bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased JNK3 levels are associated with amyloid plaque and neurofibrillary tangles in dementia patients
Authors: Cheng Ai Ling , Chong Joyce R , Lee Jasinda , Attems Johannes , Aarsland Dag , Francis Paul T , Lai Mitchell Kim Peng
Published: December 2020

Background

Many studies have provided strong evidence to support JNK3 isoform‐specific involvement in several processes underlying Alzheimer’s Disease (AD) pathogenesis including dysfunction of synaptic plasticity and cognition, phosphorylation of tau and amyloidogenic processing of the amyloid precursor protein. Moreover, the tissue‐specific expression of JNK3 primarily in the brain suggests a potential pivotal role of JNK3 in the central nervous system.

Method

Using immunoblotting, JNK3 levels were measured in the post‐mortem parietal lobe cortex (Brodmann Area 40) of a cohort of longitudinally assessed Alzheimer’s Disease (AD), Lewy Body Dementia (LBD), and healthy control patients. Although LBD brains are mainly characterized by the presence of α‐synuclein‐containing lewy bodies, It has been shown that LBD brains exhibit a substantial degree of AD pathologies, including amyloid plaques and neurofibrillary tangles particularly in cortex regions associated with higher cognitive functions. We investigated the association between levels of JNK3 and several neuropathological measures too.

Result

We found a significant decrease in JNK3 levels in all dementia groups compared to control. Our results also showed that levels of JNK3 were significantly associated with amyloid plaque (AP) and neurofibrillary tangle (NFT) pathology scores but not lewy body (LB) scores.

Conclusion

Our results suggest a possible compensatory mechanism to maintain levels of JNK3 to protect against further pathological damage. It was suggested that this compensatory effect is the brain’s adaptive means in response to pathological insults, to aid in dampening further damage during disease progression, and that these compensatory changes usually comes into play in the ‘latent’ phase of disease progression. In addition, JNK3 is likely to be involved in AD‐related processes but not in mechanisms that are associated with driving the formation of α‐synuclein pathological aggregates. The role of JNK3 in LBD could be in relation to common pathogenic pathways that underlie all dementia.
The effect of smartphone app‐based cognitive training on cognition in community‐dwelling elderly: A randomized controlled trial
Authors: Jang Hyemin , Kim Hee Jin , Seo Sang Won , Na Duk L
Published: December 2020

Background

Most of previous cognitive intervention studies provided group cognitive intervention for a short period of time, which are limited by requirement of money, time, and space in real clinical circumstances. Therefore, easily accessible way of cognitive training should be developed and tested in a large cohort of the elderly. We investigated the effectiveness of smartphone app (InBrain Trainer) based cognitive training for 12 months on cognitive improvement in the community‐dwelling healthy elderly.

Method

This App‐based Cognitive Training at Home (ACTH) study is a randomized, single‐masked, parallel group study, which was conducted between March 2018 to August 2019 at Gangnam Center for Dementia, in Seoul, South Korea. We recruited 389 healthy volunteers aged over 60 and they were randomly assigned to the intervention or control group. The intervention group experienced daily app‐based cognitive training at home (with regular feedback from administrator) and monthly group cognitive training for 12 months. All participants underwent cognitive screening test (CST) at baseline, 6 and 12 months. The primary outcome was the change in total composite score on CST, and the secondary outcomes included changes in composite scores of five cognitive domains, which were assessed using linear mixed effects models.

Result

When the intervention‐by‐visit interaction effect was investigated, the intervention group showed a larger increase on total scores (p < 0.001 at 6 months, p = 0.001 at 12 months), on language (p <0.001 both at 6 and 12 months) and memory composite scores (p=0.006 at 6 months, p<0.001 at 12 months) compared to the control group. There was no significant difference in changes at 12 months in attention (p=0.72), visuospatial (p=0.994) and executive composite scores (p = 0.929) between the intervention and the control group. (Figure 1)

Conclusion

This study demonstrated that app‐based cognitive training could enhance general cognition in the healthy elderly. Therefore, this cognitive training tool could be usefully utilized for the purpose of preventing cognitive decline on a community basis.
Threshold of white matter hyperintensity volume determines negative and positive associations between grey matter volume and hypertension
Authors: Vipin Ashwati , Wong Benjamin , Kumar Dilip , Low Audrey , Ng Kok Pin , Kandiah Nagaendran
Published: December 2020

Background

Hypertension and white matter hyperintensity(WMH) burden are major risk‐factors for Alzheimer’s disease[Pantoni et al.,2010;Sweeney et al.,2018]. Prior studies show variable grey matter alterations, involving both negative and positive associations, independently related to WMH and hypertension in early stages of late‐onset AD[Vipin et al.,2018;Foster‐Dingley et al.,2015;Tuladhar et al.,2015;Den Heijer et al.,2003]. However, the effect of incremental WMH load and concomitant hypertension on brain structure in young‐onset mild cognitive impairment(MCI) remains to be elucidated. Such investigations may provide better insight into relationships between WMH, hypertension and dementia risk. We thus examine the influence of increasing WMH load on grey matter volume(GMV) as well as on the association between blood pressure(BP) and GMV in young‐onset MCI. We hypothesize that WMH burden and BP will have derogatory effects on GMV, especially under high WMH conditions.

Method

T1‐MRI data from 78 MCI subjects(<65years) from the Singapore‐YouNg‐Dementia‐Cohort was studied. WMH load was divided into low(0.00‐1.49ml), medium(1.50‐4.99ml) and high(>5.00ml). Voxel‐based morphometry(VBM) assessed whole‐brain voxel‐wise changes related to increasing WMH load between hypertensive(systolic‐BP>130mmHg)[Whelton et al.,2017] and non‐hypertensive subjects. Pearson’s correlation analysis tested associations between GMV from key Executive‐Control‐Network(ECN) and Default‐Mode‐Network(DMN) regions‐of‐interest(ROI)[Shirer et al.,2012] and vascular risk‐factors.

Result

Whole‐brain VBM revealed less GMV reduction in hypertensive compared to non‐hypertensive subjects in frontal and temporal regions at low‐WMH load, with more pronounced effects at medium‐WMH load (Fig.1;uncorrected‐p<0.001, cluster‐size‐threshold:p<0.05). However, at high‐WMH load, hypertensive and non‐hypertensive subjects showed no differences in GMV. Additionally, at low‐WMH load, average and ROI‐specific DMN(bilateral posterior‐cingulate‐cortex, precuneus;p<0.05) and ECN(left[p<0.05] and right[p<0.10] posterior‐parietal‐cortex) GMV related positively to WMH but showed no association at medium‐WMH load. Importantly, only high‐WMH load was associated with lower ECN(p<0.05) and DMN(p<0.10) GMV(Fig.2). These associations remained regardless of hypertension status. Additionally, high systolic‐BP related to lower GMV at high‐WMH load only(Fig.3).

Conclusion

Our findings indicate that in young‐onset MCI, the relationship between WMH and GMV is determined by WMH load rather than hypertension status. WMH load also influences the relationship between systolic BP and GMV in young‐onset MCI. Importantly, our results suggest that WMH and hypertension influence GMV via different mechanisms and BP recommendations for dementia prevention may be different in MCI with and without WMH.
Correlation of protein tau and amyloid beta aggregates neuroinflammation and oxidative stress in 5xFAD and P301S mice
Authors: Rejc Luka , Group Kosmrlj
Published: December 2020

Background

The deposition of protein tau (Tau) and amyloid beta (Aβ) aggregates during Alzheimer disease (AD) is accompanied by other processes, mostly controlled by glial activation. Despite numerous attempts, there is little information on the role of these processes in the disease mechanism. Exact mapping and correlation of pathological changes would give information that could help reveal underlying causes for the onset of the disease. We set off to longitudinally investigate and correlate disease related processes in the brains of 5xFAD and P301S mice models.

Method

Neuroinflammation and oxidative stress in P301S and 5xFAD transgenic (tg) mice were monitored longitudinally by PET‐CT imaging and compared to age‐matched healthy controls (WT). PET imaging using [18F]DPA‐714, [18F]FSPG, [18F]florbetaben, and [18F]EFAPEM1 was performed to assess levels of neuroinflammation, oxidative stress, Aβ load (5xFAD mice) and Tau aggregates (P301S) load, respectively. Uptake in the cortex (CTX) was presented as SUV or SUVr when a reference region was available. IHC staining of brain slices for Aβ, Tau deposits, neuroinflammation and oxidative stress is currently in progress.

Result

PET‐CT studies showed increase of levels of Tau deposits at 8 month‐old P301S mice and Aβ levels at 6, 8 and 10 month‐old 5xFAD mice. For 5xFAD mice, [18F]DPA‐714 and [18F]FSPG uptake followed the trend of Aβ deposition, peaking at 8 months. Compared to WT mice, four‐fold increase in [18F]DPA‐714 (p<0.0001) and three‐fold increase in [18F]FSPG (p=0.0019) SUV was observed, suggesting protein deposits‐induced increase in inflammation and oxidative stress. Surprisingly, neuroinflammation and oxidative stress did not follow the trend of Tau deposition in P301S mice.

Conclusion

Longitudinal deposition of Aβ and Tau was in accordance with reported ex vivo data for the two animal models. Neuroinflammation and oxidative stress correspond well with the levels of Aβ, longitudinally. The two processes also occur in P301S mice brain but correspond poorly with Tau deposition. These results suggest that either Aβ and Tau aggregates affect neuroinflammation and oxidative stress differently, or that neuroinflammation and oxidative stress are independent processes. Further studies are in progress to confirm the observed data.
Masupirdine (SUVN‐502): Novel treatment option for the management of behavioral and psychological symptoms in patients with Alzheimer’s disease
Authors: Nirogi Ramakrishna , Jayarajan Pradeep , Shinde Anil K , Abraham Renny , Goyal Vinod Kumar , Benade Vijay , Ravulu Jyothsna , Jasti Venkat
Published: December 2020

Background

5‐hydroxytryptamine‐6 (5‐HT6) receptors are G‐protein coupled receptors localized in the brain regions primarily involved in cognition and behavior i.e., cortex, dorsal hippocampus and striatum. Evidence from the studies in animal models suggests that 5‐HT6 receptor antagonist may have a potential role in controlling behavior and psychosis. Masupirdine is a pure 5‐HT6 receptor antagonist under clinical development for the management of AD and behavioral and psychological symptoms.

Method

Triple therapy with masupirdine added to background dual combination treatment with donepezil and memantine was evaluated in a phase‐2 proof‐of‐concept, 26‐week, randomized, double‐blind, placebo‐controlled, multicenter, parallel groups study conducted across several sites in the United States. In this study, effects of masupirdine on the neuropsychiatric symptoms and cognition were evaluated using the Neuropsychiatric Inventory (NPI‐12) and Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS‐Cog 11), respectively in patients with moderate AD.

Result

Out of 564 randomized patients, 183 patients received placebo, 184 patients received 50 mg of masupirdine and 176 patients received 100 mg of masupirdine. Masupirdine attenuated the agitation/aggression scores in the subgroup of patients who had baseline agitation/aggression. The effect observed was above the minimum clinically important difference (0.4 SD). In another subgroup of patients, masupirdine attenuated the psychotic symptoms (delusions and hallucinations) and also emergence of psychotic symptoms. Significant reduction in the cognitive decline was also noticed with masupirdine treatment in the subgroups of patients having psychotic symptoms. Masupirdine was generally safe and well tolerated in this study.

Conclusion

Masupirdine treatment significantly reduced the behavioral and psychological symptoms i.e., agitation/aggression and psychotic symptoms (delusions and hallucinations) with positive effect on cognition. Masupirdine could be a differentiated novel therapeutic treatment option for the management of behavioral and psychological symptoms in patients with AD.
Masupirdine (SUVN‐502): A pure 5‐HT6 receptor antagonist ameliorates aggression‐like behavior in animal models
Authors: Tadiparthi Jayaprakash , Ganuga Narender , Grandhi Venkata Ramalingayya , Medapati Rajesh Babu , Kamuju Venkatesh , Gandipudi Sudhakar , Reballi Veena , Jayarajan Pradeep , Nirogi Ramakrishna
Published: December 2020

Background

Behavioral and psychological symptoms of dementia (BPSD) are the common behavioral changes observed in patients with Alzheimer’s disease (AD). More than 90% of people with dementia develop at least one BPSD over a 5 years time period with around 85% of patients experiences serious clinical implications. Serotonin‐6 receptor (5‐HT6R) is a G protein‐coupled receptor and is localized almost exclusively in the central nervous system including cerebral cortex and hippocampus which are important for control of mood regulation. Masupirdine is a 5‐HT6R antagonist currently in the clinical development for the management of Alzheimer’s disease.

Method

Masupirdine was evaluated for its anti‐aggressive like effects in one of the most popular preclinical aggression model i.e. Resident‐Intruder task (RIT). Male CD1 mice were used to assess the anti‐aggressive like effects in RIT. Resident animals were habituated with ovariectomized female mice and intruders were habituated socially for a period of 7 days. On day 8 and 9, basal aggression level was assessed by placing an intruder animal in the home cage of resident animal for a period of 10 min. On day 11, animals were randomized based on duration of attack and aggression level was assessed post treatment. In the control group, vehicle was administered to resident animals and for remaining groups, masupirdine was administered at doses of 1, 3 and 10 mg/kg, p.o. Additionally, masupirdine was evaluated for its effects on neurotransmitters that are involved in the modulation of behavioral and psychological symptoms using rats. Suitable statistical analysis is carried by GraphPad Prism (Version 4).

Result

Vehicle treated group showed almost equal duration of attack with respect to basal whereas, masupirdine significantly decreased the aggressive behavior of resident animal towards intruder at all tested doses with respect to basal. Treatment with masupirdine produced significant increase in the cortical levels of dopamine and norepinephrine. These neurochemical changes by masupirdine provide the support for anti‐aggressive behavior observed in preclinical models.

Conclusion

Results from the current preclinical studies indicate the promising therapeutic potential for masupirdine in the treatment of agitation/aggression.
Music‐with‐movement intervention for people with mild/early cognitive impairment: An effectiveness‐implementation hybrid cluster randomized controlled trial
Authors: Cheung Daphne Sze Ki , Lai Daniel Lok Lam , Ho Lily Yuen Wah , Lai Claudia KY
Published: December 2020

Background

A caregiver‐delivered, home‐based music‐with‐movement intervention (MM) for people with early dementia has been shown to reduce anxiety symptoms. Yet, caregivers reported their struggles when implementing the intervention, which reduced their motivation to sustain the intervention at home. This study is to evaluate the effectiveness of the strategies for overcoming the implementation challenges identified in the previous research and to investigate the efficacy of the intervention on psychosocial well‐being of people with mild/early cognitive impairment.

Method

This was a multi‐centre, two‐arm, cluster randomized controlled, effectiveness‐implementation hybrid trial. The program was designed to improve the psychosocial well‐being of people with mild/early dementia. Partnered centres were randomized into the intervention or wait‐list control groups, and the families recruited by them followed the group allocation correspondingly.

Seven community partners recruited eighty families from different districts in Hong Kong. Intervention participants received a 12‐week MM intervention, delivered by trained family caregivers at home, and trained staff and volunteers in the centres. Participants in the control group received the identical programme after data collection.

Implementation strategies included (1) partnering with different types of community service sectors for recruiting families; (2) training centre staff and volunteers for delivering the intervention and providing support; (3) using information and communication technology (ICT) for disseminating intervention materials, communication, and fidelity monitoring; and (4) introducing centre‐based activities for enhancing programme sustainability. To assess program efficacy (psychosocial well‐being) and implementation outcomes (acceptability, fidelity, practicality and sustainability), multi‐method and multi‐informant assessment strategies were used including clinical assessments, observation and interview.

Result

Caregivers, volunteers and staff of the centres welcomed the use of ICT, which facilitated the delivery of the intervention. Four elderly centres have continued to use the MM programme as their routine services. The findings showed that the programme was effective in improving anxiety and depressive symptoms of elderly participants and reducing stress level of family caregivers. Booster training may need to be introduced to ensure the fidelity of intervention delivery.

Conclusion

This study demonstrated that adaptive strategies were effective in overcoming the implementation challenges and the intervention helped the target population improve their emotional well‐being.
In‐vivo imaging of retinal amyloid in Alzheimer’s disease patients using curcumin as labeling fluorophore
Authors: de Ruyter Frederique Jasmine Hart
Published: December 2020

Background

The retina is increasingly recognized as a promising target to identify early changes associated with Alzheimer’s disease (AD) (London, Benhar, & Schwartz, 2013). Previous studies showed retinal amyloid in AD patients in‐vivo and in post‐mortem retinal tissue of AD patients (Koronyo et al., 2017; Koronyo‐Hamaoui et al., 2011). The objective of this proof‐of‐concept study is to non‐invasively visualize amyloid‐beta (Aß)‐plaques in the retina of AD patients with a multispectral scanning laser ophthalmoscope (mSLO), using curcumin as labeling fluorophore.

Method

Twenty‐two subjects with early‐onset AD (age<70, MMSE>16) and four matched controls were recruited from the Amsterdam Dementia Cohort. Subjects underwent imaging with the mSLO at baseline and after curcumin intake. Blood samples were taken at different time points for curcumin bioavailability analysis. Three sub studies were performed with different curcumin supplements (Theracurmin™, Novasol™ and Longvida™) in different dosages and duration of intake. In all three cohorts mSLO imaging was performed with three excitation wavelengths (486nm (blue) and 518nm (green)) in order to separate retinal autofluorescence from curcumin fluorescence. Retinal fluorescence images were visually assessed.

Result

Baseline fluorescence images showed no abnormalities in both AD‐patients and controls. Imaging using two excitation wavelengths showed no plaque‐like alterations in the retina after curcumin intake with any of the supplements. Blood analysis showed no detectable levels of free curcumin after Theracurmin or Novasol intake curcumin (results from the Longvida cohort are in preparation), however we did find curcumin conjugates with resembling binding characteristics as curcumin (den Haan, Morrema, Rozemuller, Bouwman, & Hoozemans, 2018).

Conclusion

No difference in fluorescence before and after curcumin intake was observed in this cohort of early‐onset AD patients. This may be due to insufficient uptake of curcumin, a low curcumin signal to retinal fluorescence ratio and/or absence of retinal amyloid plaques. Given the discrepancies in literature (den Haan et al., 2018; Ho, Troncoso, Knox, Stark, & Eberhart, 2014; Schon et al., 2012; Williams et al., 2017) patient cohorts including both early and late onset AD as well as replication of post‐mortem studies are needed to unequivocally proof amyloid presence in AD retinas, as potential target for in‐vivo retinal imaging.
Investigating proteostasis in development and disease using IPSC‐neurons with MAPT mutations linked to FTD
Authors: Lines Georgie , Wray Selina , Lovejoy Christopher E.J. , Arber Charles , Casey Jackie M. , Alatza Argyro
Published: December 2020

Background

Mutations in the microtubule‐associated protein tau (MAPT) are causative of Frontotemporal Dementia (FTD). Many of the features associated with the development of tau pathology, such as high levels of tau phosphorylation, are also present in early development. iPSC‐neurons have gene expression signatures similar to fetal neurons, and iPSC‐neurons with MAPT mutations do not develop tau aggregates. We hypothesise that iPSC‐neurons are resistant to developing tau aggregates due to high activity levels of the proteostasis network during early development. To test this hypothesis we investigated the RNA and protein levels of proteasome subunits (B5, RPT6, PSMD11) and associated proteins (TRIM11, BAG3) in developing MAPT mutated iPSC derived neurons.

Methods

Human cortical neurons were derived from isogenic iPSCs with the following MAPT genotypes: WT, 10+16 monoallelic, 10+16 biallelic and 10+16/P301S biallelic. RNA and protein analysis of proteasome subunits was performed by qPCR and Western blot at Days 0, 10, 30 and 100, spanning the different stages of neurogenesis.

Results

Gene and protein expression of the core proteasome subunit B5 remains consistent throughout development. The expression of regulatory proteasome subunits PSMD11 decreases at both the protein and RNA level. RPT6 decreases at the protein level but increases at the RNA level. BAG3 significantly decreases at the protein level. There is no significant difference in protein expression between disease and WT lines.

Conclusion

This data indicates that the core 20S proteasome unit remains at consistent levels throughout development, however the expression of regulatory subunits differ. A change in regulatory subunit expression could have a direct impact on the ability of the proteasome to degrade proteins. Ongoing work is using proteasome activity assays to determine how this changes through development and is impacted by MAPT mutations.
Functional brain network correlates of theory of mind and social cognition in early Alzheimer’s disease
Authors: Valera‐Bermejo Jose Manuel , Mitolo Micaela , Cerami Chiara , Dodich Alessandra , de Marco Matteo , Venneri Annalena
Published: December 2020

Background

Patients in the early stages of Alzheimer’s disease (AD) may display impairment of social cognition (SC) such as the ability to attribute intentions, beliefs or emotions to others (Theory of Mind, ToM). In healthy subjects, SC relies on multi‐network interactions that modulate brain social processing. Therefore, specific pathological changes in multiple large‐scale networks could explain the heterogeneous results of SC performance in AD found across the literature. To date, there is no resting‐state connectivity study investigating the network underpinnings of SC in AD patients.

Methods

Resting‐state functional MRI scans were acquired from early‐AD patients (n=46) and preprocessed using the Statistical Parametric Mapping (SPM) 12 software. Independent component analysis (ICA) was performed at a group level to isolate and reconstruct four intrinsic connectivity brain large‐scale networks, namely fronto‐parietal, salience, and anterior and posterior default mode networks (DMN). Multiple regression analyses were performed on three SC tasks of emotion recognition (ER) (Ekman 60 face task) and ToM (Reading‐the‐Mind‐in‐the‐Eyes‐Test, RMET and the Story‐based Empathy Task, SET) with the ICA extracted large‐scale network maps, controlling for age, cognitive reserve, brain reserve and disease severity.

Results

SC associations with functional connectivity maps showed positive correlations (increased intrinsic connectivity) between ER and the fronto‐parietal network in the right insular region (p <0.034) and ToM (SET) with the posterior DMN in the right precuneus (p <0.030). Conversely, negative associations (decreased intrinsic connectivity) were found between ToM‐RMET (p < 0.011), ToM‐SET (p< 0.049) and ER (p < 0.034) and the salience network in the left temporo‐parietal junction, precuneus, uncus, inferior temporal gyrus and right postcentral gyrus. Lastly, a negative association was found between ToM‐RMET and the anterior DMN (p < 0.013) in the right medial prefrontal cortex.

Conclusions

This study sheds light on how multiple network dynamics exhibit particular connectivity dissociation patterns of social processing in AD. Specific neural reorganisation via up‐regulation of the posterior DMN and fronto‐parietal network concomitant with a down‐regulation of the salience and anterior DMN could explain the characteristic pattern of decline of SC in AD. Notably, our results display consistency with regions involved in SC and ToM.
The anticholinergic effect on cognition (AEC) scale: Associations with mortality, hospitalisation and cognitive decline following dementia diagnosis
Authors: Bishara Delia , Perera Gayan , Harwood Daniel , Taylor David , Sauer Justin , Stewart Robert , Mueller Christoph
Published: December 2020

Objectives

To investigate associations between central anticholinergic burden (using the AEC scale), and mortality, hospitalisation and cognitive decline in patients with dementia.

Methods

The South London and Maudsley NHS Foundation Trust (SLaM) Clinical Records Interactive Search (CRIS) application was used to identify patients 65 years or older at their first recorded diagnosis of dementia. Data were linked to national mortality and hospitalisation sources, and serially recorded Mini‐Mental State Examination (MMSE) scores were used to investigate cognitive decline over the 36 months after diagnosis in mixed models.

Results

Patients for whom a review of their medication was indicated (AEC score ≥ 2 for any individual drug or total AEC score ≥ 3) had an increased risk of mortality (hazard ratio 1.07; 95% CI 1.01‐1.15) and emergency hospitalisation (1.10; 95% CI 1.04‐1.17), but there were no associations with duration of hospitalisation. Cognitive trajectory analyses showed that this exposure group had lower MMSE scores at diagnosis and a sharper increase in MMSE scores over the subsequent 6 months, but similar slopes for the 6‐36 months period to the remainder of the sample.

Conclusions

Patients with dementia receiving medication with high central anticholinergic activity (as measured on the AEC scale), appear to have worse prognosis in terms of mortality and hospitalisation risk, but have primarily acutely impaired cognitive function, rather than longer term differences in cognitive decline.
Aberrant protein O‐GlcNAcylation drives AD‐like neurodegeneration in DS mice
Authors: Domenico Fabio Di , Zuliani Ilaria , Perluigi Marzia , Lanzillotta Chiara , Barone Eugenio , Tramutola Antonella
Published: December 2020

Background

Down syndrome (DS) is related with an increased incidence of Alzheimer’s disease (AD) neuropathology. Among the putative mechanisms leading neurodegeneration, the reduction of cerebral glucose metabolism may trigger brain damage by impacting the hexosamine biosynthetic pathway (HBP). As reported in AD, defective HBP is responsible for flawed protein O‐GlcNAcylation coupled by a mutual inverse increase of protein phosphorylation on Ser/Thr residues, which gives to O‐GlcNAcylation the ability to modulate various pathways involved in AD progression. Previous studies have shown the aberrant O‐GlcNAcylation/phosphorylation ratio of tau and APP in AD brain, confirming dysfunctional O‐GlcNAcylation as a key contributor in the pathogenesis of the disease. Our work aims to unravel, for the first time, the role of protein O‐GlcNAcylation in DS neuropathology along with its possible pharmacological modulation to prevent DS cognitive decline.

Methods

We performed western blot analysis of global O‐GlcNAc levels and total protein Ser/Thr phosphorylation in the hippocampus of 6‐months‐old Ts2Cje, mouse model of DS, compared to age‐matched controls. Furthermore, we measured the activity of enzymes involved in O‐GlcNAcylation cycling (OGT and OGA), as well as the functionality of GFAT1, the rate limiting enzyme of the HBP. Additionally, we determined by immunoprecitation the O‐GlcNAcylation/phosphorylation ratio of AD‐related markers (tau and APP). Finally, we tested the efficacy of an intranasal short‐term treatment with an O‐GlcNAc‐modulating compound.

Results

We observed an early reduction of total O‐GlcNAcylation levels in young Ts2Cje mice and established its correlation with an increase in total protein phosphorylation. We measured the alteration in OGT and OGA functionality, unrelated with a dysfunctional activity of GFAT1. Moreover, we demonstrated that the reduction of O‐GlcNAcylation/phosphorylation levels affects both tau and APP, actively contributing to DS neuropathology. Lastly, our novel therapeutic strategy was able to increase O‐GlcNAc levels in Ts2Cje mice and restore AD‐related markers, possibly slowing disease progression.

Conclusion

Our research highlights the pathological role of the altered protein O‐GlcNAcylation profile in DS neurodegeneration and investigates the neuroprotective effects of an O‐GlcNAc‐modulating compound.
Neuron‐selective induction of granulovacuolar degeneration bodies: A lysosomal stress response to tau aggregation?
Authors: Wiersma Vera I. , van Ziel Marieke , Vazquez‐Sanchez Sonia , Nölle Anna , Berenjeno‐Correa Ernesto , Bonaterra‐Pastra Anna , Clavaguera Florence , van Weering Jan , Verhage Matthijs , Hoozemans Jeroen J.M. , Scheper Wiep
Published: December 2020

Background

Granulovacuolar degeneration bodies (GVBs) are membrane‐bound vacuolar structures harboring a dense core that accumulate in the brains of patients with neurodegenerative disorders, including Alzheimer’s disease and other tauopathies. Insight into the origin of GVBs and their connection to tau pathology has been limited by the lack of suitable experimental models for GVB formation.

Method

We used confocal, automated, super‐resolution and electron microscopy in different models for seeded tau aggregation.

Result

We demonstrate that the seeding of tau pathology triggers the formation of GVBs in mouse models in vivo and in primary mouse neurons in vitro. Seed‐induced intracellular tau aggregation, but not seed exposure alone, causes GVB formation in cultured neurons but not astrocytes. The extent of tau pathology strongly correlates with the GVB load. The in vitro tau‐induced GVBs are immunoreactive for the established GVB markers CK1δ, CK1ɛ, CHMP2B, pPERK, peIF2α and pIRE1α. GVBs contain a LAMP1‐ and LIMP2‐positive single membrane that surrounds the dense core and vacuole. The proteolysis reporter DQ‐BSA is detected in the majority of GVBs, demonstrating that GVBs contain degraded endocytic cargo. GFP‐tagged CK1δ accumulates in the GVB core, whereas GFP‐tagged tau or GFP alone do not, indicating selective targeting of cytosolic cargo to GVBs. In addition, GVB positive neurons have increased levels of stress related proteins.

Conclusion

We established the first in vitro model for GVB formation by seeding tau pathology in primary neurons. The tau‐induced GVBs have the marker signature and morphological characteristics of GVBs in the human brain. We show that GVBs are lysosomal structures that are distinguished by the accumulation of a characteristic subset of proteins in a dense core. Our data indicate that GVB containing neurons are in a state of enhanced cellular stress.
Exploring the effect of type 2 diabetes on brain structure and cerebral perfusion in patients with early Alzheimer’s disease
Authors: Dake Manmohi D , De Marco Matteo , Wilkinson Iain , Teh Kevin , Mitolo Micaela , Remes Anne , Liu Yawu , Pikkarainen Maria , Soininen Hilkka , Venneri Annalena
Published: December 2020

Background

Past research has shown that Alzheimer’s Disease (AD) can have a significant detrimental effect on the cerebrovascular system. Previous work has also indicated that type 2 diabetes mellitus (T2DM), along with being a risk factor for AD, shares certain similarities with AD in terms of the mechanisms affecting the cerebrovascular system. Hence, comorbid T2DM in AD could cause additional cardiovascular burden that may cause further damage to brain structure and function than that seen in AD.

Method

The current study compares 54 patients across the AD spectrum with and without T2DM (with 27 patients in each group). Voxel based morphometry was used to determine volumetric differences in grey matter using T1‐weighted magnetic resonance images. To assess whether these volumetric differences were associated with a reduction in cerebral blood flow, arterial spin labelling (ASL) was used to measure cerebral perfusion.

Results

Patients with T2DM had smaller grey matter volume compared to patients without T2DM in the anterior caudate nucleus and posterior cerebellum in the right hemisphere. Perfusion deficits mirrored the regional volumetric abnormalities, along with additional hypoperfusion observed in the right parahippocampal gyrus. These differences were also associated with deficits in cognitive function.

Conclusions

Microvascular and macrovascular complications seen in the AD patients with comorbid T2DM could therefore contribute toward the negative effects exerted on cerebral perfusion that could potentially contribute toward the structural deficits observed. Furthermore, the right lateralised effects seen in the present study could arise due to the characteristic trajectory of the arteries supplying the brain. With the increasing prevalence of cardiovascular risk factors such as T2DM combined with the rise in numbers of people living with AD, the additional cardiovascular burden caused by such risk factors may be a crucial tipping point toward conversion to AD dementia from prodromal stages. This is one of the first studies to show that the additional cerebrovascular burden resulting from comorbid T2DM in AD can result in worse structural and perfusion deficits using multi‐modal neuroimaging and that these deficits can be associated with clinical presentations.
Assessing and improving primary care physician confidence in the recognition of young‐onset and atypical dementia: A pilot intervention
Authors: Chiew Hui Jin , Choong Tanya‐Marie Yuen Oi , Chua Esther Vanessa , Mei Nyu Mei , Lim Linda Lay Hoon , Ng Kok Pin , Ng Adeline Su Lyn , Ting Simon Kang Seng , Hameed Shahul , Kandiah Nagaendran
Published: December 2020

Background

Young‐onset dementia (YOD) is defined as dementia with symptom onset below 65 years. The heterogeneous symptomatology of YOD can lead to delayed recognition and referral by primary care physicians (PCPs). Data from our tertiary referral centre in Singapore show that atypical presentations of YOD are more likely be referred and diagnosed at a later stage of disease than typical amnestic Alzheimer disease (AD) dementia.

Method

We piloted a structured, multimodal training programme to assess and increase the confidence of PCPs in the recognition of YOD and atypical dementia. The programme combined lectures, case studies and interactive workshops in 4 half‐day modules conducted between September 2019‐January 2020 (Module 1: clinical approach to cognitive impairment, overview of cognitive disorders and AD; Module 2: YOD, atypical and reversible causes of dementia; Module 3: cognitive assessment tools; Module 4: management of dementia, with a focus on YOD). Faculty included 6 cognitive neurologists and 4 dementia care nurses. 28 PCPs involved in dementia care in primary care memory clinics from all regions of Singapore were enrolled by invitation in mid‐2019. Prior to module 1, PCPs completed an anonymized questionnaire with 15 questions assessing their confidence in the recognition, diagnosis and management of YOD on a 5‐point Likert scale. An identical follow‐up questionnaire was administered upon completion of the programme.

Results

20 baseline and 20 follow‐up questionnaire responses were obtained. The PCPs had a mean of 1.93 (SD 2.10) years of dementia care experience. At baseline, they were significantly more confident in recognizing symptoms of typical elder‐onset AD (70% confident, 10% very confident) compared to YOD (30% confident) or atypical/non‐AD dementia (15% confident), (p<0.001). Upon programme completion, PCPs reported significantly increased confidence in recognition of YOD (70% confident, 15% very confident; p<0.001) and atypical/non‐AD dementia (75% confident, 10% very confident; p<0.001). These findings persisted even when stratified by years of dementia care experience.

Conclusion

A structured, multimodal training programme was effective in improving PCP confidence in the recognition of YOD and atypical dementia. Follow‐up assessment of PCP knowledge and longitudinal monitoring of referral trends will help to determine its long‐term efficacy.
Functional enrichment analysis of differentially expressed genes leads to dysregulation in biological processes networks in Alzheimer’s disease continuum
Authors: Ferreira Pamela C.L. , De Bastiani Marco Antônio , Bellaver Bruna , Povala Guilherme , Brum Wagner Scheeren , Ramos Vanessa G. , Bieger Andrei , Froehlich Pedro E , Zimmer Eduardo R.
Published: December 2020

Background

Reliable blood‐based biomarkers are of urgent need in Alzheimer’s disease (AD). In this context, whether changes in blood cells are present in AD remains unresolved. An interesting strategy to identify dysregulated biological pathways is the use of omics technologies, bioinformatic tools and, biological networks. Applying these contemporary techniques to blood samples of individuals in the Alzheimer's continuum may aid in understanding the periphery‐brain interface, providing the field with new pathophysiological insights and novel biomarkers. Here, we aim to investigate biological processes altered in peripheral blood cells across the Alzheimer's continuum. We hypothesized that blood transcriptomic profiles of mild cognitive impairment (MCI) and AD individuals will reflect changes in the brain.

Method

Whole blood transcriptomic profiles from 99 cognitively unimpaired (CU), 169 MCI and 48 AD individuals were obtained from the ADNI database. Afterward, we computed differential expression analyses between CU‐MCI and CU‐AD. Finally, differentially expressed genes (DEGs) (p‐value < 0.05) from each comparison were submitted to functional enrichment analysis (FEA) of Gene Ontology (GO) biological processes and pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

Result

Peripheral blood cells transcriptome analysis identified a total of 1232 DEGs for MCI and 1985 DEGs for AD patients. For MCI, FEA showed GO terms associated with energetic metabolism, lipid metabolism, and purines pathway (Figure 1A). For AD, GO terms are related to immune and inflammatory response and amino acid metabolism (Figure 1B). Curiously, DEGs are mainly downregulated in MCI but upregulated in AD patients.

Conclusion

Here, we demonstrate a prominent difference between blood transcriptomic profiles of MCI and AD individuals using FEA. Interestingly, the transcriptomic profile of MCI individuals presented changes in energetic metabolism, which is in line with the well‐established early cerebral glucose metabolism changes observed in the MCI stage. In AD individuals, more pronounced changes in immune and inflammatory processes were found, which also fits with the known late neuroinflammation peak verified in the AD stage. In summary, our findings indicate that blood transcriptomics may reflect aspects of pathophysiological brain events, offering a great opportunity for identifying new peripheral biomarkers and disease stage‐specific treatments.
Regulation of insulin transport across the blood‐brain barrier by CNS insulin receptor signaling
Authors: Rhea Elizabeth , Banks William A.
Published: December 2020

Background

Impairments in the regulation of central nervous system (CNS) insulin are clearly associated not only with metabolic syndrome and diabetes mellitus but also with Alzheimer’s disease (AD), age‐related cognitive decline, and mild cognitive impairment (MCI). Evidence exists for both decreased brain insulin levels and impaired brain insulin signaling (i.e., insulin resistance) as causes for this decreased insulin action. Insulin therapy can improve cognition in both healthy subjects as well as those suffering from cognitive impairments. While much of the focus in this area has been placed on overcoming CNS insulin resistance at the molecular level, we believe the impairment could lie at the blood‐brain barrier (BBB). CNS insulin is derived from the blood and crosses the BBB by a saturable transport system. Therefore, the insulin resistance observed in the CNS and at the neurovascular unit in these diseases could be a consequence of insulin deficiency and inadequate insulin BBB transport. Much focus has been placed on the peripheral mediators of insulin transport, with the direct role of the CNS often ignored. Therefore, the goal of this study was to investigate the communication of the neurovascular unit (NVU) in mediating CNS insulin levels in AD.

Method

We utilized the multiple‐time regression analysis technique to measure 125I‐insulin pharmacokinetics at the BBB. We were able to define the transport rate for 125I‐insulin and amount of vascular binding due to changes in CNS insulin receptor signaling. First, we inhibited CNS insulin receptor signaling by administering 1 μg S961 by intracerebroventricular (icv) injection. Second, we evaluated 125I‐insulin transport in mice lacking the insulin receptor in astrocytes.

Result

Acute, broad inhibition of the CNS insulin receptor following icv delivery of S961, a selective antagonist, led to decreased 125I‐insulin transport across the BBB that was sex specific in CD‐1 mice. Follow‐up studies revealed the astrocytic insulin receptor may be responsible for this decreased transport as mice lacking the insulin receptor in astrocytes, GFAP insulin receptor knock‐out (GIRKO) mice, also have decreased 125I‐insulin BBB transport.

Conclusion

These studies suggest the insulin receptor present on specific cell types within the CNS have a regulatory role in mediating insulin uptake by the brain.
Loss of biliverdin reductase‐a (BVR‐A) impairs beneficial effects of CNS insulin on brain energy metabolism favoring the development of Alzheimer's disease (AD) neuropathology
Authors: Lanzillotta Chiara , Tramutola Antonella , Di Domenico Fabio , Vasavda Chirag , Paul Bindu D. , Snyder Solomon , Butterfield D. Allan , Perluigi Marzia , Duarte Joao M.N. , Barone Eugenio
Published: December 2020

Background

Alterations of brain insulin signalling are a common pathophysiological mechanism leading to dementia in AD and Type 2‐Diabetes Mellitus (T2DM). These alterations are often associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration. Studies from our group identified impairment of BVR‐A – a regulator of insulin signalling – as an early event leading to insulin resistance in the brain. Here, we tested the hypothesis that reduced BVR‐A levels link failure of insulin signalling with mitochondrial stress resulting in AD neuropathology.

Method

Alterations of insulin signalling pathways, autophagic flux, total oxidative stress levels and AD neuropathology were analyzed in the hippocampus of 6‐month old wild‐type and the goto‐kakizaki (GK) model of T2DM rats. Hippocampal mitochondrial function was evaluated by measuring oxygen consumption rate (OCR), mitochondrial complexes, mitochondrial unfolded protein response (UPRmt) and oxidative stress levels. These data were correlated with peripheral metabolic measurements (fasting glucose, insulin and OGTT) and cognitive tasks (spatial memory). To confirm the role of BVR‐A, similar analyses were performed in the hippocampus of 2‐ and 6‐month old BVR‐A knock‐out mice. Additional mechanistic insights were gained by evaluating the response to insulin in Sh‐Sy5y cells lacking BVR‐A.

Results

GK rats displayed a diabetic phenotype and impaired spatial memory. Reduced BVR‐A levels along with IRS1 hyper‐activation and loss of Akt‐mediated inhibition of GSK3β were observed in the hippocampus, consistent with a regulatory role for BVR‐A. As result, hyperactive GSK3β accumulated in hippocampal mitochondria fostering their impairment characterized by reduced OCR and activation of UPRmt. Notwithstanding, reduced oxidative stress and pTau levels were observed in GK rats. BVR‐A KO mice displayed alterations of insulin signaling and mitochondrial function resembling those of GK rats with increased oxidative stress and pTau levels the adult mice. Loss of BVR‐A promoted an early protective response (UPRmt‐mediated) followed by a later general impairment (GSK3b‐mediated mitochondrial dysfunction, increased oxidative stress and pTau levels) in Sh‐Sy5y cells treated with insulin.

Conclusion

These results suggest that early BVR‐A loss impairs brain insulin signalling favoring mitochondrial stress mediated by hyper‐active GSK3β. These alterations lead to impaired energy metabolism and development of AD neuropathology.
Modeling the early accumulation of amyloid using differential equations in WRAP and BLSA
Authors: Vernhet Paul , Bilgel Murat , Durrleman Stanley , Resnick Susan M. , Johnson Sterling C. , Jedynak Bruno Michel
Published: December 2020

Background

Accumulation of beta‐amyloid plaques, an early hallmark neuropathology of Alzheimer’s disease (AD), begin more than a decade prior to the onset of clinical symptoms. Understanding the temporal progression of early amyloid accumulation is important for predicting who will become amyloid‐positive and when. Based on observations from several longitudinal amyloid positron emission tomography (PET) studies that the rate of overall amyloid burden is closely associated with baseline level of amyloid, we develop a formal mathematical model capturing this phenomenon and use it to (i) align temporal trajectories of amyloid accumulation across individuals, (ii) create a fine‐grained timeline of amyloid accumulation, and (iii) estimate the age at onset of amyloid positivity per individual.

Method

We used (PiB) PET scans from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and the Baltimore Longitudinal Study of Aging (BLSA) to assess global amyloid burden cDVR, see Figure 1. A first‐order autonomous model for the slope of cDVR as a function of cDVR was fit to the data. We used Bayesian modeling with a Gaussian process (GP) prior and independent homoscedastic noise.

Result

The best fit was obtained with a quadratic GP kernel (Figure 2). Since the system is autonomous, the trajectories are parallel and thus can be registered by translation. The progression of the Amyloid burden is thus visualized as a function of the time (in years) from PIB positivity in Figure 3. The estimated age when the PIB cDVR becomes positive is estimated. This age depends on APOE status, with a significant difference between the APOE groups [3,3] and [3,4]. p‐value=.008 in WRAP, p‐value=.054 In BLSA.

Conclusion

Large studies on aging allow studying the time‐progression of the amyloid burden. We found that an autonomous ordinary differential equation allows for a good explanatory model of the PIB‐DVR data in the WRAP as well as in the BLSA studies. Still, a few participants do not fit the data closely. It remains to understand if this is due to noisy measurements or to specific conditions. Also, alternative dynamical systems, including Hamiltonian, still need to be investigated and compared.