bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular risk and neuroimaging profile of MCI patients in the FINOMAIN Study
Authors: Guevarra Anne Cristine Deocariza , De Guzman Maria Fe Payno , Galvez Francy Joy , Rodriguez Anthony , Citron Raphael Louis B , Yu Justine Megan F , Rivamonte Vladimir , Phung Thien Kieu Thi , Dominguez Jacqueline C
Published: December 2020

Background

The Asian population has been found to be at a higher risk of developing dementia compared to other races due to the high prevalence of vascular risk factors. Utilization of different modalities that manage these vascular risk factors is the focus of this study in order to prevent progression of dementia among senior citizens with mild cognitive impairment.

Method

Community‐based participants with MCI were recruited to join the FINOMAIN Study. They were divided into control and intervention groups, to which INDAK (dance therapy) shall be given. Both groups shall receive health education, management of non‐communicable diseases, and nutrition management. 72 participants shall undergo neuroimaging. Hypertension, diabetes mellitus type 2, and dyslipidemia were derived from clinical data and ancillary procedures. Small vessel disease markers (white matter hyperintensity, chronic lacunes, enlarged perivascular spaces, global atrophy, medial temporal lobe atrophy, frontotemporal atrophy, and posterior cortical atrophy) were documented through T1W, T2W, and FLAIR sequences on MRI and with the use scales like Fazekas, modified Staal’s score, and atrophy scores. All MRI assessments were performed by a single neurologist blinded to the clinical and cognitive measures. Cognitive measures had been done including tests for global cognition (MMSE‐P and MoCA‐P). Independent t‐test was used to show descriptive results of both groups.

Result

42 subjects had completed MRI as of this writing (18 control group, 24 intervention group) with a mean age of 70 and mean years of education 9.48 years. Only 12% of the subpopulation are males. Markers of noncommunicable diseases did not show significant differences between groups. SVD burden measured through modified Staal’s score showed 2.50+0.985 for the control group and 2.33+0.917 for the intervention group (with a maximum score of 3 points) Fazekas scores for both groups showed moderate WMH burden (2.17+0.786 vs. 2.29+0.859; p = 0.125). MTA scores did not exceed the score of 2 in both groups (1.56+0.784 vs. 1.50+0.590; p = 0.794).

Conclusion

The subsample of the FINOMAIN study shows comparable demographics, clinical, and neuroimaging findings which is considered as a good pre‐intervention data. Small vessel disease burden in the neuroimaging is quite high in both study groups.
Neurofilament‐light chain in murine models of neurodegenerative and rare diseases
Authors: Schilcher Irene , Loeffler Tina , Flunkert Stefanie , Hutter‐Paier Birgit
Published: December 2020

Background

Neurofilament‐light chain (NF‐L) is known as biomarker of many neurodegenerative diseases and their progression. By analyzing amyotrophic lateral sclerosis (ALS) patients CSF or plasma progression of NF‐L levels can forecast conversion from the presymptomatic to symptomatic stage and the time of survival. So far, detailed analyses of NF‐L expression in neurodegenerative disease patient’s samples were performed, while NF‐L levels of preclinical mouse models of ALS, Alzheimer’s and Parkinson’s disease as well as lysosomal storage diseases are still unknown.

Method

We therefore evaluated NF‐L levels in the plasma of the ALS models SOD1‐G93A low expressor and TAR6/6 mice, the Alzheimer’s disease model 5xFAD, the Parkinson’s disease model Line 61 and the Gaucher disease model 4L/PS‐NA and the CSF of selected models using a commercially available ELISA kit from UmanDiagnostics.

Result

Our results show that NF‐L levels are highly increased in the plasma of ALS, Alzheimer’s and Gaucher disease mouse models, while in the analyzed PD model NF‐L plasma levels barely changed. Most of the analyzed models show a progressive increase of NF‐L levels over age.

Conclusion

NF‐L measurements in the plasma of the neurodegenerative disease mouse models of ALS and Alzheimer’s disease are thus a good tool to evaluate disease progression. Compared to analyses in human tissues, our results suggest that murine NF‐L levels and their progression have a high translation value. Furthermore, our data indicate that NF‐L might also be a good biomarker for diseases that are not classical neurodegenerative diseases but disorders with a neuronal component like some lysosomal storage diseases.
Stakeholders’ views around the concept and diagnosis of mild cognitive impairment and their understanding of dementia prevention: A qualitative study
Authors: Poppe Michaela , Mansour Hassan , Rapaport Penny , Palomo Marina , Burton Alexandra , Morgan‐Trimmer Sarah , Carter Christine , Roche Moise , Higgs Paul , Walker Zuzana , Aguirre Elisa , Bass Nicholas , Huntley Jonathan D , Wenborn Jennifer , Cooper Claudia
Published: December 2020

Background

Many people live with an awareness of mild cognitive changes and an associated dementia risk. Previous authors describe the uncertainties of this liminal state between cognitive health and dementia. The interface of this group with health services is growing, driven by early dementia diagnosis campaigns and research about the preventative potential of health promotion. This brings both preventative opportunities and risks of medicalisation, which have not previously been qualitatively explored from the perspectives of professionals, clients and their family members. We ask how services respond to people with memory concerns currently, and how future dementia prevention interventions for people with memory concerns should be structured.

Method

We conducted qualitative interviews with 18 people aged 60+ with subjective or objective memory problems, six family members, 10 health and social care professionals and 11 third sector workers. Interviews were audio‐recorded, transcribed and analysed using an inductive thematic approach. Interviews were conducted as part of the APPLE‐Tree (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline) programme, which is an international collaboration run in the UK.

Result

Three main themes were identified: 1) acknowledging the liminal state, compounded by current, discordant health service responses, which medicalise memory concerns yet situate responsibilities for their management with patients and families; 2) challenges of enabling change in contexts of physical and cognitive frailty and social disengagement, and 3) building on existing values, cultures and routines to facilitate the process of implementing and maintaining behavioural and lifestyle changes.

Conclusion

This study extends our understanding of the complex liminal position of people with memory concerns seeking help. Effective dementia prevention must empower individuals within challenging contexts and acknowledge their existing values. This cannot be realised within current memory service responses. Our findings further feed into a dementia prevention intervention which is currently being developed as part of the APPLE‐Tree programme.
Efficacy of RAA7 treatment in TG4510 mouse model of Alzheimer's disease
Authors: Tai Chin‐Yin , Jang Ming‐Kuei , Stenius Taina‐Kaisa , Paldanius Kaisa , Puoliväli Jukka , Rytkönen Jussi , Oksman Juho , Parkkari Teija , Huhtala Tuulia , Rauhala Leena , Miszczuk Diana , Nurmi Antti
Published: December 2020

Background

Tauopathies are neurodegenerative characterized by the accumulation of abnormal phosphorylated and aggregated forms of Tau protein in the brain. rTg4510 (MAPT*P301L) mouse model is a widely used tauopathy model for studying therapeutic intervention that target neurodegeneration and tau pathology.

Method

In this study rTg4510 mice (n=13‐15/group) were treated with RAA7 (10 mg/kg and 50 mg/kg) or vehicle (PBS). At 7 months of age tau pathology and neurodegeneration was characterized using cresyl fast violet staining (CFV) and NeuN for neurodegeneration, total human Tau (HT7) and phosphorylated human Tau (AT8). Sections were analyzed as % of area of positive signal. Four regions of interest were examined: cortex, CA1 and dentate gyrus regions and whole hippocampus.

Result

Our results showed that RAA7 treatment diminish neurodegeneration and affect tau pathology. In CFV and NeuN staining, RAA7 10 mg/kg increased % of stained area in all analyzed brain regions, whereas RAA7 50 mg/kg in the CA1 region when compared to PBS group. In addition, high dose treatment showed neuroprotective effect in the DG regions of hippocampus as well. NeuN/CFV ratio was decreased by RAA7 10 mg/kg treatment in all analyzed areas. Assessment of tau expression revealed that RAA7 10 mg/kg decreased level of total Tau in CA1 region and phosphorylated Tau in cortex when compared to PBS group. Unexpectedly, RAA7 50 mg/kg showed significantly higher total tau level in the whole hippocampus when compared to PBS group, and no effect on the tau phosphorylation level.

Conclusion

In conclusion, RAA7 treatment showed neuroprotective in Tg4510 mice demonstrated by reduced Tau accumulation and phosphorylation driven inhibition of neuronal cell death.
Albumin glycation in Alzheimer’s disease patients: Results from the AMBAR trial
Authors: Ortiz Ana Maria , Minguet Carla , Mestre Anna , Orellana Adelina , Núñez Laura , Boada Mercè , Ruiz Agustín , Páez Antonio , Costa Montserrat
Published: December 2020

Background

A novel therapeutic approach that includes therapeutic plasma exchange (TPE) plus albumin replacement has shown to slow cognitive and functional decline in mild‐to‐moderate Alzheimer’s disease (AD) patients (AMBAR Trial, NCT01561053). We previously described higher levels of early glycated albumin (eGA) in baseline AD plasma samples from a Phase II clinical trial using TPE with albumin replacement (EudraCT#2007‐000414‐36), compared to age‐matched healthy controls. Moreover, treatment showed a positive but transient effect in lowering eGA. Glycated albumin is known to have impaired binding capacity and to be less effective in preventing amyloid beta peptide aggregation (Ramos‐Fernández et al, 2014.JAD;643). In the present study, eGA in samples from AMBAR trial has been evaluated to confirm previous findings.

Method

We measured eGA in AMBAR baseline serum samples (n=318) from mild‐moderate AD patients (MMSE:16‐26) and compared with serum samples from age‐matched healthy controls (HC) (n=25, MMSE:28‐30). Samples collected throughout the two intervention regimens in AMBAR were also analyzed: conventional TPE period for 6 weeks (processing 1 plasma volume [2500‐3000mL]; 1TPE/week); and low volume plasma exchange [LVPE] period for 12 moths (removing approximately 1/3 plasma volume [similar to a plasma donation]; 1LVPE/month) in comparison to non‐treated AD controls. QuantiLab Glycated Albumin assay (Werfen) on Beckman‐Coulter AU5800 was used. Values are expressed as %eGA, median‐IQR.

Result

Results of eGA in AMBAR baseline samples was similar to those from HC (13.0% [12.2%‐14.0%] vs 12.6% [12.1%‐13.8%], respectively). Of note, percentage of patients with eGA above the normal reference range (9%‐16%) in AMBAR AD patients was higher than in HC (10% vs 0%). A transient effect in lowering eGA after each intervention period in AMBAR was observed: change from baseline eGA after conventional TPE and after LVPE periods were ‐4.2% (‐5.3% to ‐2.8%) and ‐1.2% (‐1.8% to ‐0.5%) respectively. Interestingly, when considering only patients with hyperglycated albumin baseline levels (eGA≥16%; n=29), all patients except one reached the normal reference range after the first TPE intervention (11.2% [10.5%‐13.0%]).

Conclusion

PE with albumin replacement, in particular conventional TPE regime, caused a transient but noticeable effect in lowering eGA levels in AD patients, which allowed patients with hyperglycated albumin to reach normal reference values.
Mild cognitive impairment and rheumatoid arthritis
Authors: McDowell Bethany , Holmes Clive , Edwards Christopher , Cardwell Christopher , McHenry Michelle , Meenagh Gary , McGuinness Bernadette
Published: December 2020

Background

Increasing evidence from the last ten years suggests that systemic inflammation may be associated with an increased risk of developing Alzheimer’s disease (AD). Some studies have found an association between rheumatoid arthritis (RA) and neurodegeneration with several finding increased incidence of mild cognitive impairment (MCI) in those with RA compared to healthy controls. This study aims to use preliminary data from the Rheumatoid arthritis, medication and memory study (RESIST) to investigate the prevalence of MCI in a population of patients with RA and explore the relationship between MCI and specific demographic and clinical characteristics.

Method

The Montreal Cognitive Assessment (MoCA) was used as a cognitive screening tool and was administered to subjects who were ≥55 years of age and had been diagnosed with RA according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. Demographic and clinical data was recorded at screening in face‐to‐face interviews and included age, gender, type of RA medication and date of RA diagnosis. 260 participants completed both screening and baseline visits as part of the RESIST longitudinal study, MoCA scores from baseline were analysed for these participants. Statistical analysis was used to provide descriptive statistics for our population and determine predictors of cognitive impairment.

Result

A total of 636 participants (mean age 68.1, 67.5% female) were screened between May 2018 and December 2019. The mean MoCA for screened participants was 25.4, 45.3% of our population scored <26 in the MoCA and were considered cognitively impaired. Age was negatively correlated to MoCA score and was the only significant predictor of cognitive impairment (p<0.001). Gender, type of RA medication and duration of disease did not contribute to the regression model. The mean MoCA score was found to differ by 0.404 points between screening and baseline.

Conclusion

A large proportion of our participants scored below the proposed cut‐off for normal cognition in the MoCA suggesting at the high prevalence of MCI in older adults with RA. This may provide further support for the role of chronic inflammation in AD and questions whether it would be worthwhile introducing routine screening for MCI in rheumatology clinics.
Different response of hypothalamus and temporal cortex to intranasal insulin in rat model of sporadic Alzheimer's disease
Authors: Knezovic Ana , Budisa Stjepan , Andrilovic Ana , Homolak Jan , Perhoc Ana Babic , Barilar Jelena Osmanovic , Salkovic‐Petrisic Melita
Published: December 2020

Background

Sporadic Alzheimer’s disease (sAD) is the most common form of dementia. Central administration of streptozotocin (STZ‐icv) has been shown to induce Alzheimer‐like changes and has been proposed as a non‐transgenic sAD animal model. Intranasal insulin administration is being investigated as a possible pharmacological treatment in order to reverse and ameliorate brain insulin dysfunction, but exact mechanism is not yet clear.

Method

Male Wistar rats were given icv vehicle or STZ (3 mg/kg). Activation of c‐fos co‐localized with neuronal, astrocytic and microglial markers was evaluated in the brain 2 hours after intranasal insulin administration (2 IU), which was given 1 month after STZ. Western blot analysis of insulin receptor (IR) and postsynaptic marker (PSD95) were performed in hypothalamus (HPT) and temporal cortex (TC) 2h after intranasal insulin administration in STZ‐icv rat model. Spectrophotometry was used to measure glucose and β‐amyloid in plasma and CSF and glutamate and insulin concentration in brain tissue samples.

Result

Intranasal insulin significantly increases c‐fos expression in TC only. C‐fos expression in TC was co‐localized with neuron marker, while in HPT was co‐localized also with microglial marker, especially with activated microglia in STZ‐icv rats. Glucose levels were found unaltered in plasma and CSF, while β‐amyloid concentration was found slightly increased after STZ and insulin administration. Increment of insulin concentration was found most pronounced in HPT of control animals after intranasal insulin (+289% vs CTR). Both insulin and STZ significantly decreases glutamate concentration in HPT (∼−92% vs CTR). treatments mostly s. At the level of IR and PSD95 expression STZ and insulin have opposite effects in HPT compared to TC.

Conclusion

In this research, we have shown that STZ and insulin have different and opposite effects in the brain, showing distinct cell response to insulin depending on brain region in rat model of sAD. Financed by CSF projects IP‐09‐2014‐4639 and IP‐01‐2018‐8938. This publication was co‐financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).
SEC24 isoform specificity regulates the assembly of γ‐secretase from dimeric subcomplexes
Authors: Wouters Rosanne , Michiels Christine , Kleizen Bertrand , Dillen Katleen , Vermeire Wendy , Demedts David , Sannerud Ragna , Schekman Randy , Annaert Wim
Published: December 2020

Background

γ‐Secretase is a diaspartyl protease with presenilin (PSEN) as the catalytic subunit. It targets a plethora of type I transmembrane proteins and, as such, affects a broad range of physiological processes. Because of this, aberrant functioning of γ‐secretase is linked to several diseases including cancer and Alzheimer’s disease (AD). Herein, mutations in the PSEN genes are associated with rare cases of familial AD and shift the production to longer, more aggregation prone amyloid β peptides. γ‐Secretase consists, besides the catalytic component PSEN, of nicastrin, APH1 and PEN‐2 that are co‐translationally translocated in the endoplasmic reticulum (ER). As γ‐secretase has a stoichiometry of 1:1:1:1, the assembly process is spatially and temporally regulated. Although it is generally agreed that this occurs in early biosynthetic compartments, it remains far from understood whether full assembly occurs already in the ER and to what extent Golgi‐to‐ER recycling is involved.

Method

We used advanced cell fractionation protocols and an in vitro reconstituted ER budding assay to explore in detail the stepwise assembly process of γ‐secretase in early biosynthetic compartments.

Result

Cell fractionation combined with blue native electrophoresis shows that subcomplexes are mainly present in ER‐enriched fractions while full complexes appear in the ER‐Golgi intermediate compartment, indicating that final assembly occurs beyond the ER. In vitro reconstitution of ER export reveals that none of the γ‐secretase subunits is required for ER‐exit of the others. However, knock‐out of any subunit induces the accumulation of preceding subcomplexes in de novo formed COPII vesicles. Mutating a motif in the cytosolic loop domain of PSEN1, which is lost in the familial AD‐associated PSEN1∆E9 mutant, abrogates ER‐exit of PSEN1 as well as PEN‐2, but not of nicastrin. This is explained molecularly by the selectivity of Sec24A/B and Sec24C/D in packaging PSEN1 and nicastrin, respectively, and further argues against full complex assembly prior to ER‐exit.

Conclusion

In conclusion, our data support a model wherein individual subunits and dimeric subcomplexes preferentially exit the ER. Full assembly likely occurs in intermediate compartment/cis‐Golgi allowing complexes to escape active Golgi‐to‐ER recycling as part of a secondary quality control mechanism in controlling cellular γ‐secretase levels and activity.
CSF and plasma biomarkers for DLB
Authors: Galasko Doug R. , Caughey Byron , Mollenhauer Brit , Leverenz James B.
Published: December 2020

Background

CSF biomarkers of amyloid and tau provide components of the A/T/N classification for AD and hold clinical prognostic value. They can help to identify how AD co‐pathology contributes to DLB. Alpha‐synuclein (a‐Syn) aggregation is a key pathogenic process in DLB, proposed to follow a staging system for spread of pathology. We review existing CSF markers in DLB and evaluate how well RT‐QuIC, a protein misfolding amplification assay for a‐Syn, detects DLB and different degrees of a‐Syn pathology at autopsy, and performs in RBD, a prodromal stage of DLB. We discuss the potential for plasma biomarkers for diagnosis and progression in DLB.

Method

1) selected studies of CSF biomarker data from RBD subjects and from published data for DLB on A/T/N biomarkers and on a‐Syn RT‐QuIC and other a‐Syn biomarkers; 2) analysis of different parameters of a‐synuclein RT‐QuIC and clinical‐pathological correlations for RT‐QuIC; 3) data on plasma neurofilament light as a progression biomarker.

Result

1) AD biomarkers in CSF support AD co‐pathology in a substantial percentage of cases of DLB, which is associated with faster cognitive progression. Data on RBD and prodromal DLB are limited. 2) RT‐QUiC has high sensitivity and specificity for PD and DLB diagnosis, including RBD. RT‐QuIC parameters (time to 50% of maximal fluorescence or peak fluorescence) do not correlate with measures of movement or cognition. Limiting dilution may provide an index of seeding burden, but in preliminary analyses shows a weak relationship to clinical progression; 3) longitudinal Nfl plasma levels in the PPMI cohort show a slight increase in early PD and RBD, to a greater extent than in aging alone, with much overlap. Concomitant AD pathology may drive plasma Nfl changes.

Conclusion

CSF biomarkers related to neurodegeneration may provide value in early DLB. CSF Aβ1‐42/Tau has prognostic value for cognitive decline in DLB. RT‐QuIC for a‐synuclein in CSF has diagnostic but not predictive value. Plasma biomarkers for diagnosis of pathology are emerging, but prognostic markers will need extensive additional research.
From diagnosis to rehabilitation: Report of a clinical case of Alzheimer's disease
Authors: Avila Renata , Porto Fabio Henrique de Gobbi
Published: December 2020

Background

A thorough investigation is necessary for the diagnosis of Alzheimer’s disease (AD). An ideal treatment is composed of drug treatment and neuropsychological rehabilitation (NR). AD still has no cure, but its adequate treatment can delay the evolution of the disease and make the patient and family live with more quality. The purpose of this case report is to describe the NR of a mild AD patient, his participation in the decision about rehabilitation objectives and his growing awareness about his difficulties. Male client, a 73‐year‐old retired electrical engineer, married, 3 sons and 4 grandsons. The neuropsychological assessment confirmed the cognitive deficits, as well as MRI showed hippocampal atrophy and PET showed typical pattern of AD. His main cognitive changes included mild memory problems, important inattention, wordy speech, and lack of planning. Disinhibition, rigidity and impulsivity where the behavior change observed, added to a lack of awareness of his difficulties in daily activities. He started individual NR sessions twice a week with a neuropsychologist. In parallel family was oriented and received support with the same professional about how to cope with the changes. He was also accompanied by a psychiatrist, neurologist, and a clinical psychologist. Four months after the RN had started, he became much more aware about his difficulties, managed to define with the therapist three goals for the treatment, stopped driving and agreed to hire a driver, and the wife reported attention, language and behavior improvement. After 8 months he said: “I am recovering from my eccentricities, the left and the right brain seem to be OK, and my wife and I are meeting again”, and the wife said, “now I think about which fights to pick. Our relationship is much better. He’s calmer, more alert, and speaking better. He himself is organizing his weekly medicine box and its working.” This single case study illustrates the importance of a team of experts working together with a person with AD and his family for maintenance of autonomy, enhancement of the behavior and cognitive changes, as well as improving the quality of life of families and their loved ones.
Extracellular vesicles derived from postmortem human brain tissue contain seed‐competent C‐terminal tau fragments, and provide proteomic clues to the identity of selectively vulnerable cell populations in human tauopathies
Authors: Fowler Stephanie L. , Bez Sumi , Gaur Pallavi , Miller Chelsea , Turkes Emir , Schaler Ari , Hernandez Villegas Nancy E. , Perez‐Gonzalez Rocio , Levy Efrat , Duff Karen E.
Published: December 2020

Background

Pathological tau is spread along anatomically connected networks, originating in areas containing particularly vulnerable cell populations. It is hypothesized that tau is released and spread as free tau, or via extracellular vesicles (EVs) that include exosomes (30‐150 nm), microvesicles (100‐1000 nm), and apoptotic bodies (1000‐5000 nM). While a variety of different EV tau species have been identified in tissue, cells, and bio‐fluids, EV tau has not yet been described from human post‐mortem tauopathy brain tissue.

Method

Using a differential centrifugation and sucrose flotation method described by Perez‐Gonzalez et al., EVs were isolated from post‐mortem human frontal cortex tissue blocks from Alzheimer’s Disease (AD), Corticobasal Degeneration (CBD), and Control cases (BA9, n=4/group).

Result

Electron microscopy (EM) confirmed the presence of vesicles with characteristic shape and size of exosomes and microvesicles. As demonstrated by immunoblotting, EV tau from tauopathy cases contains very little full‐length tau, but is specifically enriched in tau fragments of 10‐15 and 30‐35 kDa. EVs from control cases contain low levels of full‐length tau, and no tau fragments. EV tau fragments are sarkosyl‐insoluble, protected by the lipid membrane of the vesicle, and are seed‐competent (RD‐tau biosensor FRET seeding assay, seeding of primary neurons, and significant spread of AT8+ tau in EV‐injected PS19 mouse hippocampi). Epitope mapping and mass spectrometry sequencing confirm the presence of C‐terminal tau fragments, and further proteomic analyses confirm the identity of EVs as secreted vesicles. Together, these data provide the first clues to tauopathy‐specific proteomic signatures of EVs, and identify exosome components derived from the most vulnerable cell populations. This work complements the biomarker literature showing that N‐terminal regions of tau are secreted into the cerebral spinal fluid, while C‐terminal regions are retained in the brain.

Conclusion

The identification of a seed‐competent species encased in a vesicle that readily fuses with cell membranes confirms that EVs are likely a significant mediator of pathological tau spread in the human brain. Our continued investigation of EV tau cryo‐EM structure, and of EV tau‐containing vesicles will focus on identifying novel immunological targets for pathological tau, and the vesicles that facilitate its spread.
Data‐driven full‐resolution model of amyloid, hypometabolism and atrophy changes over Alzheimer's disease progression
Authors: Nader Clement Abi , Ayache Nicholas , Robert Philippe , Lorenzi Marco
Published: December 2020

Background

Neurodegenerative disorders such as Alzheimer’s disease (AD) are characterized by morphological and molecular changes of the brain, ultimately leading to cognitive and behavioral decline. A comprehensive model of the brain’s spatio‐temporal changes in AD would be a valuable instrument for improving our understanding of the disease dynamics, and for tracking disease progression in clinical trials.

Method

We propose a spatio‐temporal generative model of disease progression, aimed at disentangling and quantifying the independent dynamics of changes observed in datasets of multi‐modal imaging data. Our data consists of AV45‐PET, FDG‐PET, and structural magnetic resonance images (MRI), representing respectively amyloid deposition, glucose metabolism and gray matter atrophy for 544 individuals (137 healthy, 293 affected by mild cognitive impairment, and 114 AD patients). The model is based on a monotonicity constraint, which forces the spatio‐temporal image trajectories to evolve from a normal to a pathological stage. Moreover, we aim at automatically inferring the disease severity of a patient with respect to the estimated trajectory.

Results

The estimated spatio‐temporal processes at stake in AD are shown in Figure 1. The model identifies specific brain areas and their evolution in time in terms of gray matter atrophy, glucose metabolism, and amyloid concentration. The model describes a gray matter loss encompassing a large extent of the brain with a focus on cortical areas, but also targets subcortical areas such as the hippocampi. Concerning the glucose metabolism, the model identifies a pattern of hypometabolism involving most of the brain regions that tends to plateau, while also detecting a linear pattern of hypometabolism targeting areas such as the precuneus and the parietal lobe. Finally, the model highlights an increase of amyloid deposition mapping most of brain regions, such as the parietal and frontal lobes, while exhibiting a differential pattern of amyloid deposition targeting mostly frontal, temporal, occipital areas and precuneus. Moreover, the time‐scale associated with these spatio‐temporal processes strongly correlates with the clinical evolution of the disease (Figure 2).

Conclusion

The presented disease progression allows to disentangle differential temporal progression patterns mapping brain regions key to neurodegeneration, while revealing a disease‐specific time scale associated to the clinical diagnosis.
Modifiable factors, cardiorespiratory fitness and cardiovascular risk are associated with cognitive and structural brain health in midlife: Results from the BBHI
Authors: Morris TP , Gomes‐Osman Joyce , España‐Irla Goretti , Cattaneo Gabriele , Albu Sergiu , Solana Javier , Macià Dídac , Redondo‐Camós María , Delgado‐Gallén Selma , Alviarez‐Schulze Vanessa , Pachón‐García Catherine , Tormos‐Muñoz Josep M , Bartres‐Faz David , Pascual‐Leone Alvaro
Published: December 2020

Background

Neurodegenerative brain changes that lead to cognitive decline generally begin decades prior to the onset of symptoms. On the other hand, brain health relates to overall, and specifically cardio‐vascular health, and vice‐versa. The objective of this investigation was to assess the relationships between two important domains of cardiovascular health (cardiorespiratory fitness, CRF, and cardiovascular risk, CVR) and two important markers of brain health (cognitive performance and volumetric measures of brain structure) in late middle age.

Method

In a relatively large sample (n=327) of middle‐aged adults in the Barcelona Brain Health Initiative (Cattaneo et al., 2018), we assessed the associations between CRF (measured by VO2 max), CVR (measured by Framingham risk score), domain‐specific cognitive performance (measured by performance in a neuropsychological test battery) and brain volumes (measured by high‐resolution brain MRI). All regression models were corrected for age and education.

Result

We found differential associations between CRF and CVR and cognitive performance. CRF was significantly associated with visuo‐spatial abilities and frontal loading abstract problem solving (p=.003), whereas CVR was associated with visuo‐spatial abilities (p=.023), flexibility (p=.005), processing speed (p<.001) and memory (p<.001). Moreover we found that CRF was associated with frontal (p=.042), temporal (p=.016) and sensorimotor (p=.013) cortical volume, whereas CVR was significantly associated with all cortical volume measures (frontal, temporal, parietal, occipital and sensorimotor; ps<0.05).

Conclusion

We found that two modifiable factors in mid‐life (CRF and CVR) are significantly associated with a number of metrics of brain health in a cross‐sectional analysis. Future longitudinal analyses of this cohort will show whether these associations have predictive value for the maintenance of brain health across the lifespan. Finally, our findings suggest that lifestyle habits that promote CRF and reduce CVR, e.g. sufficient physical activity and appropriate nutrition, might help sustain brain health across the lifespan and prevent cognitive decline.
Hearing loss and cognition: A protocol for ensuring speech understanding in neuropsychological assessment
Authors: Goman Adele M , Deal Jennifer A , Arnold Michelle L , Chisolm Theresa , Coresh Josef , Hayden Kathleen M. , Owens Tiffany A , Pankow James , Reed Nicholas S , Sanchez Victoria A , Lin Frank R , Mosley Thomas H ,   ACHIEVE Study Group
Published: December 2020

Background

Many neuropsychological tests involve auditory components including test stimuli and instructions. Hearing loss may adversely affect neuropsychological performance through participants not being able to adequately understand auditory stimuli or verbal instructions, thus hampering identification and accurate classification of cognitive impairment. Formal measures to quickly assess speech understanding are lacking. Herein, we describe a protocol developed to determine adequate speech understanding and report on the relationship between hearing loss and speech understanding performance.

Method

Participants were 2864 older adults (mean age: 80.8 years; SD: 4.6) in the Atherosclerosis Risk in Communities Study visit 7 who completed a test to ensure speech understanding, had hearing data, and had covariate data. To ensure speech understanding, a psychometrist verbally presented 5 short sentences (each containing 3 key words) articulating clearly with normal inflections at a volume and pace commensurate with normal cognitive testing methods. After each sentence, the participant reported back what they heard with performance scored as the number of “key” words accurately repeated. A passing score (i.e., adequate speech understanding) was defined as ≥ 13. The protocol included steps on how to proceed with neurocognitive testing if speech understanding was not established. Better‐ear (0.5,1,2,4kHz pure‐tone‐average) hearing was categorized according to World Health Organization Criteria as normal (<25dBHL), or hearing loss (>25dBHL; mild: ≥25dBHL & <40dBHL, moderate or greater: >40dB HL). Logistic regression analyses adjusting for demographic factors (age, sex, race‐center, and education) assessed the association between hearing loss and performance on the ensuring speech understanding test.

Result

Test failure was higher with increasing hearing loss severity (normal: 0.23%; mild: 0.52%, moderate or greater: 6.61%). Adjusting for demographic characteristics, hearing loss was associated with reduced odds of passing the ensuring speech understanding test (OR: 0.14, 95% CI: 0.02, 0.44).

Conclusion

Hearing loss is associated with reduced speech understanding in environments commensurate with normal neurocognitive testing. Given the high prevalence of hearing loss among older adults, it is important to ensure neuropsychological performance is accurately captured and not adversely biased by reduced hearing. The protocol described here provides a brief measure to quickly assess speech understanding in the research setting.
The role of microglial HIF‐1α in Aβ pathology
Authors: Steinbrecher Lisa , Wendeln Ann‐Christin , Brösamle Desirée , Liu Ping , Wild Katleen , Haesler Lisa M. , Al‐Shaana Rawaa , Neher Jonas J.
Published: December 2020

Background

Microglial cells play an important role in the pathogenesis of Alzheimer’s disease. We have previously shown that microglia activate the Hypoxia inducible factor‐1α (HIF‐1α) signalling pathway in response to cerebral β‐amyloidosis in a mouse model of Alzheimer’s pathology (Wendeln et al., Nature, 2018). Importantly, we also found that activation of microglial HIF‐1α signalling correlated with disease severity and that HIF‐1α levels were particularly elevated in plaque‐associated microglia.

Method

In the experiments presented here, we analyzed the role of microglial HIF‐1α in promoting cerebral β‐amyloidosis by characterizing pathological hallmarks and microglial activation states in two APP transgenic mouse models with an induced HIF‐1α knockout (KO) in microglia cells.

Result

Our results indicate that the lack of HIF‐1α in microglia increases their clustering around amyloid‐β plaques and alters the microglial phenotype and brain inflammatory state. While plaque load was indistinguishable in mice with/out microglial HIF‐1α, our data indicate that the increase in plaque‐associated microglia limits plaque‐induced neuronal damage.

Conclusion

Our data indicate that HIF‐1α inhibition alters the microglial phenotype, leading to an increased number of microglia around amyloid‐β plaques, thereby protecting neurons.
Stage vs subtype hypothesis: A longitudinal MRI study investigating the heterogeneity in AD
Authors: Poulakis Konstantinos , Ferreira Daniel , Pereira Joana B. , Westman Eric
Published: December 2020

Background

Longitudinal measurements of brain atrophy have revolutionized our understanding of how Alzheimer’s disease (AD) pathophysiology evolves during the disease course. The distribution of neurofibrillary tangles (NFTs) in AD, varies between patients and correlates in vivo atrophy measures and specific profiles of cognitive decline. Longitudinal progression of atrophy markers in AD will help understanding the course of the disease. We wanted to investigate if atrophy differences between patients with AD dementia already exist at the time of the clinical onset and estimate their atrophy patterns over time.

Method

Our dataset consist of Freesurfer preprocessed T1‐weighted structural MRIs(2 to 5 longitudinal MRI visits) for 322 amyloid positive AD diagnosed patients and 304 amyloid negative cognitively unimpaired (CU) subjects. We applied an in‐house longitudinal clustering pipeline on the AD sample after controlling for normal ageing effect (CU sample), to explore the heterogeneous patterns of AD over time, after the AD clinical onset.

Result

The model revealed heterogeneous patterns of atrophy in the AD subjects, predominantly in the baseline data, but also in their trajectories over time. Three distinct patterns of regional brain atrophy at AD onset and decline over time were identified. Approximately 55% of the AD patients presented the typical AD atrophy pattern, including some subjects who initially showed atrophy mainly in the temporal lobes but progressed similarly to typical AD. Atypical patterns of atrophy were also found in our dataset: i) Minimal atrophy AD with very few atrophy at baseline and subtle atrophy over time (10%), ii) hippocampal sparing early onset (HSEO) with posterior cortical atrophy (15%) and hippocampal sparing late onset (HSLO) with milder posterior atrophy and later AD onset (10%). The HSEO cluster has steeper atrophy trajectories and faster decline in all cognitive domains compared to HSLO. A 10% of the sample had no clear classification in any of the groups. Regional atrophy between subtypes was associated with longitudinal cognitive performance.

Conclusion

Our results show not only that AD is heterogeneous which is known from cross sectional data, but also that atrophy subtypes exist most probably due to different diseases and not due to different stages of the disease.
Using polygenic risk scores to assess the importance of microglia in Alzheimer’s disease
Authors: Baker Emily Ann , Leonenko Ganna , Williams Julie , Hill Matt , Escott‐Price Valentina
Published: December 2020

Background

Alzheimer’s disease (AD) is a highly polygenic disorder; this has been demonstrated by the identification of a large number of risk loci from genome‐wide association studies (GWAS), and the ability of polygenic risk scores (PRS) to differentiate between AD cases and controls with high prediction accuracy (AUC = 78.2%) [Escott‐Price et al. 2015]. Many AD risk alleles have been shown to be located at open chromatin sites in immune cells, specifically microglia [Tansey et al. 2018].

Method

A whole genome PRS was produced for individuals in the Genetic and Environmental Risk for AD (GERAD) data (N = 5,113) [Harold et al. 2009]. The score was weighted using effect sizes from the Kunkle GWAS [Kunkle et al. 2019], excluding GERAD individuals, and only single nucleotide polymorphisms (SNPs) with a p‐value less than 0.5 are included in the score. Linkage disequilibrium between SNPs was removed using standard pruning methods. In addition to a whole genome PRS, which uses all available SNPs, a microglia‐specific PRS was also produced, using SNPs which reside within the microglia regions defined by Gosselin et al. 2017. We also produced microglia‐specific PRSs with microglia genes defined from alternative sources for comparison.

Result

We compare the association between the whole genome and microglia‐specific PRSs, which show a moderate correlation (r = 0.24, p = 7 × 10−10). The prediction accuracy of both PRSs was determined; preliminary results show that prediction accuracy does not decrease dramatically when comparing whole genome and microglia PRS (AUC decreases by 3% and R2 drops to 0.04 from 0.08). We also determine the proportion of prediction accuracy and SNP‐based heritability explained by the microglial component of the polygenic risk score.

Conclusion

AD research has been directed towards microglia as it has been shown to be an important cell in neurodegenerative disorders [Young et al. 2019]. The decrease in prediction accuracy observed is due to the reduced number of SNPs; the goal to improving prediction accuracy is reducing SNP numbers whilst retaining heritability [Wray et al. 2019]. Microglial PRS show improved signal‐to‐noise ratio by reducing SNP numbers and are therefore a valuable approach to experimental design and cell line selection.
Plasma phospho‐tau in familial Alzheimer’s disease
Authors: O'Connor Antoinette , Karikari Thomas K. , Poole Teresa , Khatun Ayesha , Swift Imogen , Heslegrave Amanda J. , Abel Emily , Chung Elisha , Weston Philip S.J. , Polke James , Pavisic Ivanna M. , Rossor Martin N. , Ryan Natalie S. , Blennow Kaj , Zetterberg Henrik , Fox Nick C.
Published: December 2020

Background

Blood biomarkers have the potential to advance clinical care and accelerate the development of disease‐modifying treatments. P‐tau181 is a promising blood biomarker, with levels increasing in Alzheimer’s disease (AD) dementia (doi:10.1016/j.jalz.2018.02.013). However, a better understanding of the timing and trajectory of plasma p‐tau181 changes is needed. Therefore, we conducted a longitudinal study in familial AD (FAD).

Methods

Using an in house Single molecule array method, P‐tau181 was measured in 153 plasma samples from 70 individuals from families with PSEN1 or APP mutations (mean ± SD = 2.2 ±1.3 samples/participant;median [IQR] duration of follow up =1.0 (0, 3.7) years). We compared plasma p‐tau181 between symptomatic mutation carriers, presymptomatic carriers, and noncarriers, adjusting for age and sex. We also examined the relationship between plasma p‐tau181 and estimated years to/from symptom onset (EYO), as well as years to/from actual symptom onset (AAO) in a symptomatic subgroup. In addition, we studied associations between plasma p‐tau181 and clinical severity, as well testing for differences in concentration between genetic subgroups (PSEN1 vs APP carriers, PSEN1 pre‐codon 200 vs PSEN1 post‐codon 200 carriers).

Results

24 of the asymptomatic participants were mutation carriers (mean baseline EYO ‐9.6 years); 27 were noncarriers. Compared with noncarriers, plasma p‐tau181 concentration was higher in symptomatic (p<0.001) and presymptomatic mutation carriers (p<0.001) (Figure 1). Plasma p‐tau181 discriminated symptomatic (AUC 0·93[95% CI 0·84−0·98]) and presymptomatic (AUC 0.86 [95% CI 0·73−0·95]) carriers from noncarriers. Plasma p‐tau181 concentration increased in mutation carriers from 16 years prior to estimated symptom onset (p=0.049) (Figure 2). Plasma p‐tau181 in symptomatic mutation carriers, modelled using AAO, appeared eventually to plateau. Longitudinal p‐tau181 measures demonstrated significant inter‐ and intra‐individual variability, with some participants exhibiting large changes over relatively short time intervals. We did not find a difference in plasma p‐tau181 concentration between APP and PSEN1 carriers, but there was weak evidence (p=0.053) that symptomatic PSEN1 post‐codon 200 carriers had a 54% higher p‐tau181 concentration (95% CI:1% lower, 138% higher) than pre‐codon 200 carriers.

Conclusion

Our finding that plasma p‐tau181 concentration is increased in presymptomatic and symptomatic FAD suggests its potential utility as an easily accessible biomarker of AD pathology.
Description of amyloid beta influence on synaptic plasticity and tau hyperphosphorylation by mechanistic quantitative systems pharmacology model
Authors: Lerner Stepan , Karelina Tatiana
Published: December 2020

Background

Long‐term potentiation (LTP) is a dependent increase in synaptic plasticity that may be an appropriate experimental and theoretical model for learning and memory. In animal models of Alzheimer’s disease (AD), amyloid beta (Aβ) impacts the LTP decline and tau hyperphosphorylation. Increase of the intracellular calcium level, mediated by NMDA and nACh receptors, is responsible for appearance of LTP, which depends on increased in AMPA phosphorylation. Quantitative systems pharmacology (QSP) model of synaptic plasticity was developed to investigate influence of Aβ on impairment of LTP and tau hyperphosphorylation.

Method

The model describes a calcium influx in postsynapse through acetylcholine and glutamate receptors, activation of efflux from intracellular stores, activation of kinase/phosphatase cascade, tau phosphorylation and level of phosphorylation of AMPA receptors, which is associated with LTP. AD pathology is modeled by Aβ impact on receptors (inhibits nACh) and glial glutamate uptake. Model is developed step by step from simpler variants by consecutive addition of new mechanistic details, using in vitro data. In vitro data from the literature on synaptic plasticity in presence of different effectors, are used for verification.

Result

The model qualitatively describes impairment of LTP and tau hyperphosphorylation by Aβ influence and effect of receptor blockers, kinase and phosphatase inhibitors. It demonstrates that: 1) cholinergic and glutamate stimulation leads to LTP, depending on the timing of cholinergic input relative to glutamate input; 2) impaired LTP may recover due to extrasynaptic NMDA receptor blockers (e.g. memantine) or agonists of nACh receptors (e.g. SSR180711); 3) inhibitors of calcineurin decreased tau phosphorylation and recover LTP

Conclusion

The QSP model describes an influence Aβ on different postsynaptic mechanisms (receptors activation and kinase/phosphatase cascade, phosphorylation and dephosphorylation of AMPA receptors), which seems to underlie LTP and tau hyperphosphorylation.