

AbstractBackgroundImproving dementia knowledge among older populations has the potential to reduce risk factors or enable early diagnosis and timely treatment. This study compared dementia knowledge between older Chinese adults in Melbourne, Australia, and Beijing, China, and explored similarities and differences in relation to dementia knowledge between these two groups. Ultimately, this study aims to inform the development of tailored dementia education programs for older Chinese adults.MethodA cross‐sectional design was employed in this study. In total, 379 participants (153 from Melbourne, and 226 from Beijing) completed the questionnaire. Dementia knowledge was assessed with the Alzheimer's Disease Knowledge Scale (ADKS). Demographic characteristics, dementia‐related experience, and mental health status of study participants were also collected.ResultIn general, older Chinese adults in Melbourne and Beijing present a fair level of dementia knowledge (Mean±SD: 17.2±2.9 versus 17.5±2.9, P=0.179) and patterns of scores of dementia knowledge sub‐domains with highest scores in life impact and lowest scores in caregiving. In these seven domains, the correct response rates of life impact were 77% in Melbourne versus 78% in Beijing (P=0.812), treatment and management were 70% versus 72% (P=0.497), course were 66% versus 70% (P=0.096), assessment and diagnosis were 61% versus 62% (P=0.517), symptoms were 60% versus 59% (P=0.744), risk factors were 47% versus 48% (P=0.604), caregiving were both 36% (P=0.647). Multiple linear regression analysis found that younger age (B=‐0.059, P=0.025) and positive self‐report dementia impact (B=2.955, P=0.042) were significantly associated with a higher level of dementia knowledge in Melbourne, whereas the positive family history of dementia (B=1.415, P=0.040) was significantly associated with a higher level of dementia knowledge in Beijing.ConclusionOlder Chinese adults living in Melbourne and Beijing only had a fair knowledge about dementia, especially about the sub‐domains of risk factors and caregiving information. Different factors associated with dementia knowledge in these two groups. These findings suggest that dementia education programs for older Chinese adults need to focus on risk factors and caregiving.
Amyloid β redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade
Authors: Wang Qin 
Published: December 2020

AbstractBackgroundStrong genetic and experimental evidence indicates toxic amyloid β (Aβ) peptides as a key driving factor of Alzheimer’s disease (AD) pathogenesis. The microtubule‐associated protein tau is an essential mediator of Aβ toxicity. Yet, the molecular pathway from Ab to tau pathology remains elusive, presenting a major gap in in‐depth understanding of the pathological cascade of AD. The brain noradrenergic system is highly vulnerable in AD; despite of being a sensitive target of Aβ and tau toxicity, whether it is directly involved in AD pathogenesis is unknown.MethodWe examined the activity of α2A adrenergic receptor (α2AAR) in AD animal models and human postmortem brains using pharmacological methods, performed bioinformatic analysis of cases from the National Alzheimer’s Coordinating Center, characterized Aβ binding of α2AAR using biochemical, cell biological and pharmacological methods, and performed pathological and behavioral studies with AD animal models.ResultIn AD human brains and animal models, α2AAR activity is elevated as compared with non‐AD controls. Activation of this receptor is associated with worsened cognitive function in patients with cognitive deficits. Aβ oligomers bind to an allosteric site on α2AAR with nanomolar affinity. Aβ oligomer binding redirect norepinephrine‐elicited signaling through this receptor to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine‐dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50‐100 fold lower than the amount required to activate GSK3β by Aβ alone. In vivo treatment with an α2AAR blocker reduces Aβ‐induced GSK3β activation and tau hyperphosphorylation. Moreover, this treatment ameliorates AD‐related pathological changes and improves cognitive function in the two independent AD mouse models.ConclusionWe reveal a previously unappreicated direct role of norepinephrine signaling in connecting Aβ and tau, two key pathological components of AD pathogenesis. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design, and for understanding the selective vulnerability of noradrenergic neurons in AD.
Longitudinal plasma levels of neurofilament light in Down syndrome: A multicenter study
Authors: Alcolea Daniel , Carmona‐Iragui Maria , Barroeta Isabel , Videla Laura , Muñoz Laia , Van Pelt Kathryn L , Schmitt Frederick A , Lightner Donita , Koehl Lisa , Sacco Silvia , Mircher Clotilde , Pape Sarah , Nübling Georg , Levin Johannes , Zaman Shahid , Strydom Andre , Rebillat Anne‐Sophie , Head Elizabeth , Blesa Rafael , Lleó Alberto , Fortea Juan 
Published: December 2020

AbstractBackgroundPlasma Neurofilament light (NfL) has been proposed as a useful biomarker to detect Alzheimer’s disease dementia in Down syndrome. To validate its clinical utility and implement it in clinical trials, it is essential to understand the longitudinal changes of this biomarker, and the association of these changes to clinical progression.MethodWe included participants with Down syndrome evaluated in six different centers. All participants provided at least two plasma samples and were clinically classified as asymptomatic (aDS), prodromal Alzheimer’s disease (pDS) or Alzheimer’s disease dementia (dDS). The aDS and pDS participants were subsequently classified as “Progressors” when their diagnosis changed to pDS or dDS, respectively, at any time throughout follow up visits. Plasma NfL levels were measured using commercially available kits for the Simoa SR‐XTM (Quanterix). We performed ANCOVA and Cox regression to evaluate group differences in baseline NfL levels and their association with prognosis. We used linear mixed models to estimate longitudinal trajectories of plasma NfL in all groups.ResultWe analyzed 575 samples from 226 participants classified as aDS (n=165), pDS (n=32) or dDS (n=29). Participants in the pDS and dDS groups were older than aDS (50.6 and 53.3 vs. 38.9, respectively; p<0.001). After adjusting for age, sex and intellectual disability, levels of NfL were 79.9% higher (p<0.001) in dDS and 40.5% higher (p<0.001) in pDS compared to aDS (Figure 1). The highest tertile of baseline plasma NfL was associated to a 5.9 fold risk of clinical progression (p<0.001; Figure 2). Longitudinally, aDS non‐progressors showed an annual increase of 2.7% (0.2%‐5.3%, p=0.036) in NfL levels, significantly different from 12.2% (5.1%‐19.9%, p=0.014) in aDS progressors, 16.1% (8.7%‐24%, p=0.001) in pDS progressors and 21.7% (13.2%‐30.9%, p<0.001) in dDS (Figure 3).ConclusionThis study confirms the clinical utility of plasma NfL to diagnose symptomatic Alzheimer in Down syndrome, but also shows that the annual increase in NfL levels do not plateau in dementia stages. These longitudinal trajectories enable its use as a theragnostic marker in clinical trials.
Dominantly inherited Alzheimer disease: Frequency, genetic heterogeneity, and clinical phenotype in Latin America
Authors: Guerra Jorge J Llibre , Mendez Patricio Alexis Chrem , Allegri Ricardo F. , Surace Ezequiel , Llibre‐Rodriguez Juan , Ibarrola Mariana Longoria , Cornejo‐Olivas Mari , Sosa‐Ortíz Ana Luisa , Takada Leonel Tadao , Lopera Francisco , Sanchez Victor , Jiménez‐Velazquez Ivonne Z. , Acosta Daisy , Behrens María Isabel , Doering Michelle , Li Yan , Morris John C. , McDade Eric , Bateman Randall J. 
Published: December 2020

AbstractBackgroundMore than 300 pathogenic variants in APP, PSEN1 and PSEN2 genes have been reported causing Dominant Inhered Alzheimer Disease (DIAD); most of these reports come from Northern hemisphere countries. In recent years, a growing number of familial AD cases have become known in Central and South American countries; however, little is known about epidemiology and clinical‐genetic profile of DIAD in Latin American (LatAm) countries. We aimed to systematically review and describe DIAD cases reported in LatAm populations.MethodA systematic review for all DIAD cases reported in LatAm was completed between September 2019 to December 2019. The search strategy included the following major databases: MedLine, SciELO, Cochrane, and LILACS. More than 927 records were screened and 106 peer‐reviewed publications on DIAD families from LATAM were included in the final analysis. We extracted individual‐level data on the age at onset(AAO), disease course, and the presence/absence of neurological findings. Findings extracted from literature were updated by local researchers . The combined dataset included 843 family members, of whom 237 were affected by DIAD. Analyses were done using descriptive statistics, comparisons of means and frequencies.Result24 DIAD pathogenic variants have been reported in LatAm countries, including 21 PSEN1, two PSEN2 and one APP variant. Countries with higher DIAD frequency were Colombia, Puerto Rico, Mexico, and Cuba, usually related to founders' effects on these regions. AAO differed by causing gene, with a younger age at onset for individuals harboring PSEN1 variants, followed by APP and PSEN2 carriers (43.8 ± 8.9 years vs 48.6 ± 1.6 years vs 52.2 ± 2.1 years respectively, p < 0.0001). The most common clinical presentation was amnestic. Atypical features were described with M146V‐PSEN1(Argentina) and A431E‐PSEN1 (Mexico) presenting with FTD‐like syndrome and spastic paraparesis respectively. We found that affected individuals carrying PSEN1 mutations also experience myoclonus, pyramidal, and cerebellar signs (p < 0.001, p = 0.002, and p = 0.003, respectively).ConclusionThis work describes an initial overview of DIAD in LatAm. The discovery and clinical characterization of DIAD families from Lain America will inform the development of the DIAN‐observational study in the region and will create a cohort ready population for clinical the upcoming trials.
Evaluation of the efficacy and safety of orally administered BI425809 during a 12‐week treatment period compared with placebo in patients with cognitive impairment due to Alzheimer’s disease
Authors: Wunderlich Glen , Blahova Zuzana , Garcia Miguel , Huang Songqiao , Pollentier Stephane , Jessen Frank 
Published: December 2020

AbstractBackgroundAlthough currently approved therapies for Alzheimer’s dementia (AD) are used to treat impairments in memory and function, there is an unmet need for additional symptomatic therapies in mild‐to‐moderate AD. As N‐methyl‐D‐aspartate (NMDA) receptor hypofunction has been hypothesised to be associated with cognitive impairment in AD, improving post‐synaptic NMDA receptor signalling through glycine transporter 1 (GlyT1) inhibition may improve cognitive function. This proof of clinical concept study investigated the efficacy and safety of the investigational drug BI 425809, a GlyT1 inhibitor, in mild‐to‐moderate AD and evaluated dose‐ranging data to define a suitable dose of BI 425809 in this population.MethodA Phase II, multicentre, double‐blind, parallel‐group study including patients aged ≥55 years with mild‐to‐moderate AD (according to the recommendations from the National Institute on Aging‐Alzheimer’s Association workgroups on diagnostic guidelines for AD), a mini‐mental state exam score of 15–26 at screening, and a reliable study partner who was in close contact with the patient and could contribute to the neuropsychological rating scales. Concomitant acetylcholinesterase inhibitor use was permitted but not required. Eligible patients were randomised (1:1:1:1:1) to receive BI 425809 2, 5, 10, 25 mg, or placebo once daily for 12 weeks. The primary endpoint was change from baseline in Alzheimer’s Disease Assessment Scale‐cognitive subscale (ADAS‐Cog11) total score at Week 12. Secondary endpoints included change from baseline in the Alzheimer’s Disease Cooperative Study/Activities of Daily Living score and Clinician's Interview‐Based Impression of Change at Week 12. The pre‐specified primary analyses for proof of concept and dose finding was the multiple comparison procedure with modelling for mixed model repeated measures. Adverse events were evaluated throughout the study.ResultA total of 610 patients were randomised. No significant non‐flat dose‐response relationship was detected for the primary endpoint. Secondary endpoints similarly did not detect any significant benefit for BI 425809 treatment groups compared with placebo. BI 425809 was generally well tolerated with no new safety issues identified.ConclusionNo clinically meaningful changes from baseline were observed across a range of BI 425809 doses administered to patients with mild‐to‐moderate AD. Funding: Boehringer Ingelheim: Study 1346‐0023 (NCT02788513).
Sex difference in white matter degeneration in MCI adults: Multi‐modal MRI analysis
Authors: Kim Jeongchul 
Published: December 2020

AbstractBackgroundAlthough the development and progression of Alzheimer's disease (AD) are characterized by significant sex differences, the factors underlying sex differences in AD are not well understood. This study explored sex differences in white matter (WM) degeneration patterns among mild cognitive impairment (MCI) adults in an exercise intervention study.MethodLongitudinal MR images for 32 adults with MCI were acquired as part of a randomized controlled trial investigating an exercise intervention (n=15 aerobic exercise, n=17 stretching control). Brain MRI was acquired at baseline and 6 months later after the exercise intervention on a 3T scanner using a 32‐channel head/neck coil. High‐resolution structural anatomic T1‐weighted and diffusion tensor images of each subject were collected, from which the longitudinal changes of diffusion metrics (FA, MD and Fiber Volume Fraction [FV]) and volume changes (Jacobian Determinant, JD) rate were estimated for 48 WM regions of interest (ROIs) defined by the JHU‐WM Atlas. The total WM degeneration for each individual was defined by counting the number of ROIs demonstrating > 5% changes in diffusion metrics or JD compared to the baseline considering fiber crossing environments (Figs. 1 and 2).ResultNo statistically significant change was observed in FA, MD, FV, JD and WM degeneration for both groups during the 6‐month period. But, increase in FA was observed in Right Posterior Corona Radiata for the whole study population (p=0.0087). A wide distribution of WM degeneration was observed over the different brain regions with a higher probability of WM degeneration in Left Posterior Limb of Internal Capsule (59%), Right Retrolenticular Part of Internal Capsule (56%) and Left Anterior Corona Radiata (56%). Higher WM degeneration was observed in women compared to men (p=0.029) after adjustment for age, exercise intervention and APOE4 status.ConclusionGroup‐level changes or differences were not observed for most longitudinal MRI measures due to the heterogeneity of WM degeneration in MCI adults. However, a multi‐modal MRI approach integrating morphometric information with diffusion properties could elucidate the sex differences in WM degeneration among MCI adults.