bluuebunny/crossref_metadata_2025_split huggingface dataset:
TopMed‐imputed genome‐wide association study of Alzheimer’s disease in more than 100,000 European samples from the EADB project
Authors: Bellenguez Céline ,   EADB
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS), and more recently the next‐generation sequencing strategy, improved greatly our knowledge of the genetics of Alzheimer’s disease (AD), with more than 40 risk genes/loci now identified. As part of the genetic component of AD remains unknown, we conducted a complementary GWAS study with increased sample size and improved imputation quality of low frequency variants thanks to the new TopMed imputation panel.MethodThe GWAS was performed in the European Alzheimer DNA Biobank (EADB) dataset. It combines genome‐wide genotyping data from several studies and from more than 18,000 AD cases and 21,000 controls never included in previous AD discovery GWAS, for a total of more than 35,000 AD cases and 65,000 controls of European ancestry. Imputation was performed with the TopMed reference panel for the majority of the samples or with the Haplotype Reference Consortium panel. Variants with imputation quality below 0.3 were excluded. Logistic regressions were performed in each study with adjustment on principal components and results were combined across studies with a fixed‐effect inverse variance meta‐analysis.ResultPreliminary association results were available for 27,752,571 variants following quality control, including 8,633,349 common variants (minor allele frequency (MAF) above 1%), and 1,324,211 low frequency variants (MAF range between 0.5% and 1%). We identified 57 loci with at least suggestive evidence (P < 1 × 10−6) of association, including 31 known AD loci. Among the 26 new loci, 10 loci reached genome‐wide significance (P < 5 × 10−8) and 9 loci had a rare lead variant (MAF below 1%).ConclusionPreliminary results of the EADB project allowed to identify several new associated loci for AD, including several good candidate genes linked to the APP metabolism. Additional insights on the genetics of AD are expected from ongoing analyses, including gene‐based tests of rare variants, fine‐mapping, functional annotations and pathway analyses.
Novel genetic effects on amyloid and tau protein levels in cerebrospinal fluid
Authors: Jansen Iris E. , Van Der Lee Sven J. , Bellenguez Céline , Grenier‐Boley Benjamin , de Rojas Itziar , Zettergren Anna , Kleineidam Luca ,   EADB
Published: December 2020

AbstractBackgroundAssuming measurable biological properties to be more strongly related to the underlying Alzheimer’s disease (AD) pathogenesis than the diagnostic classification, we studied the genetics of AD‐relevant protein levels in cerebrospinal fluid (CSF). Initiated by the European Alzheimer’s disease DNA biobank (EADB), we established the largest collaborative effort on CSF amyloid beta and tau, and aimed to improve the current understanding on the genetic etiology of AD, including the identification of novel genetic risk factors.MethodA collection of 10 European dementia cohorts was explored to study the genetic effects on CSF amyloid beta (n = 6529 individuals), tau (n = 6455 individuals) and phosphorylated tau (n = 5865). Most of the genetic data was generated with Illumina Global Screening Array, and imputed with TOPMed reference genome. The protein level data was log transformed and normalized. Per variant linear regressions were performed within cohorts using PLINK v2.0, followed by meta‐analysis. We corrected for population structure (principal components), gender, age and biomarker assay type (if applicable within a cohort).ResultsBesides APOE (p = 3.16 × 10−251), no other loci reached genome‐wide significance for amyloid beta protein levels. For tau protein levels, we discovered 5 loci, including the known AD loci APOE (p = 1.61 × 10−61) and HLA‐DRB1 (p = 4.67 × 10−8). We additionally confirm the GMNC locus (p = 1.23 × 10−12) that previously was associated with CSF tau by an independent consortium. Two novel loci are seen on chromosome 9 (p = 5.76 × 10−8) and chromosome 16 (p = 3.67 × 10−8). These tau findings are strengthened by the identification of these same 5 loci for phosphorylated tau which has been measured by a different protein level assay. Both novel loci have shown associations with brain ventricular volume in previous large‐scale studies performed by other consortia, such as CHARGE and ADNI.ConclusionThe novel loci identified for CSF tau protein levels suggest an overlap in genetic etiology for tau and brain ventricular volume, thereby strengthening the theory that neurodegeneration and tau pathology are highly correlated in dementia patients.
Data‐driven biomarker approaches to disentangle mixed pathologies in AD
Authors: Tosun Duygu 
Published: December 2020

AbstractBackgroundBiomarker data related to AD are being collected at an ultra‐scale and are likely to unlock numerous opportunities for AD treatment. While most persons with AD dementia are confirmed to have a pathologic diagnosis of AD, additional vascular and non‐AD degenerative pathologies (e.g., Lewy bodies, TDP‐43, and hippocampal sclerosis) are found in most cases. Each of these pathologies has been previously shown to lower the threshold for cognitive impairment. Due to lack of good biomarkers for non‐AD degenerative pathologies, and overlapping cognitive phenotypes, there are few guidelines for diagnosis of multiple versus single etiology dementias.MethodWe used innovative harmonized structural MR image processing and artificial intelligence (AI) methods to model and subtype the vast and complex imaging data in relation to comorbid pathologies. We cost‐efficiently harnessed the available wealth of autopsy validated neuropathological confirmations from landmark neuroimaging studies (e.g., ADNI, NACC, ROS, MAP) and combine with efficient, scalable, and publicly available tools, powered by ‘cognitive systems’ including AI. Since prevalence of each pathology is not mutually exclusive of existence of other pathologies, we developed multi‐class deep learning models for simultaneous prediction of presence of these pathologies.ResultWhen combined with age, sex, MMSE, and Apoe 4 information, within clinically normal participants (independent validation), structural‐MRI based prediction accuracy was 86%/87%/93% for AD degenerative pathologies of amyloid, tau, and neurodegeneration, respectively, with expected 4%‐6% increase in performance in MCI and AD validation cohorts. Within the clinically diverse autopsy cohort, structural‐MRI was predictive of non‐AD pathological confirmations of comorbid TDP‐43 with an AUC of 0.83‐0.85 and comorbid neocortical diffused Lewy bodies with an AUC of 0.76‐0.79.ConclusionThere is an urgent need for biomarkers to identify patient’s neuropathology profile in vivo to inform public health planning, clinical trial enrichment, and development of effective early interventions. Our recent work aims to associate comorbid pathological confirmations across various autopsy studies with in vivo brain metrics, genomics, and plasma biomarkers for deeper understanding of pathologic basis of heterogenous trajectories of cognitive decline in aging. Focusing on routinely collected structural MRI data maximizes translational impact both in clinical practice as well as in clinical trials on AD.
Pattern of degeneration of sleep‐wake nuclei correlates with objective sleep measurements in progressive supranuclear palsy: A quantitative clinicopathological study
Authors: Oh Jun Yeop , Walsh Christine M. , Mladinov Mihovil , Petersen Catherine , Ruoff Leslie , Robbins Claire M. , Eser Rana A. , Li Song , Lew Caroline , Varbel Jonathan , Heuer Hilary W. , Boxer Adam L. , Seeley William W. , Miller Bruce L. , Neylan Thomas , Grinberg Lea Tenenholz 
Published: December 2020

AbstractBackgroundIndividuals with progressive supranuclear palsy (PSP), a form of 4‐repeat tauopathy, show an extreme sleep phenotype featuring a short sleep duration. This is likely due to tau‐associated lesions in the subcortical sleep‐wake network. Nevertheless, it is unknown how the pathological lesions in the brainstem and hypothalamus relate to sleep phenotypes in PSP because detailed clinicopathological studies focusing on sleep are lacking. To elucidate this mechanism, here we correlate objective sleep‐wake measurements with quantitative pathological findings in the key sleep‐wake network in PSP for the first time.MethodParticipants with a diagnosis of probable PSP based on the Litvan criteria were recruited at the Memory and Aging Center, UCSF from 2013 to 2019. Twenty participants (68% male; mean age: 70.95 ± 5.3) were asked to complete overnight polysomnography (PSG) and multiple sleep latency tests (MSLT) the subsequent day. Measures of interest on the PSG and MSLT are indicated in Figure 1. Of these individuals, 13 have undergone an autopsy, neurotransmitter and tau immunohistochemistry staining, and neuronal quantification using unbiased stereology in the following nuclei: noradrenergic Locus Coeruleus (LC), orexinergic lateral hypothalamic area (LHA), and histaminergic tuberomammillary nuclei (TMN).ResultSleep parameters and pathological parameters (nuclei neuronal number, neurotransmitter expression, and tau burden), show significant and variable correlations (Figure 1).ConclusionNeuronal loss and tau burden in the key neuromodulatory systems may explain clinical sleep signatures in PSP. For instance, shorter MSLT correlated with fewer histaminergic neurons which suggest that impaired histaminergic wake‐promoting system may lead to a higher tendency to fall asleep. Altogether, our preliminary data highlights the importance of clinicopathological study combining objective sleep measurements with unbiased postmortem evaluation in clarifying the contribution of subcortical tau pathology to sleep‐wake disturbances in tauopathies.
Differential dynamics of Aβ and tau oligomer synaptic binding may suggest diverse therapeutic targets for early vs. late Alzheimer's disease
Authors: Marcatti Michela , Krishnan Balaji , Kayed Rakez , Taglialatela Giulio 
Published: December 2020

AbstractBackgroundAt the basis of the Alzheimer’s Disease (AD) cognitive decline there is the targeting of synapses by small Ab and tau oligomers, which results in synaptic dysfunction and later disruption that underscore disease progression. Recent failures of Aβ‐directed therapeutics in multi‐center clinical trials suggest that Ab may not be playing a critical role in later disease stages, when clinical features of AD become manifest; rather, tau, which occurs later in the AD brain, may be the primary synaptotoxic element at that advanced stage. While attention is being currently given to the development of tau‐directed therapies for clinical AD, the mechanisms by which tau becomes the prevalent driver of synaptic dysfunction at later disease stages is still unknown.MethodSynaptosomes were isolated from the human and mouse cortex and hippocampus and Aβ and tau binding evaluated ex vivo using a flow‐cytometry based approach employing fluorescence‐labeled preformed oligomers. Western blots were used to confirm flow‐cytometry results and electrophysiology measurements of hippocampal long‐term potentiation (LTP) used to evaluate functional outcome of oligomer synaptic impact.ResultHere we show that the binding of tau to both human and mouse hippocampus and cortex synaptosomes competes Aβ oligomers off the synapses, thus becoming the most prevalent and toxic oligomeric form. On the other hand, Aβ oligomers are not able to compete off tau oligomers thus suggesting that the mechanism is tau specific. Surprisingly, the presence of Aβ oligomers promotes tau synaptic binding and levels of tau that would normally fail to negatively affect LTP becomes effective in the presence of Aβ oligomers.ConclusionThese results suggest a previously unappreciated mechanism whereby as the levels of Aβ oligomers increase and tau oligomers appear during disease progression, tau oligomers becomes the prevalent toxic species at synapses. This mechanism is consistent with failure of Aβ‐targeting therapies in late AD and further support the credence of tau oligomers as the main culprit in clinically‐manifest AD. Supported by NIH/NIA grant R01AG060718
Brainstem tau protein burden is associated with cortical hyper‐excitability in healthy aging
Authors: Van Egroo Maxime 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) neuropathology spreads over decades prior to cognitive symptom onset. Its first signs consist in misfolded tau protein accumulation in the brainstem, particularly in the locus coeruleus (LC). Neuronal hyper‐excitability also occurs early in the pathogenesis of AD and contributes to neuronal network dysfunction. Here, we tested whether early cortical hyper‐excitability may be related to tau aggregates in the brainstem.MethodWe probed cortical excitability over the frontal cortex using transcranial magnetic stimulation combined with electroencephalography in a sample of late middle‐aged healthy individuals (n = 65; 50‐70 years). We assessed whole‐brain tau protein burden with [18F]THK5351 positron emission tomography and we extracted radiotracer uptake values in a brainstem monoaminergic compartment including notably the LC. Diffusion‐weighted magnetic resonance imaging data were also acquired to explore cortico‐LC white matter pathways.ResultWe found that higher tau burden in the brainstem monoaminergic grey matter was specifically associated with increased cortical excitability. By contrast, tau deposits in the hippocampus and entorhinal cortex, although correlating with brainstem tau signal, were not associated with cortical excitability. Tractography analysis revealed that frontal cortical excitability was linked to the integrity of the tracts connecting the frontal cortex and a dorsal pontine tegmentum area encompassing the LC.ConclusionThese findings reveal potential brain substrates for increased cortical excitability in preclinical and early AD, and they constitute the first human functional correlates of in vivo early tau protein accumulation in the brainstem.
Significant reduction of Alzheimer’s disease symptoms by transcranial pulse stimulation, TPS
Authors: Novak Pavel 
Published: December 2020

AbstractBackgroundLow intensity shock waves proofed to be efficient for the treatment of non‐unions, tendon and muscular pain, wound healing, heart insufficiency, erectile dysfunction, aesthetic and finally neurological indications. The working principle is the mechanical stimulation of biological processes called mechanotransduction resulting in increased cell metabolism, release of nitric oxide (eNO) and numerous growth factors. There is also an anti‐inflammatory effect, stimulation of stem cells and the innate immune system. Alzheimer’s disease or dementia in general is multi modal disease resulting from different causes like deposition of dedicated proteins (tau, beta‐amyloid), inflammation, reduced blood supply and others.MethodTranscranial Pulse Stimulation (shockwave pulses) was applied to patients suffering from minor Alzheimer’s disease in two centers. 35 patients were treated in this multicenter clinical pilot study. The treatment consisted of 6 sessions in 2 weeks, with 6000 pulses per session, energy flux density of 0.2 mJ/mm2 at 5Hz. It was performed with an unshaved head through the hair. The treatment is painless and very well tolerated by the patients.ResultThe patients showed a significant improvement of the Alzheimer’s disease symptoms of over 10% measured with CERAD Plus battery of tests. The improvement was maintained until 3 months follow‐up. No side effects have been observed.ConclusionIn spite of the unique positive results, further clinical evaluations are needed. Placebo controlled, randomized trials are ongoing. The device (Neurolith) has meanwhile the CE mark clearance in Europe and there are regulatory activities in further regions. References: [1] Beisteiner R, Matt E, Fan C, Baldysiak H, Schönfeld M, Philippi Novak T, Amini A, Aslan T, Reinecke R, Lehrne J, Weber A, Reime U, Goldenstedt C, Marlinghaus E, Hallett M, Lohse‐Busch H. Transcranial Pulse Stimulation with Ultrasound in Alzheimer’s disease – A new navigated focal brain therapy. Advanced Science 2019. [2] Lohse‐Busch H. Reime U, Falland R. Symptomatic treatment of unresponsive wakefulness syndrome with transcranially focused extracorporeal shock waves. Neuro Rehabilitation 35(2014) 235‐244.
Conceptual model of the purpose of meaningful occupation for people living with dementia developed through qualitative evidence synthesis
Authors: Strick Katherine Elizabeth , Garside Ruth , Thompson‐Coon Jo , Abbott Rebecca A 
Published: December 2020

AbstractBackgroundGuidance for the provision of care for people with dementia asserts that occupation people find meaningful is essential for wellbeing, however definitions of meaningful occupation are often broad with the intrinsic meaning coming from within the person rather than the activity. As such the purpose of meaningful occupation, and how to gauge its effectiveness can be inconsistent. Through analysing the different purposes that occupation for people with dementia is perceived to have, this study created a conceptual model depicting the types of meaning that are seen as stemming from occupation.MethodThe conceptual model was developed through systematic review of 20 qualitative papers with synthesis based on meta‐ethnography.ResultThe fundamental purpose of occupation identified was to support the person with dementia to feel they were living a meaningful and fulfilling life. Three domains support a person to gain a sense of fulfilment through their occupations: A catalytic environment: For an occupation to be meaningful for a person with dementia it must be perceived by them as having value and legitimacy, this is supported by the physical and social environment around the person. A meaningful life: Living a meaningful life involves the person with dementia continuing to maintain links from across their life course in a way which supports their sense of personal value. This is reflective of their past, though also supports their present and future identity to evolve. Occupation as a tool: Occupation can also be used as a tool by people with dementia and those supporting them as a means to bring about a specific desired effect e.g. maintaining functional skills for independent living.ConclusionThe model proposes how occupation could support meaning in multiple ways, and considers how these forms of meaning were influenced by the world views and values of the individual and context in which they were experienced.
Novel MRI markers of small vessel disease in relation to Alzheimer’s disease
Authors: van den Brink Hilde 
Published: December 2020

AbstractBackgroundVascular brain injury, particularly small vessel disease (SVD), is a common cause of cognitive decline and is detected on brain MRI in the majority of patients with dementia, including Alzheimer’s disease (AD). Established MRI markers of SVD related brain injury are white matter hyperintensities, lacunar infarcts, microbleeds and enlarged perivascular spaces. Yet, these MRI markers clearly do not cover the full extent of SVD related injury. Also, these lesions represent an end‐stage of injury to the parenchyma, rather than the actual abnormalities that occur in the small vessels themselves. In my presentation I will address a novel marker of more subtle parenchymal injury, cortical microinfarcts (CMI), and emerging markers of cerebral small vessel function.MethodsEstimates from autopsy studies are that 100s to 1000s of CMI may be present in the brain of a single affected individual. High field strength imaging on 7Tesla MRI and further developments onto 3Tesla MRI has enabled in vivo detection of the largest CMI, and MRI rating criteria have been published. 7Tesla MRI is also used to zoom in on the small vessels themselves, and markers of cerebral small vessel function are emerging.ResultsMRI studies in patients with a clinical diagnosis of AD observe a CMI prevalence ranging between 8‐55%. These studies allow to investigate potential causes and consequences of CMI for the first time in vivo. It appears that CMI relate with worse clinical outcome and may be caused by various etiologies, including hypoperfusion, microemboli, and SVD pathology, in particular cerebral amyloid angiopathy. The novel measures of small vessel function that will be reviewed include measures of small vessel reactivity, and measures of blood flow velocity and pulsatility in individual penetrating arteries (diameter 100‐800 µm). Initial studies show abnormalities of these measures in patients when compared with healthy controls. I will review ongoing studies in patients with hereditary and sporadic SVD that aim to establish the value of these small vessel function markers in clinical research.ConclusionWith these efforts we aim to advance insight into disease processes in SVD to help better understand the mechanisms underlying cognitive impairment and dementia.
Remote cognitive assessment approaches in the Dominantly Inherited Alzheimer Network (DIAN)
Authors: Hassenstab Jason , Aschenbrenner Andrew J. , Balota David A. , McDade Eric , Lim Yen Ying , Fagan Anne M. , Benzinger Tammie L.S. , Cruchaga Carlos , Goate Alison M. , Morris John C. , Bateman Randall J. ,   The Dominantly Inherited Alzheimer Network
Published: December 2020

AbstractBackgroundThe “one‐shot” paradigm used in traditional in‐clinic cognitive assessments often produces unreliable data due to daily fluctuations in stress, sleep, test anxiety, and fatigue. In DIAN, an international study of familial Alzheimer’s disease (AD), these difficulties are compounded by the scarcity and younger age of the population. We have developed two assessment strategies to address these issues, which we are also validating in the Knight ADRC cohort. The first is a smartphone‐based cognitive assessment platform based on principles from ecological momentary assessment that uses frequent but extremely short (<60 seconds) tests of episodic memory, attentional control, and processing speed administered at random times over 7 days. We examine average performance and variability metrics across 7 days of assessments. The second is a web‐based assessment that focuses on repeated daily administration to measure long‐term memory decay and also skill acquisition learning. The rates of forgetting and rates of learning become the outcome measures.MethodDigital assessments were completed on cognitively normal DIAN participants (n = 56 mutation carriers, n = 60 non‐carriers) and 120 mostly cognitively normal older adults from the Knight ADRC. Follow‐up evaluations were available for approximately 40 DIAN participants. Digital assessments were compared with standard in‐clinic cognitive tests and also with AD biomarkers including amyloid PET, cerebrospinal fluid (CSF) tau, tau PET, and structural MRI.ResultReliabilities of all remote cognitive measures ranged from 0.90‐0.98. All measures (Smartphone and web‐based) correlated with age (r’s 0.22‐0.69), indicating worse performance with increasing age. Correlations with standard in‐clinic measures ranged from 0.24‐0.77, suggesting that remote tests are valid measures of cognition. Test‐retest reliability from repeated smartphone assessments was exceptional for two smartphone measures (ICC’s = 0.89‐0.94). Critically, smartphone measures and web‐based measures demonstrated sensitivity to all AD biomarkers, including amyloid PET, tau PET, CSF tau, and structural MRI. We will present data on relationships with AD biomarkers and data on technical validation of smartphone cognitive measures and adherence strategies for remote studies.ConclusionRemote assessments that rely on short‐term but high frequency testing can be deployed worldwide in adults of all ages and demonstrate excellent reliability and validity compared to standard in‐clinic cognitive assessments.