bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre‐clinical dose ranging efficacy testing of ADx: A contrast agent for magnetic resonance imaging of amyloid burden in Alzheimer’s disease
Authors: Badachhape Andrew , Srivastava Mayank , Stupin Igor , Devkota Laxman , Tanifum Eric , Annapragada Ananth , Ghaghada Ketan
Published: December 2020

Background

Early detection of amyloid plaque deposits is crucial for identifying pre‐symptomatic Alzheimer’s disease (AD) patients. An amyloid imaging magnetic resonance imaging (MRI) contrast agent would have substantial utility in the clinic due to its ease of distribution and the standard use of MRI in AD patient workup. In this work, we describe dose‐ranging efficacy study of an amyloid‐targeted liposomal macrocyclic gadolinium (Gd) contrast agent, ADx‐001, for in vivo MRI of amyloid plaques.

Method

In vivo studies were performed in an APPswe/PSEN1dE9 double transgenic mouse model of early‐onset Alzheimer’s disease that develop amyloid plaques starting at 6‐7 months of age. ADx‐001 was tested at three dose levels: 0.10, 0.15 and 0.20 (mmol Gd/kg). At each dose level, ADx‐001 was tested in transgenic (n=6) and age‐matched wild‐type (mice that lacked both mutations) mice (n=6). MRI was performed on a 1 Tesla permanent magnet MR scanner using a T1‐weighted spin‐echo (T1w‐SE) sequence and a fast‐spin echo inversion recovery (FSE‐IR) sequence that approximates a fluid‐attenuated inversion recovery (FLAIR) sequence. Images were acquired pre‐contrast and at 4 days after intravenous administration of ADx‐001. Animals were euthanized after post‐contrast imaging for post‐mortem histological evaluation of amyloid plaques. Pre‐contrast and delayed post‐contrast MR images were qualitatively and quantitatively analyzed to determine sensitivity, specificity and accuracy against post‐mortem histological identification of Aβ plaque.

Result

ADx‐001‐enhanced MRI showed significant brain signal enhancement (p < 0.05) in transgenic mice (amyloid‐positive) relative to wild‐type (amyloid‐negative) mice in T1w‐SE (Figure 1) and FSE‐IR (Figure 2) images at all dose levels (Figure 3). ADx‐001‐enhanced T1w‐SE imaging showed high sensitivity (>80%) at 0.2 and 0.1 mmol Gd/kg dose levels while FSE‐IR showed high sensitivity (>80%) at 0.2 and 0.15 mmol Gd/kg doses (Table 1). ADx‐001‐enhanced MRI showed excellent specificity (100%) at all dose levels. Microscopy confirmed co‐localization of ADx‐001 with amyloid plaque deposits in cortex and hippocampus regions of the brain in transgenic mice (Figure 4).

Conclusion

ADx‐001 demonstrated high sensitivity and excellent specificity for in vivo MRI of amyloid plaques in transgenic mice even at moderate and low concentrations. An MRI‐based amyloid imaging agent holds great promise for early detection of AD and potential therapeutic studies.
Alzheimer’s disease biomarker roadmap 2020: Fluid biomarkers
Authors: Ashton Nicholas J , Leuzy Antoine , Karikari Thomas K , Dodich Alessandra , Boccardi Marina , Barthel Henryk , Bischof Gerard N , Carrillo Maria C , Chiotis Konstantinos , Corre Julie , Démonet Jean‐François , Drzezga Alexander , Gietl Anton F. , Johnson Karen C , Lorenzi Marco , Nordberg Agneta K , Ossenkoppele Rik , Rabinovici Gil D , Ratib Osman , Sabri Osama , Treyer Valerie , Unschuld Paul G. , Villemagne Victor LL , Winblad Bengt , Wolters Emma E , Frisoni Giovanni B , Garibotto Valentina , Mattsson Niklas , Zetterberg Henrik , Blennow Kaj , Hansson Oskar
Published: December 2020

Background

Though cerebrospinal fluid (CSF) Aβ42, p‐tau181 and t‐tau have been shown to increase diagnostic accuracy for early Alzheimer’s disease (i.e. AD at the MCI stage), several challenges remain with respect to their routine clinical use. In order to address these and related issues, a multidisciplinary task force was formed (Geneva Biomarker Roadmap Initiative). Adapting a five‐phase framework for the development of cancer biomarkers (Pepe et al., 2001), this task force recently convened (2019) to provide an update on earlier publications (2017). We here provide an update for the core CSF AD biomarkers (Aβ42/Aβ40, p‐tau181 and t‐tau) and for the first time provide a review of the same measures in blood in context of the five‐phase framework.

Method

In a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of CSF and blood biomarkers was assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were systemically assessed by subgroups before the meeting, and presented and discussed during the workshop.

Result

CSF biomarkers continued to demonstrate the highest level of maturity according to the strategic roadmap. Significant improvements compared to the 2017 summary (Mattsson et al., 2017) included the development of fully‐automated assays and the introduction of standard operating procedures for the preanalytical handling of CSF. Despite being in their infancy, the data presented and discussed for certain blood biomarkers demonstrated promising results. While t‐tau in blood did not satisfy the criteria for phase 2 (diagnostic discrimination), p‐tau181 and Aβ in blood either fully or partially fulfilled the criteria for this phase. It was agreed that only preliminary, albeit encouraging, evidence was available for the ability of blood measures to predict AD dementia in subjects with MCI (phase 3). An overview of novel CSF and blood tau biomarkers will also be discussed.

Conclusion

The core CSF AD biomarkers (t‐tau, p‐tau181 and Aβ) have the highest level of maturity for clinical utility. Blood biomarkers for p‐tau18, and to a lesser degree Aβ, show excellent discrimination for AD from controls and non‐AD neurodegenerative disorders.
Microglial activation in vivo is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of Alzheimer’s disease
Authors: Biechele Gloria , Franzmeier Nicolai , Ewers Michael , Blume Tanja , Eckenweber Florian , Sacher Christian , Luque Jose Medina , Beyer Leonie , Ruch‐Rubinstein Francois , Lindner Simon , Gildehaus Franz Josef , von Ungern‐Sternberg Barbara , Bartenstein Peter , Rominger Axel , Höglinger Günter , Herms Jochen , Brendel Matthias
Published: December 2020

Background

In vivo assessment of neuroinflammation by 18 kDa translocator protein positron‐emission‐tomography (TSPO‐PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO expression in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on TSPO expression in amyloid and tau mouse models and wild‐type (WT).

Method

Longitudinal 18F‐GE‐180 TSPO‐PET (18F‐GE180) data of AppNL‐G‐F
(amyloid model), P301S (tau model) and C57Bl/6 (WT) mice were evaluated between two and twelve months of age. AppNL‐G‐F
received additional longitudinal amyloid‐PET (Aβ‐PET; 18F‐florbetaben). Immunohistochemistry also served for validation of microglial (Iba1, CD68) and tau (AT8) markers at the terminal time point. PET and immunohistochemistry were quantified in cortical regions and compared by linear mixed models (PET) and analysis of variance (immunohistochemistry) between male and female mice.

Result

The amyloid model AppNL‐G‐F
revealed a distinct cortical increase of TSPO‐PET values from 2.5 to 10 months in female mice (+31%), whereas male mice only increased slightly (+6%). The linear mixed model indicated a significant sex x time interaction (T=‐2.953, b/SE=‐0.011/0.004, p=0.0048, Figure 1A), validated by Iba1 and CD68 immunohistochemistry (Figure 2). Aβ‐PET values in the same AppNL‐G‐F
mice indicated no significant time x sex interaction (T=0.425, b/SE=0.001/0.003, p=0.673, Figure 3). The P301S tau model showed strong cortical increases of TSPO‐PET from 2 to 8.5 months of age (female: +32%, male: +36%) but no significant sex x time interaction (T=‐0.671, b/SE=‐0.003/0.005, p=0.504, Figure 1B) and no differences in Iba1, CD68 or AT8 were observed. TSPO‐PET values in WT mice indicated an increase with time (female: +23%, male +4%) and a significant time x sex interaction was found (T=‐4.171, b/SE=‐0.009/0.002, p<0.001, Figure 1C).

Conclusion

Female mice indicate a sex dependent elevation of glial activation in response to amyloidosis but not to tau pathology which could be related to differences in sex dependency of microglial activation pathways in presence of both proteins. Sex requires attention when microglia activation is evaluated in mouse models of Alzheimer’s disease and requires detailed studies in human disease.
Supporting caregivers to increase confidence can delay functional decline in older adults
Authors: Tomita Machiko R
Published: December 2020

Background

Informal caregivers of Alzheimer’s disease and other dementia (ADOD) have higher burden compared to caregivers of other illnesses, and caregivers’ well‐being affects their care recipients (CR). We hypothesized that with tangible support for caregivers' challenges related to daily activities, CR’s functional levels in the intervention group will be maintained while that in the control group will be declined.

Method

This randomized controlled trial involved a 3‐month intervention taking place in Caregiver's homes. Participants (21 intervention and 15 control) were caregivers of community‐dwelling older adults with ADOD who are members of the Programs of All‐inclusive Care for the Elderly (PACE). Challenges were described by caregivers, and solutions were derived from literature reviews, experiences and brain storming among geriatric occupational theorists, and delivered after a discussion with caregivers. Outcome measures were CR’s Activities of Daily Living (ADLs) and Instrumental ADLs, and caregivers’ burden, depression, physical fatigue, and confidence to continue care. T‐tests compared these group differences at baseline and 3 months due to much lower cognition of CR in the intervention group. All scores for the intervention group was much worse than those of the control group.

Result

The intervention group improved in confidence, depression, and physical fatigue, in contrast to the control group’s decline in all these measures. At baseline, CR’s functional levels of the intervention groups were much lower than those of the control group, and both groups declined further over 3 months. However, the decline of care recipients of the control group was much larger: 2.8 times for ADLs and 5.3 times for IADLs more than the intervention group.

Conclusion

Effective tangible support including working with caregivers to organize life and make schedules, training for transfer of CRs, use of a gait belt, and effective a communication method, and reviewing educational material with them improved their confidence, resulting in delaying CR's function decline. Even with CR's very low cognition, this type of support was effective to improve informal caregivers' confidence for continued care; therefore, we have to find a way to translate exiting knowledge of ADOD care to a practical support system.
Longitudinal assessment of amyloid‐beta deposition in initially amyloid‐negative individuals with [11C]‐PIB PET imaging
Authors: Hatashita Shizuo , Wakebe Daichi
Published: December 2020

Background

The earlier stage of amyloid‐beta (Aβ) deposition, before Aβ is widespread throughout cortex, remains poorly understood. The longitudinal change of Aβ deposition was evaluated with [11C]‐PIB PET in initially amyloid‐negative subjects.

Method

Sixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (age 60‐75 years) who were amyloid‐negative at baseline underwent cognitive assessment and 60‐min dynamic [11C]‐PIB PET at two or more over 5.0 to 9.4 years of a long follow‐up, and apolipoprotein‐E (APOE) genotype assessment. Regions of interest were defined in the bilateral cortex on co‐registered MRI. A quantitative analysis for [11C]‐PIB was used with the distribution value ratio (DVR). Longitudinal changes in PIB DVR values were evaluated in the same regions and an annual rate of change in PIB DVR was calculated.

Result

Seven (30.4%) of 23 initially amyloid‐negative subjects converted to be globally amyloid‐positive (global DVR ≥1.40) over a follow‐up of 6.5±1.4 years (converter). A global DVR increased from 1.22±0.07 at baseline to 1.63±0.15 (n=7, p<0.01) at a last follow‐up. In contrast, in the 16 subjects, a global DVR was 1.15±0.07 at baseline and did not change over a follow‐up period (stable). An annual increase of global DVR in converters was 0.057±0.019 per year (n=7, p<0.01), larger than that in stable subjects (0.004 ± 0.013, n=16). An increase of global DVR was not correlated with baseline global DVR (r=0.26, n=23, p=0.22) or baseline age (r=0.15, n=23, p=0.47). Four (66.6%) of 6 APOE ε4 carriers converted to be amyloid‐positive while 3 (17.6%) of 17 APOE ε4 non‐carriers did (Fisher’s exact p<0.05). Among cortical regions, regional DVR in the lateral temporal cortex increased to 1.48±0.06 (n=6) above regional positivity threshold over 2.9±1.5 years of a follow‐up and its period was the shortest. Furthermore, an increase of regional DVR prior to reaching the globally positive threshold was 0.084±0.050 per year in the precuneus, which was the largest.

Conclusion

Amyloid‐negative individuals, especially with APOE ε4, could convert to be globally amyloid‐positive with extensive cortical spread of Aβ, based on an early Aβ deposition in lateral temporal cortex and a large increase of Aβ deposition in precuneus.
Mapping the contribution of clinical risk factors and MRI‐based imaging features to cognitive impairment in community elders
Authors: Zhao Lei , Yiu Brian , Lam Bonnie Y.K. , Biesbroek J. Matthijs , Luo Yishan , Shi Lin , Mok Vincent C.T. , Wong Adrian
Published: December 2020

Background

It is still not clear about the clinical risk factors of cognitive impairment in community elderlies. Although many studies have investigated the association of imaging features with cognitive impairment, none has applied location‐specific information for the prediction.

Method

We included 609 stroke‐ and dementia‐free elderlies with comprehensive clinical information collected (Table 1). T1‐weighted (T1W) images, T2‐weighted images, FLAIR and diffusion tensor imaging (DTI) were acquired. T1W images were processed with AccuBrain to quantify brain volumes of anatomical structures (Table 2). White matter hyperintensities (WMHs) were automatically segmented using AccuBrain and normalized to standard space for the quantification of regional burden. Other small vessel disease features, including lacunes, cerebral microbleed and enlarged perivascular spaces (EPVS) were visually rated (Table 2). Peak width of skeletonized mean diffusivity (PSMD) was calculated on DTI sequence. These vascular imaging features and clinical variables were used predict Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) with support vector regression (SVR). We compared three prediction models here: (1) with clinical variables as predictors, (2) imaging features as predictors, and (3) the combination of clinical and imaging features as predictors. Different feature selection methods were attempted. Further statistical inference was performed with permutations to investigate independent contributing factors.

Result

Participant characteristics were shown in Table 3. When predicting MoCA or SDMT (Figure 1), Model 3 performed no better than Model 2 or 1, and Model 1 performed better than Model 2 (p<0.001). In addition to age and education level, only average sitting systolic blood pressure presented significant independent contribution to MoCA, while for SDMT, no clinical variables had significant independent contribution (Table 4 and 5). The imaging features that had significant independent contribution included EPVS in basal ganglia, WMH volume in left superior corona radiata, and atrophy of right parietal lobe and insular for MoCA, and right insular atrophy for SDMT.

Conclusion

Combining clinical variables and MRI‐based features did not achieve better prediction of cognitive impairment than using either type of features alone. The highlighted predictors that presented independent contribution to MoCA or SDMT may help to understand the cognitive risk factors in community elderlies.
Stakeholder engagement in dementia care research: Identification of stakeholders and their perspectives on participatory research
Authors: Kowe Antonia , Köhler Stefanie , Klein Olga A , Lüthje Corinna , Teipel Stefan J
Published: December 2020

Background

Although stakeholder engagement is increasingly being incorporated in research internationally, there is still a lack of participatory research in dementia care. Participatory research fosters the dialogue between different stakeholder groups, improves the quality and relevance of research, and supports efficiency of care. In the absence of a general definition for the term stakeholder, relevant groups must be identified for dementia care and analysed in terms of group commonalities and differences. In this study, we examined how stakeholder groups differed in terms of their preferences for participatory dementia care research to develop recommendations for optimal stakeholder engagement.

Method

A group discussion was held in the format of a World Café. We identified stakeholders via two routes, with the help of dementia experts from local institutions and by using snowball sampling. The discussion session was attended by 16 people who were divided into two groups: (1) professional service providers (n = 8) and (2) patient representatives and informal caregivers (n = 8). A qualitative content analysis was carried out on the basis of protocols from the stakeholder responses, which were prepared by two researchers during the group discussion.

Result

With respect to preferred research areas where patients and the public should actively be involved, both groups were particularly interested in research on early detection of dementia. Digital media formats were seen as useful aid for recruitment of stakeholders and communication between scientists and non‐scientists. Both groups identified transparency in the research process as most important prerequisite for participatory dementia care research. The groups differed in their views on possible risks including data misuse, excessive demands on participants, and time expenditure for researchers.

Conclusion

We conclude that stakeholders in dementia care represent a heterogeneous group whose different demands on stakeholder engagement in dementia care research must be taken into account for target group‐specific participation. The recommendations for the implementation of public involvement provide methodological clues for participation of patients with dementia in research.
Alzheimer’s disease and vascular disease: The clinical spectrum
Authors: Chen Christopher
Published: December 2020

Background

The terms Vascular Cognitive Impairment (VCI), Vascular Cognitive Disorder (VCD) and Vascular Contributions to Cognitive Impairment & Dementia (VCID) were introduced to emphasise the important contribution of vascular pathology to any severity of cognitive impairment, ranging from subjective cognitive decline and mild cognitive impairment (MCI) to dementia. Although vascular pathology and Alzheimer’s Disease (AD) is common in elderly individuals with and without cognitive impairment or dementia, pure vascular dementia (VaD) or AD is uncommon. Indeed, most patients with VaD or AD also have other types of pathology, the most common of which is a combination of AD (characterised by the diffuse accumulation of amyloid‐β plaques and neurofibrillary tangles composed of tau) and cerebrovascular disease (CeVD).

Method

Several different VCI criteria have been proposed. The more recent VASCOG, DSM‐5 and the VICCCS criteria may have greater sensitivity, modest concurrent validity and better predictive validity than older criteria such as the NINDS‐AIREN and DSM‐4 criteria for VaD. Importantly, diagnoses for vascular MCI can now be made using the newer criteria which may be useful for clinical and research purposes which include establishing cognitive trajectories, prognostic biomarkers and better understanding of the underlying mechanisms.

Result

As vascular imaging biomarkers of small vessel disease of the brain are established, well characterized, and easy to recognize, it has been suggested that these vascular biomarkers should be incorporated into the AD Research “ATN” Framework for a biological definition of AD. This presentation will discuss ways in which the AD and VCI criteria can be bridged.

Conclusion

Whether this effort to bridge AD and VCI is achieved by integration or combination, it would enable a better understanding of both AD and VCI pathophysiology and aid in treatment efforts which is currently mainly through prevention by treating vascular diseases and other risk factors, such as hypertension and diabetes mellitus, until the much anticipated advent of disease‐modifying treatments.
Investigating the feasibility of using wearable technologies and machine learning techniques to recognise distress and agitation in people living with dementia
Authors: Steer Zeke , Pipe Anthony , Battle Steve , Cheston Richard
Published: December 2020

Background

People in the later stages of dementia often express their needs and distress through their behaviour in ways that challenge care staff to respond appropriately. Technological solutions may help staff to recognise this distress at an early stage and take preventative action. The aim of this project is to develop and test the feasibility of using wearable technologies and machine learning algorithms to identify stress and agitation.

Method

Two laboratory‐based feasibility studies were undertaken with healthy adult volunteers. In study 1, 20 participants took part in a computer‐based exercise designed to elicit stress. In study 2, 20 participants completed eight different physical activities which a person living with dementia might undertake during a typical day, plus two additional activities which were designed to be positively‐ and negatively‐stimulating. In both studies, participants’ physiological responses were recorded using wearables – in study 1, using commercially‐available devices worn around the wrist and waist, and in study 2, using an additional device developed by the researcher, worn in a sock. Participants also provided information on their affective states – in study 1 they rated their stress, and in study 2 they completed the Positive and Negative Affect Schedule (PANAS) before and after each activity. Participants’ responses were used to train and evaluate different binary classifiers for their ability to recognise reported stress in the physiological data.

Results

In study 1, the K‐nearest neighbours algorithm and an ensemble classifier called bagged trees recognised periods when participants reported feeling most stressed with accuracy rates exceeding 90% (98% sensitivity, >99% specificity), using five‐fold validation. However, in study 2 which used a different group of participants, the algorithms trained in study 1 failed to reliably identify the negatively‐stimulating activity from the other activities.

Conclusion

Technological solutions can facilitate a proactive approach to the management of stress and agitation in dementia. However, for these kinds of solutions to be effective in practice, they must be able to generalise to new users and different environments including uncontrolled environments. These kinds of solutions also raise ethical considerations, such as privacy and data security, which are particularly important when users may lack capacity.
Impact of repetitive transcranial magnetic stimulation with computerized cognitive enhancement training on change in cognitive function of mild cognitive impairment patients: Existing, sham treatment‐controlled, pilot study
Authors: Lee Chang Uk , Kang Dong Woo
Published: December 2020

Background

This study aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) and computerized cognitive enhancement training combined treatment on cognitive function in mild cognitive impairment (MCI) patients, comparing to the application of the rTMS alone and the sham stimulation.

Method

Six MCI patients received high‐frequency rTMS applied to the bilateral dorsolateral prefrontal cortex, followed by the computerized cognitive enhancement training. In addition, six MCI patients took high‐frequency rTMS alone. A sham stimulation was used as a control condition in 7 MCI patients. All stimuli were delivered at a frequency of two sessions per week for four weeks. Neuropsychological test was performed at each time points in each group.

Result

Although there was the main effect of interaction between time and group on the score of the Korean version of Montreal Cognitive Assessment, only participants of the rTMS single treatment group showed significant improvement of this score.

Conclusion

In order to overcome the weaknesses of previous studies confirming the efficacy of the combination therapy, this study included patients with MCI, which was the pre‐dementia stage, and included rTMS single treatment group, but did not confirm the clinical efficacy of the combination therapy. Small sample size, the baseline cognitive function score, and the ceiling effect of the group were considered to be the bias factor of this study and further studies supplementing these factors are needed.
Role of the lysosomal‐associated membrane protein 2 in the AD‐like neurodegeneration induced by HSV‐1
Authors: Aldudo Jesus , Mejias Victor , Sastre Isabel , Fuentes Maria , Aljama Sara , Bullido María J.
Published: December 2020

Background

A growing number of studies have shown that herpes simplex virus type 1 (HSV‐1) infection could be involved in the pathogenesis of Alzheimer´s disease. Our group have developed a neuronal cell model of HSV‐1 infection showing the characteristic markers of Alzheimer‐type neurodegeneration. Gene expression studies of this cell model identified a set of oxidative stress‐regulated genes in infected cells. Analysis of these genes revealed that the main pathway altered was the lysosomal system (Neurobiol Aging. 2018 Aug;68:5‐17. doi:0.1016/j.neurobiolaging.2018.03.025). The lysosomal‐associated membrane protein 2 (LAMP2) gene was one of the most strongly modulated ones, pointing to LAMP2 as a strong candidate to mediate the lysosomal alterations induced by the virus. The objective of the present work is to study the involvement of LAMP2 in the neurodegeneration events induced by HSV‐1 infection.

Methods

In this work, we used murine neuroblastoma cell lines (N2a) with a stable knockdown for LAMP2. LAMP2 deficient and wild type N2a cells were infected by HSV‐1 for different times. Virus replication was assessed by quantitative PCR of viral genes. Levels of viral proteins were determined by western blot and infectious virus production was evaluated by titer plaque assays. Immunocytochemistry, western blot and ELISA assays were used to monitor AD neurodegeneration markers—tau hyperphosphorylation and Aβ accumulation.

Results

In this project, we have focused on studying the role of LAMP2 in the neurodegeneration induced by HSV‐1 using a cellular model of neuroblastoma cells that expresses very low LAMP2 levels. The results show that LAMP2 deficiency deeply affects the efficiency of HSV‐1 infection reducing: i) the levels of viral DNA, ii) the amount of viral proteins and iii) the production of infectious viral particles. In addition, LAMP2 deficiency reduces tau hyperphosphorylation and increases Aβ secretion in HSV‐1‐infected cells. These findings indicate that LAMP2 deficiency partially blocks the neurodegeneration markers induced by the virus.

Conclusion

All these findings suggest that the lysosomal gene LAMP2 could be a suitable candidate to mediate the AD‐like phenotype induced by HSV‐1.
Ongoing electroencephalographic rhythms related to exploratory movements in transgenic TASTPM mice
Authors: Tucci Federico , Percio Claudio Del , Drinkenburg Wilhelmus (Pim) , Lopez Susanna , Pascarelli Maria Teresa , Lizio Roberta , Noce Giuseppe , Soricelli Andrea , Ferri Raffaele , Bastlund Jesper F. , Clausen Bettina , Forloni Gianluigi , Frasca Angelisa , Fabene Paolo Francesco , Bertini Giuseppe , Colavito Valeria , Kelley Jonathan , Dix Sophie , Richardson Jill , Babiloni Claudio
Published: December 2020

Background

The European PharmaCog study (www.pharmacog.org) has reported a reduction in delta (1‐6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer’s disease (AD) amyloidosis and cognitive deficits. Here, we tested under similar conditions a cohort of TASTPM mice, in order to assess the reproducibility of the results, the studies were conducted in four different research centers of the PharmaCog consortium.

Method

Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched “wild type” C57 mice (range of age: 12‐24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions.

Result

Compared with the “wild type” group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p<0.05). This effect was observed in 3 out of 4 EEG recording centers

Conclusion

TASTPM mice were characterized by “poor reactivity” of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus motivating the use of EEG biomarkers in future multicenter preclinical trials performed in TASTPM mice.
The cerebrospinal fluid fractalkine as a biomarker in mild cognitive impairment (MCI)
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Klimkowicz‐Mrowiec Aleksandra , Pera Joanna , Borawska Renata , Muszynski Pawel , Mroczko Piotr , Dulewicz Maciej , Slowik Agnieszka
Published: December 2020

Background

Mild cognitive impairment (MCI) is a neurological disorder that occurs in older adults and could be a very early phase of AD dementia. It is not only medical but also socioeconomic and legal problem. Since the MCI symptoms are not yet associated with such serious memory problems as in dementia, it may be difficult to assess the patient's legal capacity. This is an extremely important issue, among others, from the point of view of the patient's decision about his/her treatment process. His ability to fully understand his health situation and the ability to make rational decisions, including being aware of its effects, can be difficult to assess, which has significant legal effects. Therefore, the biomarkers of early stage of dementia are critically important. Growing body of evidence indicated that overexpression of CX3CL‐1 may influence on tau pathology and modulate the dementia disorders development. In our investigation we aim to measure the cerebrospinal fluid concentration of fractalkine to assess the potential usefulness of this protein in the diagnosis of MCI patients. Moreover, the CSF CX3CL‐1 level was compared to the concentrations of classical AD biomarkers, including Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181.

Method

The study included 18 patients with MCI and 18 non‐demented controls. The cerebrospinal fluid levels of CX3CL‐1 and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181, were assessed by immunoenzyme assays.

Result

The concentration of fractalkine was significantly higher in cerebrospinal fluid of MCI patients when compared to non‐demented controls. The increased CSF levels of CX3CL‐1 were observed to significantly correlate with amyloid beta 1‐42 (Aβ‐42) and phosphorylated tau protein (pTau181) in mild cognitive impairment MCI subjects. Moreover, similar association between CX3CL‐1 concentrations and Aβ‐42/Aβ‐40 ratio was revealed in the control group.

Conclusion

Presented findings indicate a potential role of CX3CL‐1 in the pathology of MCI and possible usefulness of this protein in the early diagnosis of patients with cognitive impairment. The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.
Disease duration in autosomal dominant familial Alzheimer’s disease
Authors: Pavisic Ivanna M. , Nicholas Jennifer M. , O'Connor Antoinette , Lu Kirsty , Rice Helen , Khatun Ayesha , Fox Nick C. , Ryan Natalie S.
Published: December 2020

Background

In autosomal dominant Alzheimer’s disease (ADAD) an individual’s age at onset is significantly determined by causative mutation (Ryman et al. 2014). Determinants of disease duration are less well studied.

Method

Symptomatic mutation carriers (N = 256: 201 PSEN1, 55 APP) from ADAD families referred to the Dementia Research Centre, UK, between 1987 and 2019 were included. Differences in disease duration were assessed using multilevel mixed effects Weibull survival model. We evaluated the effect of gene, sex, cognitive presentation and APOE ε4 status on disease duration and quantified the proportion of variance in disease duration and age at onset explained by mutation and family, using intra‐class correlation coefficients.

Result

There was no significant difference in survival time between genes (PSEN1: 9.7 years [SD 5.3] vs APP 11.2 [4.9], p = 0.474). In accordance with previous findings (Ryan et al., 2016), 67% of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 18% of the variability in disease duration was explained by family membership (p < 0.001) and 6% by mutation (p = 0.188). Irrespective of gene, individuals born in later generations had longer survival (p = 0.003). Within the PSEN1 cohort, APOE ε4 carriers (N = 35) had 24% longer survival time compared to non‐carriers (N = 61) (12.9 years [6.7] vs 9.4 [4.7], p = 0.046, Figure 1)). No significant difference between APOE ε4 status was observed (p = 0.738) within APP. Mutations in PSEN1 exon eight included a number of individuals with particularly long disease durations (Figure 2) and the greatest prevalence of atypical symptoms. Overall, individuals with atypical presentations (N = 19) had 43% longer survival than those with amnestic presentations (N = 120) (15.5 years [7.1], vs 10.9 [5.5]; p = 0.014). There was no significant difference in survival time between sexes (p = 0.895).

Conclusion

Our results suggest, survival in ADAD appears longer in atypical presentations, has increased over time and is influenced by mutation but to a much lesser extent than age at onset. A deeper understanding of this variability may inform disease‐modifying trials and potentially highlight new avenues for targeting the disease.
Hippocampal vascularization pattern exerts local and global effects on structural and functional brain integrity
Authors: Vockert Niklas , Perosa Valentina , Ziegler Gabriel , Schreiber Frank , Yakupov Renat , Spallazzi Marco , Düzel Emrah , Schreiber Stefanie , Maass Anne
Published: December 2020

Background

The main contributor to hippocampal blood supply is the posterior cerebral artery. Additional contribution of the anterior choroidal artery distinguishes potential dual from single hippocampal vascular supply. In a previous study on patients with cerebral small vessel disease (CSVD) and older controls by Perosa et al. (Brain, in press), dual hippocampal vascularization was functionally associated with better cognition and structurally associated with increased anterior hippocampal volumes. The CSVD patients showed declined cognitive abilities. However, dual supply was able to alleviate performance loss in CSVD patients, indicating resilience against pathology. We examined the effect of dual vascular supply on anterior/posterior hippocampal volume and global grey matter (GM) volume, which might mediate the beneficial effect on cognition, and whether it conveys resistance against CSVD.

Methods

47 subjects (71±8yrs) with/without CSVD (20/27) underwent 7T time‐of‐flight MRA for categorization of hippocampal vascularization pattern (HVP) and 3T T1‐weighted structural MRI. As measure of global cognitive function we focused on the MoCA. Automatic segmentations of the anterior and posterior hippocampus were obtained via the ASHS (Automatic Segmentation of Hippocampal Subfields) 3T T1 atlas. GM volumes were obtained by segmentation in SPM (Statistical Parametric Mapping). The effect of the HVP and CSVD on structural and cognitive measures was estimated using ANCOVAs. A mediation effect of GM volume on cognition was examined via bootstrapping. Fisher’s exact test assessed contingency of the observed pattern to both clinical groups to make inferences about resistance against CSVD.

Results

A region‐based approach revealed a greater bilateral anterior (but not posterior) HC volume and increased global GM volume in the dual supply group. In a mediation analysis, GM volume offset the effect of the HVP on the MoCA score, whereas bilateral anterior HC volume did not. While the HVP seems to convey some resilience against CSVD, no evidence for resistance against CSVD was found.

Conclusions

Previous findings of structural effects on anterior HC volume via VBM were confirmed. Besides its local effects, dual hippocampal vascular supply exerts global effects on brain structure. These effects partially account for better cognitive performance of the corresponding individuals. An int42708eraction with pathology might be restricted to resilience, but not resistance.
A novel method for integrating transcriptomics and neuroimaging
Authors: Povala Guilherme , Bastiani Marco Antônio , Bellaver Bruna , Ferreira Pamela C.L. , Souza Débora Guerini , Brum Wagner Scheeren , Zatt Bruno , Zimmer Eduardo R.
Published: December 2020

Background

Positron emission tomography (PET) imaging has been playing a fundamental role in diagnosis of Alzheimer’s disease (AD). Also, in the context of AD, blood‐based biomarkers that are capable of predicting PET brain imaging findings are of high interest. Both PET imaging and transcriptomics are rich sources of different biological information. Hence, an interesting strategy to find potential novel blood biomarkers is by integrating PET imaging data with blood transcriptomics. We aim to develop a method for combining blood transcriptomics profile and PET imaging data, which may highlight novel AD biomarkers. Here, we hypothesize that by integrating blood transcriptomics and PET imaging data we will be able to identify clinically relevant novel peripheral biomarkers.

Method

Imaging and transcriptomics data were acquired from Alzheimer’s Disease Neuroimaging Initiative (ADNI). Microarray gene expression profiling from blood samples of 69 cognitively unimpaired (CU) individuals and 158 mild cognitively impaired (MCI) were submitted to differential expression (DE) analysis using the limma R package. The [F18]FDG‐PET standardized uptake ratio (SUVr), using cerebellum as the reference region, were calculated. Genes obtained from DE analysis were selected to undergo integration with [F18]FDG‐PET images using voxel‐wise generalized linear regressions (GLR) (RMINC package).

Results

The DE analysis resulted in 1232 differentially expressed genes (DEGs) (p‐value < 0.05). The GLR computed the associations between gene expression and [F18]FDG for each voxel, resulting in t‐value maps. Afterwards, only gray matter voxels presenting absolute t‐values higher than 2.3 were retained. Then, we transformed t‐value maps into proportion maps. In brief, each volume of interest (VOI) shows the percentage of voxels statistically correlated with gene expression (see Figure 1). Finally, we ranked DEGs according to the amount of VOIs with a proportion higher than 30%.

Conclusion

With the use of the proposed method, we were able to integrate blood transcriptomics with PET neuroimaging. The implementation of this method shows great potential in the search for new blood biomarkers, which can accelerate early diagnosis and provides a template for future research in the field.
Recessive missense variants in VWA2 increase risk of developing Alzheimer’s disease
Authors: Hoogmartens Julie , Hens Elisabeth , Engelborghs Sebastiaan , Vandenberghe Rik , De Deyn Peter Paul , Cacace Rita , Van Broeckhoven Christine ,   BELNEU Consortium
Published: December 2020

Background

Alzheimer’s disease (AD) is the most frequent cause of neurodegenerative dementia and presents at early (age at onset (AAO) ≤65 years, EOAD) or late age (LOAD). Only 5‐10% of EOAD patients are explained by dominant mutations in AD genes, APP, PSEN1 or PSEN2. We aimed at finding recessive mutations in patients that are not genetically explained.

Methods

The Flanders‐Belgian AD cohort (n = 1166) included 170 EOAD (AAO 57.96 ± 6.32 years; range 29‐65) and 996 LOAD (AAO 77.55 ± 6.30 years; range 66‐95) patients. Whole Genome Sequencing (WGS) was provided by Complete Genomics, BGI. The WGS data was searched for recessive variants, altering protein sequences and a minor allele frequencies ≤5%. Gene‐based resequencing was performed using target amplification assays.

Results

We selected 18 EOAD patients with a well‐documented clinical or pathological diagnosis for WGS analysis. Mean AAO was 56.17 ± 6.90 years (range 37‐65) and 6 patients had pathological confirmed EOAD. One EOAD patient (AAO 64) was homozygous for p.V366M in the gene Von Willebrand Factor A Domain Containing 2 (VWA2). Resequencing of VWA2 in the AD patient cohort identified 1 additional EOAD (AAO 60) and 3 LOAD patients (AAO range 74‐90) with homozygous (p.R69M, p.V366M) or heterozygous (p.V366M/p.L715F) compound variants. Allele sharing analysis of the compound carriers identified common haplotypes flanking p.V366M and p.L715F, suggesting shared ancestors.

Conclusions

We identified 5 AD patients with trans compound variants in VWA2, 2 EOAD patients (2/170; 1.2%) and 3 LOAD patients (3/996; 0.3%). None of the compound carriers had first‐degree relatives with dementia, fitting autosomal recessive inheritance. The observed frequency of compound carriers in the AD patient groups was higher than expected based on the single allele frequencies calculated in our Flemish‐Belgian population. Overall, our genetic results suggest that compound variants in VWA2 might increase risk for AD. VWA2 is likely part of the extracellular exosomes, which are contributing to neuronal interaction and have a role in AD pathology. Genetic replication in independent AD patients cohorts and functional studies will be needed to understand the contribution of the biological function of VWA2 to AD.
Policy makers' perception on the potential of adoption of the Tailored Activity Program (TAP) in Chile
Authors: Moraga Carolina , Gajardo Jean , Fuentes‐García Alejandra , Gitlin Laura N
Published: December 2020

Background

The Tailored Activity Program (TAP) is an evidenced‐based program targeting behavioral and psychological symptoms of dementia and caregivers’ readiness, among other outcomes. TAP has been tested and implemented in different settings and countries. Evidence‐based interventions face the challenge of transference and adoption with a complexity of dimensions. This study explored the perception of key stakeholders and policy makers related to dementia care on the potential adoption of TAP in Chile, utilizing Roger’s Model of Innovation‐Decision Process (1983).

Method

Qualitative study. Key policy makers related to Chile’s Ministry of Health, Ministry of Social Development, and National Plan of Dementia, were introduced to TAP’s main features, process, and outcomes, and later interviewed to describe the following five attributes of TAP: relative advantage, compatibility, complexity, trialability, observability. These attributes were extracted from the Persuasion Phase of Rogers’ Model of Innovation‐Decision Process (1983). Interviews were recorded and transcribed, and narrative content analysis was used to produce content categories. Ethical approval was obtained from the Scientific Ethics Committee of Adults, Metropolitan Health Service, Santiago, 2019. Informed consent was completed by all participants.

Result

Seven interviews were performed to policy makers at a national level part of Chile’s National Plan of Dementia. Participants described TAP in a low‐level of complexity, easy to understand, and highly feasible for implementation, as well as highly compatible with existing efforts on dementia care in Chile, highlighting its observable results, pertinence for local testing and its comparative advantage to existing interventions.

Conclusion

Policy makers value positively TAP’s features and its adoption is highly feasible within current initiatives on dementia care in Chile.
Neuroinflammation imposes vulnerability to tau propagation
Authors: Rosa‐Neto Pedro , Pascoal Tharick A. , Benedet Andréa Lessa , Kang Min Su , Savard Melissa , Mathotaarachchi Sulantha , Edison Paul , Chamoun Mira , Stevenson Jenna , Therriault Joseph , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge
Published: December 2020

Background

Translocator protein (TSPO) is an 18 kDa protein has been considered a target for neuroinflammation. Using multiparametric acquisitions, we tested in a large‐scale cohort the hypothetical framework proposing that neuroinflammation imposes vulnerability to neurofibrillary tangles (NFT) formation and propagation.

Methods

We studied cognitive unimpaired and impaired individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort who had a complete baseline clinical and cognitive assessments, structural MRIs, [11C]PBR28, [18F]MK6240 and [18F]AZD4694 (PET proxies for TSPO, NFT and Αβ, respectively). The PET outcome measure was the SUVR. A fraction of these individuals also had CSF cytokines analysed using the Olink Platform. We conducted ROI path analysis and voxel‐based analysis to establish the associations between [11C]PBR28, [18F]MK6240 and [18F]AZD4694.

Results

A total of 138 (CN=90; MCI=30=; AD=18) individuals were included in this analysis. We found that brain [11C]PBR28 uptake was correlated with CSF biomarkers of neuroinflammation. We also found an age‐related increase of [11C]PBR28 uptake. [11C]PBR28 was increased brain in AD related areas across the its clinical spectrum. [11C]PBR28 was associated with cognitive deficits in these individuals. In regards to tau aggregates, we found that [18F]MK6240 uptake in the mesial temporal structures derives from local interactions between [18F]AZD4694 and [11C]PBR28. Importantly, path analysis revealed that [11C]PBR28 and [18F]AZD4694 uptake potentiated the propagation of [18F]MK6240 from early to late Braak stages (Figure 1).

Conclusions

Our results reveal that TSPO upregulation is part of the repertoire of biomarker alterations in patients within the entire AD clinical spectrum. TSPO is critical for the early and late tangle formation on medial temporal structures as well in advanced Braak stages. Neuroinflammation imaging agents such as [11C]PBR28 provide critical information regarding inflammatory tissue responses amenable of pharmacological interventions.