bluuebunny/crossref_metadata_2025 huggingface dataset:
Catecholamine activity in delirium with and without pre‐existing dementia
Authors: Henjum Kristi , Godang Kristin , Quist‐Paulsen Else , Hassel Bjørnar , Neerland Bjørn Erik , Sandvig Heidi , Jens Bollerslev , Watne Leiv Otto
Published: December 2020

Background

Delirium “acute confusion” is an unpleasant but common complication of acute illness in the aged population associated with prolonged hospitalization. Dementia is a substantial risk factor for delirium that may be apparent already in preclinical Alzheimer’s disease, but a delirium is also a risk factor for dementia. Effective agents for preventing and treating delirium are therefore searched. This include administration of antipsychotics targeting anticipated excessive dopaminergic activity in delirium and alpha‐2‐receptor (α2) agonists reducing noradrenergic activity. Data of noradrenergic and dopaminergic activity in delirium is however limited. We therefore aimed to characterize the cerebrospinal fluid (CSF) levels of dopamine and noradrenaline (norepinephrine) in delirium, with or without pre‐existing dementia.

Method

CSF levels of dopamine and noradrenaline were determined by high‐performance‐liquid‐chromatography (HPLC) in: 1) cognitively healthy (controls; n=122) 2) Hip fracture patients (n=118) with and without delirium and pre‐fracture dementia 3) Patients with delirium precipitated by another medical condition (n=26). Non‐parametric statistical analyzes were applied.

Result

Patients with delirium following a hip fracture and another medical condition had lower CSF dopamine levels relative to hip fracture patients without delirium and controls respectively. Stratified analyzes of hip fracture patients according to dementia status and separating patients with delirium before and after surgery showed differences in the two stratas. Interestingly there was a trend for higher levels of noradrenaline in incident delirium among those without pre‐fracture dementia, but there were few patients in this group (n=7).

Conclusion

The lower levels of dopamine in CSF in delirium align with recent meta‐analyzes not recommending use of antipsychotics. Further evaluation of α2‐agonists for delirium prevention, in particular in those without pre‐existing dementia is supported, although the data should be reproduced in larger studies.
White matter integrity disruption in early amyloid accumulators
Authors: Collij Lyduine , Top Herwin , Stickney Kristine , Ingala Silvia , Tomassen Jori , Alves Isadora Lopes , Yaqub Maqsood , Wink Alle Meije , van 't Ent Dennis , Scheltens Philip , Van Berckel Bart N.M. , Visser Pieter Jelle , Barkhof Frederik , den Braber Anouk
Published: December 2020

Background

Amyloid‐β (Aβ) accumulation is the pathological hallmark of Alzheimer’s disease (AD), suggested to be closely followed by white matter (WM) integrity alterations in preclinical subjects. However, reports on the relationship between the two measures have been conflicting. This study aimed to investigate the relationship between amyloid burden and WM integrity in preclinical AD on a regional level.

Methods

179 subjects from the EMIF‐AD preclinAD study who underwent Diffusion Weighted MRI (DWI) and dynamic [18F]flutemetamol PET imaging (Philips Ingenuity PET‐MR) were included (Table 1). Global and tract‐level Fractional anisotropy (FA) and mean diffusivity (MD) were determined using the JHU WM atlas. Amyloid burden was determined by the non‐displaceable binding potential (BPND+1) with cerebellar grey matter as the reference region. The relationship between amyloid burden and WM integrity was tested using Generalized estimating equations, correcting for family relatedness (Figure 1). Linear and quadratic fits were tested using QIC. Analyses were corrected for age, sex, and white matter hyperintensity load. The strongest associations are shown (significance set at p<0.05, Bonferroni‐corrected).

Results

Low amyloid burden was associated with increased FA and decreased MD, followed by decreased FA and increased MD upon higher amyloid burden. This relationship was most robustly observed in the body of the corpus callosum (body CC), for which a quadratic fit was preferred according to QIC, and was mainly driven by amyloid accumulation in the precuneus (FA: β
linear=0.352, β
quadratic=‐0.103, ΔQIC=6.7; MD: β
linear=‐0.434, β
quadratic=0.128, ΔQIC=8.0, Figure 2), PCC (MD: β
linear=‐0.393, β
quadratic=0.101, ΔQIC=4.0), and to a lesser extent by the insula (MD: β
linear=‐0.256, β
quadratic=0.063, ΔQIC=2.0).

Conclusion

Early amyloid deposition is associated with WM changes, particularly evident in the body CC. Importantly, a quadratic fit was preferred by QIC, and this pattern might reflect multiple stages of axonal damage, with initial oligodendrocyte proliferation and axonal swelling upon lower amyloid burden, and actual axonal degeneration only becoming apparent at a higher amyloid burden. Thus, WM integrity specifically in the body CC could be considered as an indicator of early AD pathology in addition to amyloid burden in preclinical subjects.
White matter microstructure and cerebrospinal fluid biomarkers of Alzheimer’s disease in middle‐aged cognitively unimpaired participants (the ALFA study)
Authors: Operto Greg , Milà‐Alomà Marta , Suárez‐Calvet Marc , Falcon Carles , Kollmorgen Gwen , Eichenlaub Udo , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis , Gispert Juan Domingo ,   ALFA Study
Published: December 2020

Background

Previous studies comparing white matter (WM) integrity and biomarkers of Alzheimer’s disease (AD) at early stages have yielded inconsistent results and findings have remained inconclusive. In this work, we used diffusion‐weighted imaging (DWI) and cerebrospinal fluid (CSF) biomarkers to study the relationship between neuropathological burden and neural injury in the WM in a middle‐aged cognitively unimpaired population: the ALFA+ study.

Methods

N=318 cognitively unimpaired individuals from the ALFA+ study, aged from 45 to 74 (mean: 60.79∓4.66) underwent DWI and lumbar puncture. Biomarkers were measured with Elecsys® and NeuroToolKit robust prototype assays (Roche Diagnostics). Using tract‐based spatial statistics, we assessed their association with DWI metrics using individuals models including CSF markers of core AD pathology (A𝛃42, A𝛃42/40 ratio, p‐tau), neuronal injury (neurofilament light [NfL], t‐tau), synaptic dysfunction (neurogranin [NGR], 𝛂Synuclein), and inflammation (sTREM2, YKL40, GFAP, IL6, S100b). Age, sex and APOE e4 carriership were included as covariates. Supplementary analyses were performed including levels of AD core biomarkers as additional covariates and stratifying the sample into A/T groups.

Results

DWI metrics showed significant associations with A𝛃42, YKL40, IL6, NFL, NGR, pTau, tTau, S100, 𝛂Synuclein; none with GFAP, sTREM2, nor A𝛃42/40 ratio (Figures 1 and 2). Positive associations in fractional anisotropy (FA) (and negative with diffusivity) were found with A𝛃42, YKL40, NFL, NGR, S100, p‐tau and t‐tau. Negative association in FA (positive in diffusivity) was found for IL6 only. p‐tau showed the only association to be significant in both directions with FA, positive in cingular/callosal and negative in corticospinal tracts. Post‐hoc analyses on p‐tau showed significant interaction with A/T stage (Figure 3) with positive association with FA in A‐T‐ and negative in A+T+ subjects (inversely with diffusivity).

Conclusion

WM microstructural properties correlate in extensive regions with CSF AD core biomarkers, inflammation and axonal degeneration markers. Such associations illustrate the interplay of multiple pathways in early stages of Alzheimer’s continuum such as deleterious effects of amyloid deposition or the involvement of glial activation/inflammatory processes, resulting in observed reduced diffusivity. Furthermore, interaction with A/T stage suggest the presence of non‐monotonic dynamics occurring along the Alzheimer’s continuum.
Ultra long‐acting oral therapies for Alzheimer's: Proof of principle
Authors: Scranton Richard E. , Avery William , Kruger Cecilia , Bellinger Andrew , Silverman Bernard
Published: December 2020

Background

Poor compliance [1] and high rates of discontinuation [2] with daily oral therapy, such as memantine hydrochloride (HCl) and donepezil HCl, in Alzheimer’s patients compromises the effectiveness of medications that may slow progression of disease severity. Lyndra Therapeutics is developing extended release (ER) capsules for long‐acting oral therapies in several therapeutic areas, including Alzheimer’s disease. Weekly administered oral therapies may improve adherence, provide more consistent plasma drug levels, and facilitate observed administration.

Method

The Lyndra ER capsule has modular features serving specific functions for extended delivery to the stomach. The features include a star‐shaped drug‐releasing formulation (stellate) with up to six drug‐loaded polymer arms formulated to achieve controlled drug release while maintaining gastric residence. Polymer‐coated arms yield a steady rate of drug release into the stomach. The formulation is designed to lose its structural integrity after a period of residence and to pass safely through the GI tract. To test the feasibility of this approach, 8 healthy volunteers received a single dose of LYN‐157 containing 40 mg of memantine HCl and 38mg of donepezil HCl while under observation in a Phase 1 unit for 7 days.

Results

Plasma drug concentrations peaked within 48‐72 hours. LYN‐157 achieved consistent and linear release of both memantine and donepezil, with concentrations maintained over 7 days. No serious adverse events were observed. The most common adverse events were headache, abdominal pain and nausea, generally beginning near time of administration and resolving within 2 days.

Conclusion

Lyndra's novel drug delivery technology achieved controlled release of memantine and donepezil resulting in consistent pharmacokinetics (PK) exposure over 7 days. The ability to deliver one or more oral drugs over one week with a single oral capsule has the potential to improve compliance, quality of life, and care of people with Alzheimer's disease. References: 1. Austrom MG, Boustani M, LaMantia MA. Ongoing Medical Management to Maximize Health and Well‐being for Persons Living With Dementia. Gerontologist. 582018. p. S48‐57. 2. Haider B, Schmidt R, Schweiger C, Forstner T, Labek A, Lampl C. Medication adherence in patients with dementia: an Austrian cohort study. Alzheimer Dis Assoc Disord. 2014;28(2):128‐33.
Development of a primary calibrator and candidate reference method for metrological traceability of tau protein results
Authors: Giangrande Chiara , Vaneeckhoutte Hélène , Boeuf Amandine , Lalere Béatrice , Reimann Sophie Vaslin , Hirtz Christophe , Lehmann Sylvain , Quaglia Milena , Delatour Vincent
Published: December 2020

Background

Early and accurate diagnosis of Alzheimer’s disease relies on different techniques, including cognitive tests, imaging and biomarkers measurement. Here we describe the potential of the use of a well characterized primary calibrator (traceable to the SI) and the development of a candidate reference method by LC‐IDMS for worldwide standardization of t‐tau measurements in CSF.

Method

A recombinant form of tau‐441 has been produced: the impurity profile has been carried out by high resolution mass spectrometry coupled to liquid chromatography and amino acid analysis. The primary calibrator has then been used to calibrate a candidate reference method for absolute quantification of t‐tau in CSF samples. Calibration blends and CSF samples are subjected to the same experimental workflow including the spiking with a 15N‐labelled standard, the protein precipitation followed by solid phase extraction (SPE), the trypsin digestion and the analysis by LC‐MS exploiting the potential of PRM (Parallel Reaction Monitoring) in the measure of the ratio between the unlabeled and the labeled form of the tryptic peptide GAAPPGQK finally used as quantifier.

Result

A SI‐traceable primary calibrator has been developed and an LC‐IDMS candidate reference method for t‐tau quantification in CSF samples is under validation. A time‐course experiment to evaluate the completeness of the digestion has allowed choosing the best digestion time. The use of a protein primary calibrator and of a labeled protein internal standard has reduced the effect of digestion time on ratio GAA/GAA*. Three different CSF pools, corresponding to three different concentration ranges (low, medium, high) have been successfully quantified and the uncertainty has been determined by considering different parameters: the weighing of the CSF samples, the internal standard and the primary calibrator, alongside its concentration, the calibration curve and the intermediate precision, calculated as the standard deviation of the individual results.

Conclusion

In collaboration with reference laboratories taking part in IFCC working group on CSF proteins the candidate reference method will be used to certify t‐tau concentration in international standards with which all t‐tau immuno‐assays will be recalibrated. This enables optimal uptake of mass spectrometry methods directly in routine clinical practice or for standardization purposes.
Augmented reality detects gait deterioration over time and predicts AD risk in Asian older adults
Authors: Tseng Benjamin
Published: December 2020

Background

Alzheimer’s Disease (AD) and AD related dementia (ADRD) are under‐recognized and under‐treated in individuals with Asian cultural heritages due to the social stigma. Asians account for more than 60% of the world population. With the rapidly aging society, it is imperative to effectively detect and prevent AD & ADRD prior to its onset in order to alleviate social healthcare burden in the next decades to come.

Method

We conducted a 1‐year observational study in 42 non‐AD adults of Asian races (age=55±9, m=13, f=29) to monitor changes in gait profile using augmented reality (AR) technology via RADAR (i.e. Report for Alzheimer’s Disease Accumulated Risks), an in‐house smart device app developed by the PI. Gait profile (i.e. velocity (m/s), stride length (cm), deviation (%)) was recorded and calculated at baseline, 6 months, and 12 months with and without dual‐task conditions (i.e. delayed recall+sorting). Cognitive performance was evaluated using previously described methods. To the best of our knowledge, this was the first attempt to use a novel behavioral marker (i.e. gait deteriorations under dual‐task conditions) to predict early stages of cognitive decline in Asian adults.

Result

Using multiple linear regression modeling, we found that gait velocity decline (i.e. >10%Δ compared to baseline under dual‐task conditions or >20%Δ compared to non‐dual‐task condition) independently predicts AD risks (adjusted R2=.38, p=.01) in Asian adults.

Conclusion

We have demonstrated a cost‐effective alternative instrument that is shown to be sensitive in detecting early dementia. Current consensus emphasizes the prominence in early AD diagnosis. Although existing diagnostic tools such as positron emission tomography (PET) is effective in detecting beta‐amyloid protein, the hallmark of AD, PET scan is costly and not readily accessible for most patients. Emerging literature suggests that gait deteriorations at middle age are predictive of AD. Further more, AD prevalence and care in Asian people is under‐recognized; this novel tool that can be implemented in those cultures that might be reluctant to seek professional consultation due to cultural bias.
Prevention of dementia using mobile phone applications (PRODEMOS): A randomized controlled trial in progress
Authors: Eggink Esmé , van Charante Eric P Moll , Hoevenaar‐Blom Marieke P , Andrieu Sandrine , Hafdi Melanie , Coley Nicola , Sadhwani Shan , Wimo Anders , Barnes Linda , Handels Ron , Kivipelto Miia , Song Manshu , Georges Jean , van Der Groep Bram , van der Meijden Mark , Wang Youxin , Wang Wei , van Gool Willem A , van Marwijk Harm , Brayne Carol , Richard Edo
Published: December 2020

Background

The rising prevalence of dementia will largely occur in low‐ and middle‐income countries. Up to 30% of all dementia cases may be attributable to potentially modifiable risk factors. Therefore, lifestyle interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile Health (mHealth) may be a suitable way to improve accessibility to such prevention strategies in vulnerable and hard to reach populations. We will investigate the implementation and effectiveness of an interactive, coach‐supported mHealth intervention to reduce the risk of dementia by targeting dementia risk factors.

Method

Design and participants: Our prospective open‐label blinded endpoint (PROBE) RCT is ongoing in the United Kingdom (UK) and in China. Following a pilot study, enrollment of 2400 participants (1200 in UK and 1200 in China) takes place over 2020. People are eligible if they are 55‐75 years, are of low socio‐economic status (for those in the UK) or from the general population (China), have ≥ 2 dementia risk factors, and have a smartphone. Intervention: Participants will be randomized to a coach‐supported, interactive mHealth platform, facilitating self‐management of dementia risk factors (including hypertension, diabetes, dyslipidemia, overweight, physical inactivity, smoking, and poor diet) or to a control platform with static health information only. The intervention and follow‐up will be 18 months. Outcomes: The primary effectiveness outcome is dementia risk, as measured by the CAIDE dementia risk score. The main secondary outcomes are improvement of individual risk factors and cost‐effectiveness. Implementation outcomes include acceptability, adoption, feasibility, fidelity and sustainability of the intervention. Implementation outcomes will be evaluated using both qualitative and quantitative methods.

Result

The mHealth platform has been developed and is being tested in a pilot study. Qualitative studies in China and UK have yielded valuable insights to optimize the dementia prevention intervention tailored to the target population.

Conclusion

The current study, targeting populations with a high dementia risk and poor access to preventive care, may provide proof of principle for the implementation potential and effectiveness of a coach‐supported mHealth intervention to reduce the risk of dementia.
Assessing the landscape of Alzheimer’s disease cohort data
Authors: Birkenbihl Colin , Salimi Yasamin , Domingo‐Fernández Daniel , Fröhlich Holger , Hofmann‐Apitius Martin
Published: December 2020

Background

Data collected in cohort studies lay the groundwork for a plethora of Alzheimer’s disease (AD) research endeavours. While there exist numerous cohort datasets in our field, few dedicated efforts have focused on comparing these datasets to each other. In recent years, large research consortia, such as EMIF and ROADMAP, were formed to investigate and evaluate the AD data landscape. To the best of our knowledge, such previous approaches have solely investigated cohorts at the metadata level without considering the cohort dataset itself. In this work, we explored eight major AD cohort datasets with the aim of 1) characterizing their underlying data, 2) assessing the quantity and availability of data, 3) evaluating the interoperability across distinct cohort datasets, and 4) presenting our findings in an interactive web application. Thus, we allow researchers to investigate the AD data landscape and find the most suited datasets for their research.

Method

We collected data from multiple major AD cohort studies. Through intensive manual curation of these datasets, we identified which data modalities can be found in the shared data. Using descriptive statistics and visualizations, we highlighted differences and similarities between cohorts focusing on key demographic characteristics and AD biomarkers. Finally, we assessed and compared the longitudinal follow‐up data for each study.

Result

We show that demographics can vary substantially across cohorts (Table 1). The overlap between datasets is limited with regard to assessed measurements (Figure 1). Additionally, distributions of the same variables often differ across cohorts due to differences in processing and normalization; thus, hampering dataset interoperability. By investigating longitudinal follow‐up data, we demonstrate that although there is reasonable longitudinal coverage on cognitive assessments, important biomarkers were only collected for a small fraction of study participants over time (Figure 2). All results can be explored at: https://adata.scai.fraunhofer.de

Conclusion

Our investigation shows that while multiple major AD cohort studies willingly share their data, there is still a severe lack of interoperability within the AD data landscape. To address these issues, it is necessary to define a common AD data model powered by a semantic layer that maps and aligns measurements across datasets.
Association of plasma neurofilament light chain (pNfL) with neuroimaging markers of neurodegeneration and cerebrovascular disease
Authors: Chong Joyce R , Blennow Kaj , Zetterberg Henrik , Schöll Michael , Ashton Nicholas J , Karikari Thomas K. , Saridin Francis , Tanaka Tomotaka , Hilal Saima , Lai Mitchell Kim Peng , Chen Christopher
Published: December 2020

Background

Cerebrospinal fluid (CSF) concentrations of neurofilament light chain (NfL) have previously been reported to be associated with severity of white matter hyperintensity (WMH) (Bjerke, M. et al. 2014; Jonsson, M. et al. 2010; Sjogren, M. et al. 2001). CSF NfL level has also been reported to be significantly increased in vascular dementia (VaD) patients compared with cognitively normal controls (NCI) (Zhao, Xin et al. 2019). However, plasma NfL (pNfL) in VaD subjects and its association with WMH or other magnetic resonance imaging (MRI) markers of cerebrovascular disease (CeVD) have yet to be investigated. The objectives of this study were to (1) examine whether pNfL levels differ between diagnostic groups (NCI, cognitive impairment no dementia [CIND], Alzheimer’s disease [AD] and VaD, and (2) assess the association between pNfL with neuroimaging markers (amyloid PET, MRI) and cognition (Mini‐Mental State Examination [MMSE] scores).

Method

This study included participants who were clinically diagnosed as NCI (n=43), CIND (n=99), VaD (n=22) or AD (n=44). Presence of significant CeVD burden (CeVD+) was defined as occurrence of cortical infarcts and/or ≥2 lacunes, and/or confluent white matter lesions on MRI. Presence of neurodegeneration (N+) was determined by medial temporal atrophy scores. Presence of elevated brain amyloid (A+) was determined by visual assessment of amyloid PET, performed with either PiB (n=178) or NAV (n=30) ligand. pNfL was measured on the Simoa‐HD 1 platform.

Result

pNfL level was significantly increased in VaD and AD patients compared with NCI. Across all participants, pNfL was higher in CeVD+ or N+ groups. pNfL was associated with WMH (rho=0.304, p<0.001) and lacunes (rho=0.221, p<0.001), but not cortical infarcts. There was no difference in pNfL level between the A+ and A‐ groups. Similarly, pNfL did not correlate with SUVR measured by PiB or NAV amyloid PET tracer. Correlation between pNfL and MMSE was moderate but significant (rho=‐0.340, p<0.001). pNfL was independently associated with WMH and worse performance in MMSE.

Conclusion

pNfL level was increased in both VaD and AD. pNfL was associated with cognitive decline and WMH.
The Caribbean‐Hispanic Alzheimer’s brain transcriptome reveals ancestry‐specific disease mechanisms
Authors: Felsky Daniel , Sariya Sanjeev , Schneider Julie A. , Bennett David A. , Mayeux Richard , De Jager Philip L. , Tosto Giuseppe
Published: December 2020

Background

Ethnicity substantially impacts risk for Alzheimer’s disease, with elevated risk in Caribbean‐Hispanics (CH). However, the mechanisms of this population‐specific risk are unknown. Here we report the first transcriptomic analysis of brain tissue from a population of CH Alzheimer's disease (AD) patients.

Method

RNA sequencing was performed on postmortem dorsolateral prefrontal cortex tissue from A) 38 genetically‐confirmed CH subjects (nAD = 20, nnon‐AD = 18), and B) 596 non‐Hispanic Caucasians (nAD = 359, nnon‐AD = 238). Robust regression was used to identify AD‐associated genes in both samples and transcriptome‐wide results were compared to identify genes with concordant vs. discordant associations.

Result

In CH, 893/17 301 genes were associated with AD status. Of these 893 genes, 107 were also significantly associated with AD in Caucasians after correction (all but 2 with the same direction of effect). Genome‐wide, association t‐statistics were positively correlated between samples (rho = 0.37). Rank‐based gene ontology enrichment analysis revealed several processes discordantly (signal recognition particle (SRP)‐dependent protein targeting and cell killing) and concordantly (neurotransmitter secretion) associated with AD between populations.

Conclusion

The CH‐specific upregulation of SRP‐related genes in AD suggests unique etiopathogenic mechanisms in this population and links to the P.gingivalis hypothesis of AD. This is the first step toward identifying AD‐related disease mechanisms in CH as we have identified target genes and pathways for further investigation.
Two distinct molecular patterns of TDP‐43 pathology in cases with Alzheimer’s disease pathology
Authors: Tomé Sandra , Vandenberghe Rik , Ospitalieri Simona , Van Schoor Evelien , Tousseyn Thomas , Otto Markus , von Arnim Christine , Thal Dietmar Rudolf
Published: December 2020

Background

TDP43 is a nuclear protein involved in transcription regulation, which is cleaved, phosphorylated and mislocated to the cytoplasm in pathological conditions. TDP43‐positive neuronal inclusions define frontotemporal lobar degeneration (FTLD‐TDP) and limbic predominant age‐related TDP43 encephalopathy (LATE). Neuronal TDP43 inclusions are also seen in Alzheimer’s disease (AD) brain, in ca. 70% of AD patients. We aimed to investigate the role of TDP43 in the development of AD and whether this role differs from that seen in FTLD‐TDP.

Method

We selected non‐diseased (n=20), preclinical AD (n=16), neuropathologically‐confirmed AD (n=45), and FTLD‐TDP (n=10) cases. Paraffin‐embedded human brain tissue of the hippocampal formation, amygdala, frontal and occipital cortices was immunohistochemically analyzed with antibodies against pathological phosphorylated TDP43 (pTDP43409/410, pTDP43409 and pTDP43403/404) and the N‐ and C‐terminus of TDP43 (N‐t or C‐t‐TDP43).

Result

We found that the majority of p‐preAD (n=11) and AD cases (n=34) presented neuronal cytoplasmic inclusions (NCIs) and neurofibrillary tangle‐like material (NFTs) positive for pTDP43, phosphorylated at serines 409/410 but not 403/404. Non‐phosphorylated TDP43 epitopes were absent in these cases, except for single lesions positive for C‐terminal TDP43 epitopes. The remaining AD cases (with full‐blown AD neuropathology) presented a molecular pattern similar to that observed in FTLD‐TDP: NCI, dystrophic neurites or NFTs positive for all TDP43 markers used in this study. We referred to these cases as AD/FTLD. These cases presented either typical AD symptoms, a mix of AD and FTD symptoms, or an FTD clinical picture. The majority of AD cases presented a classical AD clinical phenotype.

Conclusion

TDP‐43 presents two distinct molecular patterns: one AD‐related pattern, which was associated to clinical AD symptoms; and a second AD/FTLD pattern molecularly similar with FTLD‐TDP lesions, that was associated to an FTD clinical picture.
Regional brain glucose metabolism and gray matter volumetry for the evaluation of chronic traumatic encephalopathy in retired male soccer players: An [18F]FDG‐PET/MRI study
Authors: Aranha Mateus Rozalem , Coutinho Artur M , Carneiro Camila de Godoi , Neto Adalberto Studart , Tsunemi Miriam , Moreira Everton Luis Santos , Ianof Jessica N , Anghinah Renato , Nitrini Ricardo , Cerri Giovanni Guido , Fortea Juan , Buchpiguel Carlos A , Leite Claudia da Costa
Published: December 2020

Background

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy mostly described in military personnel, boxers and American football players. Soccer / European football players are also exposed to long‐term repetitive mild traumatic brain injuries (mTBI), which can lead to CTE. We hypothesized that retired soccer players may present with brain damage, as measured by regional brain glucose metabolism (rBGM) and gray matter (GM) volume in comparison to individuals without exposure to traumatic brain injury. We aim to evaluate rBGM measured with [18F]FDG‐PET, GM volume and the load of white matter lesions (WML) measured with MRI in a group of retired soccer players.

Methods

This prospective study included 19 retired male soccer players (mean = 57,6 years old) and 20 controls matched by age (mean = 60,6 years old), submitted to brain MRI and [18F]FDG‐PET in a 3 Tesla SIGNA PET/MRI scanner (GE Healthcare) from January 2017 to September 2019. Assessment of rBGM, GM volume and load of WML were performed with the SPM8 software. Both groups were compared using the appropriate statistical tests available at SPM8 and R. The p‐value used for significance was 0.001, and correction for multiple comparisons was applied to the SPM analyses (pFWE/FDR< 0.05).

Results

Retired soccer players presented with reduced rBGM in both temporal lobes, reaching statistical significance in left temporal pole and anterior aspect of left inferior temporal gyrus (pFWE/FDR<0.05). Reduction of grey matter volume were observed in similar regions, however with a lower extension, and without surviving correction for multiple comparisons (puncorrected<0.001). There were no differences between groups regarding WML.

Conclusion

Our study shows a significant reduction in rGBM and less evident reduction in GM volume in the lateral and medial temporal lobes of retired soccer players in comparison to controls, which may be attributable to repetitive mTBI.
Alzheimer‐like pathology in trisomy 21 cerebral organoids amenable to pharmacological inhibition reveals BACE2 as a gene‐dose‐sensitive AD‐suppressor in human brain
Authors: Alic Ivan , Goh Pollyanna , Murray Aoife , Portelius Erik , Gough Gillian , Gkanatsiou Eleni , Wallon David , Rovelet‐Lecrux Anne , Rostagno Agueda , Ghiso Jorge , Francis Paul T. , Strydom Andre , Hardy John , Zetterberg Henrik , Nizetic Dean
Published: December 2020

Background

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β‐amyloid‐(Aβ)‐precursor‐protein gene (APP). This is in contrast to non‐DS patients who inherit just the duplication of the APP gene (DupAPP), who develop EOAD with 100% penetrance, raising hypotheses of potential other AD‐suppressing genes on chromosome 21.

Method

Cerebral organoids were grown in vitro from isogenic T21 and normal induced‐pluripotent‐stem‐cells (iPSCs), as well as a DupAPP patient. Trisomy of chromosome‐21 gene BACE2 was corrected to disomy by CRISPR/Cas9 editing. Organoids were analysed histologically and organoid pools profiled for β‐amyloid secretion by immunoprecipitation‐mass spectrometry (IP‐MS). Tissue‐quantity‐independent peptide ratios were compared between organoid conditioned media (CM) and cerebrospinal fluid (CSF) from DS and age‐matched euploid individuals.

Result

We found that T21, but not DupAPP, organoids secrete increased proportions of putative BACE2‐θ‐secretase (Aβ1‐19) and BACE2‐Aβ‐degrading protease (AβDP or Aβ‐clearance) products (Aβ1‐20 and Aβ1‐34) compared to isogenic normal controls. Increased ratios of BACE2‐related to BACE2‐unrelated anti‐amyloidogenic cleavages were reproduced in CSF of people with DS, mirroring organoid secretions. Finally, CRISPR/SpCas9‐HF1‐reduction of BACE2 (3 to 2 copies) in T21‐iPSC significantly decreased AβDP/amyloidogenic ratio and triggered early and accelerated AD‐like pathology in T21 organoids. The pathology consisted of insoluble amyloid plaque‐like deposits, fibrillar aggregates, pathologically altered Tau, and premature neuronal loss, and was preventable by an early application of a combination of β‐secretase and γ‐secretase inhibitors.

Conclusion

Our combined data demonstrate the role of BACE2 as a genetic‐dose‐dependent AD‐suppressor in human brain, and organoid technology as a potential assay for screening for other protective genes and disease‐preventive drugs.
Neighborhood disadvantage is associated with accelerated cortical thinning and cognitive decline in cognitively unimpaired adults
Authors: Hunt Jack FV , Vogt Nicholas M , Jonaitis Erin M , Buckingham William R , Koscik Rebecca L , Zuelsdorff Megan , Okonkwo Ozioma C , Clark Lindsay R , Johnson Sterling C , Asthana Sanjay , Bendlin Barbara B , Kind Amy J
Published: December 2020

Background

Social and economic conditions of an individual’s living environment constitute an important social determinant of health. Exposure to high neighborhood‐level socioeconomic disadvantage is associated with negative health outcomes. Recent cross‐sectional studies demonstrated that living in the most highly disadvantaged areas was associated with lower hippocampal volume, total brain volume1 and cognitive performance2 in an unimpaired older cohort. Using longitudinal data from a subset of the same cohort, we tested associations between high neighborhood‐level disadvantage, longitudinal cortical thickness and cognitive function.

Method

Cognitively unimpaired participants from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center Clinical Core cohorts who had completed >=2 MRI scans were included (N=645, mean[s.d] baseline age=60.6[7.3], 66.2% female). Cortical thickness was estimated in Alzheimer’s disease (AD) signature regions3 using the CAT12 toolbox and annualized change rates between baseline and follow‐up scans were calculated. Neighborhood‐level disadvantage was indicated by Area Deprivation Index (ADI)4,5 and relative quintiles were determined based on state of residence. Cognitive outcomes included a Preclinical Alzheimer’s Cognitive Composite (PACC3)6 and its component sub‐tests (Trails Making Test‐B (TMTB, executive function), Rey Auditory Verbal Learning Test Trials 1‐5 and one of two delayed logical memory tests). Parameters of linear fixed‐effect models (cortical thickness) or mixed‐effects models (cognitive testing), including age, sex, race and years of education were estimated in R. Cognitive test models additionally controlled for practice effects and age2 to account for non‐linear age‐related decline.

Result

Living in the most disadvantaged neighborhoods (top 20% ADI vs all others) was associated with decreasing cortical thickness over time within AD‐signature region (b[95%CI]=‐0.02mm/year[‐0.03,‐0.005], p=0.01) and sub‐regions (Fig.1). Additionally, rates of decline in PACC3 and TMTB were steeper for those in the most disadvantaged neighborhoods (Fig.2, Table).

Conclusion

In cognitively unimpaired adults, exposure to the highest relative levels of neighborhood‐level disadvantage was associated with increased rates of cortical thinning and declining cognitive test performance, particularly in the executive function domain. Using longitudinal data, this work extends previous cross‐sectional studies, providing additional evidence that living in highly disadvantaged neighborhoods may be associated with accelerated neurodegeneration and cognitive decline with implications for AD and related dementia risk assessment.
Assessment of vitamin B12 and erythrocyte levels in Alzheimer's disease
Authors: Santos Gustavo AA , Fazan Valeria Paula Sassoli , Pardi Paulo Celso
Published: December 2020

Background

The reduction in serum levels of erythrocytes and vitamin B12 may be related to the cognitive decline in elderly people with Alzheimer's.

Method

A case control study was carried out in healthy patients (n = 39) and diagnosed with Alzheimer's Disease (n = 44). Inclusion and exclusion criteria were established. We performed a complete blood count and B12 and folic acid evaluation. The collections, material processing and sample analysis took place according to the recommendations of the Brazilian Society of Clinical Pathology.

Result

in patients with Alzheimer's disease, vitamin B12 levels were 267.72 pgml, while in healthy subjects, 388.52 pg / ml. Red blood cells in patients with Alzheimer's, 4.39; and in the healthy 4.75.

Conclusion

the early diagnosis of Alzheimer's disease represents a primary goal, and the role of biomarkers appears to be crucial to the routine of the clinical environment. Our studies have demonstrated low levels of B12, being compatible with literature that associates low concentrations of B12 with cognitive decline.
The pathological role of Pb in AD through impairing functions of blood‐brain barrier system
Authors: Du Yansheng , Territo Paul R. , Zheng Wei
Published: December 2020

Background

Lead (Pb) is an environmental factor has been suspected of contributing to Alzheimer’s disease (AD) and other dementia. Our previous study has shown that chronic Pb exposure increased brain levels of beta‐amyloid (Aβ) and amyloid plaques, a pathological hallmark for AD, in APP transgenic mice possibly by inhibiting Aβ clearance. However, it remains unclear how different levels of Pb affect Aβ clearance and the blood‐brain system (BBBS) in the blood‐brain barrier system.

Method

Tg‐APP mice were administrated with Pb‐acetate at three different doses by oral gavage for 4 weeks. Dynamic contrast‐enhanced CT (DCE‐CT) imaging method was used to quantify the real‐time brain regional blood flow, blood volume, and BBBS permeability.

Result

Chronic Pb exposures significantly increased permeability surface area product (PS) and brain perfusion, indicating that Pb disrupted the mouse blood‐brain barrier system was possibly mediated by inflammation.

Conclusion

Chronic Pb exposure at toxic and even subtoxic levels would damage the BBBS and induce dementia by allowing blood contents to escape into the brain parenchyma.
Cholinergic network disruption in AD subtypes: A study using graph theory
Authors: Gonzalez‐Burgos Lissett , Grothe Michel , Teipel Stefan J. , Westman Eric , Ferreira Daniel
Published: December 2020

Background

Cholinergic dysfunction is central in Alzheimer’s disease (AD). Recent advances in neuroimaging techniques and availability of larger postmortem datasets have opened new opportunities to understand the role of the cholinergic network in AD pathogenesis. However, there is pathophysiological heterogeneity within AD. AD subtypes with different distribution of neurofibrilary tangles, regional atrophy, and network disruption have been revealed in neuropathological and structural magnetic resonance imaging (sMRI) studies. We aimed to identify the cholinergic network using graph theory on sMRI data, and investigate whether differential cholinergic network disruption underlies the subtypes of AD.

Method

We applied graph theoretical analysis to structural MRI data from 75 Ab‐positive AD patients and 64 Ab‐negative controls from ADNI‐1. AD patients were classified into three subtypes according to Murray et al., (2011): typical AD, limbic‐predominant and hippocampal‐sparing. We built brain structural networks from 68 cortical regions and 14 subcortical gray matter structures. Network disruption was investigated through modular analyses by applying the Newman algorithm on weighted graphs.

Result

We identified 43 AD patients with a brain atrophy pattern consistent with typical AD; 17 patients with a limbic‐predominant pattern; and 15 patients with a hippocampal‐sparing pattern. We identified the cholinergic network in healthy controls, which included the basal forebrain, medial temporal lobe, precuneus, lateral parietal and occipital cortex, basal ganglia and thalamus. This network was completely fragmented in AD patients, but disruption differed according to subtype. The basal forebrain retained correlations only with basal ganglia and medial temporal lobe regions in typical AD; while in hippocampal‐sparing and limbic‐predominant subtypes these correlations also extended to new regions in frontal and lateral temporal cortices.

Conclusion

Graph theory on sMRI is able to identify a cholinergic network similar to that previously described in postmortem and in vivo diffusion imaging studies. AD subtypes have a distinct signature of cholinergic network disruption largely associated to their atrophy patterns. It is thus possible that pathology targeting the cholinergic system is one of the factors contributing to the emergence of these distinct subtypes. Our results may help to further understand pathophysiological heterogeneity in AD, with potential applications to research, clinical work and drug decision.
Orderings of biomarker changes for Alzheimer disease in cognitively normal individuals from 18 to 101 years of age
Authors: Xiong Chengjie , Luo Jingqin , Masters Colin L , Johnson Sterling C. , Albert Marilyn S. , McDade Eric , Fagan Anne M. , Benzinger Tammie L.S. , Hassenstab Jason , Cruchaga Carlos , Bateman Randall J. , Morris John C.
Published: December 2020

Background

The temporal orderings of pathologic biomarker changes during preclinical AD have been hypothesized graphically, incorporated into diagnostic criteria of preclinical AD, and further extended to the A/T/N framework. These hypotheses, however, remain to be rigorously and statistically tested.

Methods

Biomarker and cognitive data were harmonized across eight ongoing longitudinal studies: 1) Washington University (WU) Adult Children Study; 2) Johns Hopkins University Biomarkers for Older Controls at Risk for Dementia Study; 3) Wisconsin Registry for Alzheimer's Prevention; 4) Australian Imaging, Biomarkers and Lifestyle Study; 5) WU Dominantly Inherited Alzheimer Network; 6) WU Healthy Aging and Senile Dementia study; 7) WU Knight Alzheimer Disease Research Center (ADRC); and 8) Wisconsin ADRC. Cerebrospinal fluid (CSF) analytes, molecular imaging of cerebral fibrillar β‐amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound‐B (PIB), magnetic resonance imaging (MRI)‐based brain structures, and clinical/cognitive outcomes for 3284 cognitively normal individuals aged 18 to 101 years, were analyzed. The age at which each marker exhibited an accelerated change (called the change‐point) was estimated by piecewise regression models, and compared across the markers by bootstrapping.

Results

Accelerated changes in CSF Aβ1‐42 (Aβ42) occurred at 48.28 years of age, followed by PET PIB mean cortical standardized uptake value ratio (SUVR) with a change‐point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change‐point at about 60 years, similar to those for MRI hippocampal volume and cortical thickness. The change‐point for a cognitive composite occurred at 62.41 years. The change‐point for CSF Aβ42, albeit not significantly different from that for PIB SUVR, occurred significantly earlier than that for CSF Tau and Ptau, MRI markers and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.

Conclusions

These findings support the hypothesized early changes in amyloid in preclinical AD, and further suggest that changes in neuronal injury and neurodegeneration markers occur close in time to each other and to cognitive decline. These results have important implications for the design and analysis of future prevention trials in AD.
A pilot multiple crossover, randomized controlled trial of methylphenidate in mild cognitive impairment using standardized tests and daily brain games to track cognition
Authors: DesRuisseaux Libby A. , Williams Victoria J. , McManus Alison J. , Gupta Anoopum S. , Bolling Anna M. , Schwab Nadine A. , Riley Misha M. , Carlyle Becky C. , Azami Hamed , Gerber Jessica A. , Betensky Rebecca A. , Arnold Steven E.
Published: December 2020

Background

Conventional clinical trial design in AD and AD‐related disorders (ADRD) is the parallel‐group randomized controlled trial. However this design requires large sample sizes to detect meaningful effects in an "average" patient. They are costly, and have not yielded new treatments for many years. As an alternative, the multi‐crossover, randomized control trial (MCRCT) is a design in which patients serve as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of a parallel group trial, yielding unbiased assessment of individual treatment effects ("N‐of‐1") regardless of unique patient characteristics. The goal of this study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild‐stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using standard and novel outcome measures suited for this design.

Methods

Ten participants with mild cognitive impairment or mild‐stage dementia due to AD/ADRDs will undergo a four‐week lead‐in period followed by three, month‐long treatment blocks (two weeks of treatment with methylphenidate, two weeks placebo in random order). The primary outcome of interest is cognition, measured using standard office‐based assessments at the end of each treatment period and daily home‐based brain games played throughout the study. Secondary and exploratory outcomes include neuropsychiatric and functional assessments, actigraphy, and other novel digital cognitive and neurophysiological assessments.

Result

Currently, five participants (three male, mean age = 65.6, mean education = 17.6 years, mean MoCA = 23/30) have been screened and randomized. Preliminary interim analyses are ongoing.

Conclusion

This pilot study will gauge feasibility of conducting a MCRCT trial for symptomatic treatment in early AD/ADRDs, compare home‐based daily brain games with standard office‐based cognitive measures, and explore practicability and potential utility of novel digital phenotyping tools within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between home and office‐based assessments. These data will provide guidance for more efficient trial design and use of potentially more robust, ecological outcome measures in AD/ADRD research.