bluuebunny/crossref_metadata_2025 huggingface dataset:
An enriched environment improves cognitive impairment in an Alzheimer’s disease model by enhancing the secretion of exosomal miR‐146a from the choroid plexus
Authors: Nakano Masako
Published: December 2020

Background

An enriched environment (EE) is reported to prevent the cognitive impairment and ameliorate the pathologic changes in mouse models of Alzheimer's disease (AD), however the mechanisms have not been fully clarified. In this study, we examined whether an EE enhance the secretion of exosomal miRNA(miR)‐146a from the choroid plexus (CP) and ameliorate the pathologic changes in AD model.

Method

Male 5×FAD mice (B6.Cg‐Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax) which develop Aβ plaques in the brain and exhibit cognitive decline were used. At 3 months of age, these mice were divided into control cage (CC) or EE, then housed in either cage until 6 months old. Then, cognitive function was evaluated using Morris Water Maze (MWM) test and mice were sacrificed. In vitro experiments, the secretion of exosomal miR‐146a from CP epithelial cells were evaluated after stimulating of interferon (IFN)‐γ. In addition, we cultured hippocampal astrocytes and added 1 µM Aβ fibrils and 250 ng/ml lipopolysaccharide (LPS) to them to mimic the pathological change of astrocytes in AD. Then we transfected miR‐146a into Aβ/LPS induced inflammatory astrocytes to evaluate the effect of miR‐146a

Result

In MWM test, the cognitive impairment in 5×FAD mice was completely prevented by EE. In morphological study, EE ameliorated the expression of TNFα in astrocytes and increased the intensity of synaptophysin in the subiculum area of the hippocampus. In AD model mice treated with EE, increased levels of micro RNA (miR)‐146a and down‐regulation of NF‐κB were observed in the hippocampus. In addition, increased levels of IFN‐γ were seen in serum from mice exposed to an EE. In vitro, enhanced miR‐146a expression was observed in exosomes derived from the CP after IFN‐γ treatment. In further in vitro experiments, miR‐146a transfection ameliorated Aβ/LPS induced astrocytic inflammation by down‐regulating tumor necrosis factor receptor‐associated factor 6 and NF‐κB.

Conclusion

The secretion of exosomal miR‐146a from CP, that is enhanced by EE, is a key factor in ameliorating astrocytic inflammation, leading to synaptogenesis and correction of cognitive impairment.
“Bridge” project: An intergenerational approach with prototype games for young people and people with dementia
Authors: Tsolaki Magda , Makri Marina
Published: December 2020

Background

People with dementia (PwD) are often excluded from intergenerational social activities due to stigmatization. The generation gap is constantly widening while young people are losing their interest to participate in volunteering actions concerning elderly people. The Erasmus+ funded “Bridge” program is a 3 year pan‐European initiative that aims to develop a set of prototypes Serious Games (SGs) (physical, digital or phygital) acting on cognitive and behavioral symptoms of dementia, involving also younger and older people.

Method

A Methodological Guide related to Bridge's workshops methodology, key points for prototype SGs and e‐platform was developed. This step was followed by Co‐Creation Workshops in 3 countries, development of working games prototypes and finalization of 8 selected games. A second Implementation of Workshops will be organized in each country in order to figure out these results. The Bridge web‐platform (https://projectbridge.eu/), containing MOOCs on the methodology of the game‐creation workshops and the final 8 selected prototypes games will be the final result.

Results

In the Methodological Guide, the Bridge workshops and the game co‐design process is defined. In Greece (Alzheimer Hellas), Italy (Anziani e non solo) and Romania (Asociatia Habilitas), 24 PwD co‐designed and played several games in collaboration with 6 game‐designers, 16 healthcare professionals, 7 caregivers and 21 young volunteers. After the implementation of the workshops 11 prototypes of the games have been developed. The team project decided which of them can be the final 8 games for the Bridge platform, which have been refined through and digitalized. The final 8 prototypes games are: Next destination, flea market, find the word, bird‐watching, emotions, the directors, blooming flowers, speciatite.

Conclusion

The intergenerational workshops, in which PwD and young people create and use SGs, can narrow the gap between generations, decrease the stigma of dementia and promote civic participation of young people by developing the role of volunteering for social inclusion. This intervention and the final result of this program can create awareness and motivation about importance and possibilities of SGs as a tool for improving the quality of life of older people and their families and improve cognitive and behavioral dysfunctions of PwD.
Systematic review on the method and type of convergence study of Inertial Measurement Unit
Authors: Lee Hey Sig , Shin Ga‐In , Woo Ye‐Shin , Park Da‐Sol , Park Hae Yean
Published: December 2020

Background

The purpose of this study is to analyze trends in the method and type of Inertial Measurement Unit (IMU) by investigating studies on the type and method of convergence study of the IMU by systematic review.

Method

The study was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines.

Result

23 studies that meet the selection criteria were selected from 630 studies identified by three databases. As a result of this study, showed that various research using IMU was being conducted around the world, and the type of IMU was strap, full body suit, belt, wrist watch, shoes and glove. Among them, the number of strap‐type IMUs was the largest at 11. The IMU's strengths were simplicity, real‐time data collection and ease of application, which were used as measurement methods such as task, walking, and range of joint.

Conclusion

The result of this study is expected to be used as basic data for experts in the medical and rehabilitation fields that conduct IMU research.
Utility evaluation and radio‐pathological analysis of a tau tracer, 18F‐PI‐2620, in Alzheimer’s disease (AD) and non‐AD tauopathies
Authors: Tezuka Toshiki , Takahata Keisuke , Tabuchi Hajime , Ueda Ryo , Miura Eisuke , Okita Hajime , Takao Masaki , Mashima Kyoko , Kubota Masahito , Seki Morinobu , Yoshizaki Takahito , Nakahara Tadaki , Yamamoto Yasuharu , Sano Yasunori , Momota Yuki , Shiraiwa Mika , Shibata Mamoru , Jinzaki Masahiro , Mimura Masaru , Nakahara Jin , Ito Daisuke
Published: December 2020

Background

Tau aggregates are one of key pathological features of Alzheimer's disease (AD) and other neurodegenerative diseases. Recently, PET probes for tau have been developed for in vivo detection of tau accumulation, but have limitations such as off‐target binding and lower ability to detect tau in non‐AD tauopathies. Preclinically, a tau tracer, 18F‐PI‐2620, has a high binding‐affinity and specificity for aggregated tau, and was indicated to have desirable properties for visualization of tau accumulation in both AD and non‐AD tauopathies (Kroth H. et al, Eur J Nucl Med Mol Imaging, 2019). The aim of present study is to assess the ability of 18F‐PI‐2620 to detect regional tau burden in AD and non‐AD tauopathies.

Method

We recruited healthy volunteers (N=4, 64‐79 years old), patients with AD (N=4, 65‐80 years old), and with non‐AD tauopathies (three PSP cases and two CBS cases) (N=5, 65‐78 years old). One clinically diagnosed PSP case was pathologically confirmed as CBD after the autopsy. PET imaging with 18F‐PI‐2620 was performed, and its accumulation in the cortical and subcortical region were assessed by calculating standardized uptake value ratios (SUVR), along with amyloid PET using 18F‐flobetaben. Furthermore, a postmortem analysis for radio‐pathological correlation was performed in one CBD patient.

Result

In AD, focal retention of 18F‐PI‐2620 was apparent in the temporal, parietal, and cingulate cortex. SUVR analysis revealed that more prominent uptake in the globus pallidus (GP) and midbrain was observed in PSP, CBS, and CBD cases in comparison to AD cases, whereas such discrepancies were not apparent in other regions with expected four repeat (4R) tau accumulation. In a CBD case, radio‐pathological analysis failed to show a strong correlation between region‐matched 18F‐PI‐2620 retention in vivo and postmortem burden of tau (AT8 immunohistochemistry).

Conclusion

Although 18F‐PI‐2620 may be a promising tracer for tau in AD cases, in vivo retention of this tracer doesn't correlate with expected 4R tau burden in non‐AD tauopathies. 18F‐PI‐2620 may have limited utility for reliable detection of 4R tau pathology.
Optical coherence tomography angiography in cognitively impaired patients: Vascular and neurodegenerative perspectives
Authors: Lee Ju‐Yeun , Kim Jun Pyo , Jang Hyemin , Kim Jaeho , Kim Ji Sun , Jung Young Hee , Seo Sang Won , Na Duk L , Oh Sei Yeul , Lee Jong Min , Kang Sung Hoon , Kim Hee Jin
Published: December 2020

Background

Vascular and neuronal changes in the retina may reflect cerebral small vessel disease (CSVD) and neurodegeneration in the brain. We aimed to compare radial peripapillary capillary (RPC) network density and RNFL thickness between diagnostic groups using optical coherence tomography angiography (OCTA) imaging. Then, we evaluated whether the RPC network density correlated with CSVD markers and whether RNFL correlated with Aβ or brain cortical thickness.

Method

In this prospective, cross‐sectional, observational study, subjects were recruited from February 2018 to March 2019. Retinal vascular [Capillary density (CD) of the radial peripapillary capillary (RPC) network] and neurodegeneration markers [retinal nerve fiber layer (RNFL) thickness at four quadrants] were measured using optical coherence tomography (OCT) and OCT angiography (OCTA) imaging. Brain vascular (CSVD score), and neurodegeneration markers [brain cortical thickness] were assessed using 3D brain magnetic resonance imaging. We compared CD and RNFL thickness between ADCI, SVCI, and CN group. Then, we evaluated correlation between retinal imaging markers (CD and RNFL) and brain imaging markers (CSVD score and cortical thickness)

Result

The mean (SD) age of total 60 participants was 70.3 (9.0) years and 21 (35%) of them were male. The SVCI group showed lower CD in the temporal quadrant of RPC network compared to the CN group (mean (sd), 42.34 (6.29) vs 48.45 (7.08); p = 0.002), and lower CD in the superior quadrant of RPC network (mean (sd), 60.14 (6.42) vs 64.15 (6.39); p = 0.021) compared with the ADCI group. The CD was negatively correlated with CSVD score in the superior (regression coefficient, ‐0.050; 95% CI, ‐0.083 to 0.017; p=0.004) and temporal (regression coefficient, ‐0.042; 95% CI, ‐0.070 to ‐0.014; p=0.004) quadrants of the RPC network. RNFL thickness did not differ among the groups nor did it correlate with cortical thickness.

Conclusion

The importance of the CD of the RPC network rather than RNFL thicknesses should be highlighted in evaluating cerebral pathology. Moreover, noninvasive and rapid acquisition of OCTA images has the potential to be used as a peripheral imaging tool to screen for the degree of CSVD.
The effects of self‐management program for elderly with chronic illness in the community and its measurement
Authors: Shin Ga‐In , Park Hae Yean
Published: December 2020

Background

At present, there is an increasing number of studies that carry out self‐care programs for elderly people living in the community who have chronic illness.

Method

Databases used for study search were Google Scholar, RISS, and Dbpia. And research questions were selected based on the PICO framework. We searched the study published from January 2010 to September 2019 and selected the final six studies by applying inclusion criteria and exclusion criteria.

Result

The selected study had qualitative level of Level 1‐2. In general characteristics of the program, nurses conducted the most programs, and the program was operated for 50 elderly people or less. In addition, the program was conducted mainly in public health centers, senior centers. The subjects were the most studies for chronic patients with hypertension. The dependent variables of the program covered the cognitive domains in all the studies, and many of the studies measured the physical domains as the dependent variables.

Conclusion

This study provide the effectiveness of self‐management intervention for the elderly with chronic diseases living in the community, and highlight the need for the development of programs for chronic diseases in the community. In addition, this study suggests measuring tools related to various cognitive, physical, mental, social and quality of life of the elderly, and suggests the necessity of multidisciplinary research.
Association of plasma YKL‐40 with brain amyloidosis, memory performance, and sex in subjective memory complainers
Authors: Baldacci Filippo , Lemercier Pablo , Vergallo Andrea , Chiesa Patrizia Andrea , Zetterberg Henrik , Blennow Kaj , Potier Marie‐Claude , Habert Marie‐Odile , Cavedo Enrica , Caraci Filippo , Dubois Bruno , Lista Simone , Hampel Harald
Published: December 2020

Background

Neuroinflammation – a crucial early pathomechanistic alteration of Alzheimer's disease (AD) – may represent either a detrimental or a compensatory mechanism or both, based on the disease stage. YKL‐40, a glycoprotein highly expressed in human glia cells, is a candidate biomarker to in vivo track glial‐related neuroinflammation in AD. Few studies explored, in cognitively healthy individuals, the potential influence of key biological factors – age, sex, Apolipoprotein E (APOE) ε4 allele – on YKL‐40 plasma concentrations as well as its association with other AD pathophysiological mechanisms and cognitive scores.

Method

We assessed the cross‐sectional and longitudinal impact of relevant biological factors – sex, age, APOE ε4 allele – on YKL‐40. Moreover, we explored the cross‐sectional and longitudinal association of YKL‐40 with: 1) global/regional brain amyloid beta (Aβ) deposition using Aβ‐positron emission tomography (PET) imaging; 2) synaptic loss, using [18F]‐fluorodeoxyglucose‐PET ([18F]‐FDG‐PET); 3) neurodegeneration using magnetic resonance imaging (MRI), i.e. hippocampal, entorhinal cortex, and basal forebrain volumes. We also sought for the potential association between YKL‐40 and the degree of cognitive performance. The study was performed in the INSIGHT‐preAD cohort (N=314, M=114, F=200, aged 70 to 85), a large observational monocentric French academic cohort (Pitié‐Salpêtrière University Hospital, Paris) of individuals with subjective memory complaints (SMC), a condition at risk for AD. We used mixed models with interaction of YKL‐40 with time.

Result

Men displayed higher YKL‐40 concentrations than women at each time point investigated (b=0.171, t=2.434, P=0.015). YKL‐40 presented an age‐associated increase at each time point investigated (b=0.029, t=3.004, P=0.003). YKL‐40 was negatively associated with baseline Aβ deposition, at both global (b=‐0.025, t=‐1.992, P=0.047) and regional level. Besides, one‐year increase of YKL‐40 concentration was positively associated with memory performance, longitudinally (b=0.308, z=2.280, P=0.023). YKL‐40 showed no effect on synaptic loss or neurodegeneration.

Conclusion

Plasma YKL‐40 concentrations present an age‐associated increase with men showing higher levels than women, irrespective of the time point, thus indicating a potential sexual dimorphism in neuroinflammation. Moreover, the association of higher YKL‐40 concentrations with lower overall/regional cross‐sectional Aβ deposition and higher memory scores over time indicates a non‐clinical detrimental/potential protective effect of glia activation on incipient brain amyloidosis and synaptic network homeostasis.
How gender and sex influence clinical trial recruitment in Alzheimer's disease: Findings from Fundació ACE Barcelona Alzheimer Treatment and Research Center
Authors: Abdelnour Carla , Valero Sergi , Rosende‐Roca Maitee , Lafuente Asuncion , Hernandez Isabel , Tartari Juan Pablo , Santuccione Antonella , Ferretti Maria Teresa , Maguire Peggy , Buendía Mar , Pancho Ana , Tarraga Lluis , Benaque Alba , Gurrutxaga Miren , Ruiz Agustín , Boada Mercè
Published: December 2020

Background

FDA has made great efforts to promote inclusion of women in clinical trials. The aim is to protect specific biological gender and sex issues and encourage drug developers to consider specific clinical outcomes and drug‐safety profiles in terms of gender and sex. Alzheimer’s disease (AD) affects predominantly women, who double men in the number of patients diagnosed with dementia. Therefore, we explored gender and sex bias in the inclusion criteria for clinical trials in AD. Here our aim was to compare main inclusion criteria for clinical trials in MCI and dementia patients in terms of sex.

Method

Patients evaluated at FACE from 1996 to 2019 with CDR 0,5 to 2 were analysed. Then, we used the main inclusion criteria for AD clinical trials to compare the sample in terms of sex and syndromic diagnosis. The chosen variables were age, sex, education, comorbidities, treatment and MMSE score. Logistic regression analysis accounting for age, years of education, MMSE, treatment and comorbidities was used.

Result

From a total sample of 20,203 MCI and dementia patients, we selected potential candidates for clinical trials with complete information regarding age, age, years of education, MMSE, comorbidities and treatment. After adjusting for age, years of education, MMSE, comorbidities and treatment, in the dementia sample only age and years of education showed statistically significant differences. Whereas in the MCI sample: age, years of education, treatment and comorbidities showed statistically significant differences (Tables 1 and 2)

Conclusion

Women with MCI and dementia are less likely to participate in a clinical trial due to older age and less years of education than men. Another factor that prevent women for participating in clinical trials is their comorbidities when compared to men, whereas men are excluded due to treatment criteria more often than women. These results show that there is a pre‐selection bias against women in AD clinical trials because of demographic characteristics. Therefore, participation of women in clinical trials does not reflect the prevalence of AD among women and is not representative of reality. Efforts should be made to provide equal opportunities to potential clinical trials candidates regardless of gender.
Aging and sex impact plasma NFL and t‐Tau trajectories in individuals at risk for Alzheimer’s disease
Authors: Baldacci Filippo , Lista Simone , Manca Maria Laura , Lemercier Pablo , Chiesa Patrizia Andrea , Zetterberg Henrik , Blennow Kaj , Potier Marie‐Claude , Habert Marie‐Odile , Cavedo Enrica , Dubois Bruno , Vergallo Andrea , Hampel Harald
Published: December 2020

Background

Neurofilament light (NFL) chain and total Tau (t‐Tau) proteins are established biomarkers of axonal degeneration. Increased plasma concentrations of both proteins are associated with worsening rate of cognitive performance, cerebral atrophy, and hypometabolism in prodromal and dementia phases of Alzheimer’s disease (AD). Few studies explored, in cognitively healthy individuals, the potential influence of key biological factors – age, sex, Apolipoprotein E (APOE) ε4 allele – on NFL and t‐Tau plasma concentrations as well as their association with comorbidities, brain amyloid beta (Aβ) deposition, and cognitive scores.

Method

The ultrasensitive SiMoA platform was used to measure plasma NFL and t‐Tau concentrations at three time points (baseline: N=316; one‐ and three‐year follow‐up: N=79) in the INSIGHT‐preAD cohort, a large observational monocentric French academic cohort (Pitié‐Salpêtrière University Hospital, Paris) of individuals with subjective memory complaints (SMC), a condition at risk for AD.

Result

Age affected plasma NFL concentrations (P<0.001). Sex influenced plasma t‐Tau (P=0.003), with females showing a higher concentration increase than males, across the three time points. A significant effect of sex*age interaction was also reported (P=0.038). No effect of APOE ε4 was found on either NFL or t‐Tau. Plasma vitamin B12 deficiency was associated with increased t‐Tau concentrations. Plasma NFL significantly increased at one‐year (P=0.007) and three‐year (P<0.001) follow‐up versus baseline. Plasma t‐Tau significantly increased at three‐year follow‐up (P=0.004) versus baseline. Plasma NFL was associated with plasma t‐Tau (P=0.011) and cerebrospinal fluid NFL (P<0.001) concentrations, at baseline. Baseline plasma NFL was associated with increased Aβ deposition rate, at two‐year follow‐up, in the left posterior cingulate (P=0.019) and the bilateral inferior parietal gyri (P=0.013). Baseline plasma NFL and the rate of change of plasma t‐Tau were inversely associated with cognitive score (P=0.029 and P=0.015, respectively).

Conclusion

Age and female sex affect plasma NFL and t‐Tau longitudinal trajectories, respectively, in SMC individuals. Exploring the impact of biological variables on AD biomarkers is crucial for their clinical validation in blood. Moreover, there is a potential effect of plasma NFL concentrations on brain amyloid plaques deposition.
White matter lesions are associated with CSF biomarkers of neuroinflammation in prodromal Alzheimer’s disease
Authors: Gertje Eske Christiane , Janelidze Shorena , van Westen Danielle , Palmqvist Sebastian , Hansson Oskar , Mattsson Niklas
Published: December 2020

Background

Previous studies have shown that cerebrospinal fluid (CSF) levels of different biomarkers of neuroinflammation and cerebrovascular dysfunction are increased in Alzheimer’s disease (AD), even during its preclinical and prodromal stages. However, little is known about associations between inflammatory markers and signs of cerebrovascular injury such as white matter lesions (WML) detected with magnetic resonance imaging (MRI) so far.

Method

582 cognitively unimpaired (CU) elderly and 279 patients with mild cognitive impairment (MCI) from the Swedish BioFINDER cohort were included. CSF samples were analyzed for interleukin (IL)–6, IL‐7, IL‐8, IL‐15, IL‐16, interferon‐gamma induced protein‐10 (IP‐10), monocyte chemoattractant protein 1 (MCP1), intercellular adhesion molecule 1(ICAM‐1), vascular adhesion molecule 1 (VCAM‐1), placental growth factor (PIGF), and fms‐related tyrosine kinase 1 (Flt‐1) as well as vascular endothelial growth factor (VEGF). WML volumes were determined from MRI for all subjects.

Result

More WML was associated with higher levels of IL‐6 (β=0.311, p=0.002), higher levels of IL‐8 (β=0.001, p=0.001), higher levels of PIGF (β=0.007, p<0.001), lower levels of sFLT1 (β=‐0.017, p<0.001) and higher levels of VEGF (β=0.092, p<0.001) in all patients. In the CU group more WML was associated with higher levels of PIGF (β=0.007, p<0.001) and lower levels of sFLT1 (β=‐0.018, p<0.001), whereas in MCI more WML volume was associated with higher levels of IL16 (β=0.118, p<0.001), higher levels of PIGF (β=0.007, p<0.001), and higher levels of VEGF (β=0.105, p=0.003). The associations with PIGF were seen independent of beta‐amyloid‐status. However, the other associations were mainly seen in beta‐amyloid‐negative subjects (N=179 CU and N=164 MCI). Associations were still significant after corrections for multiple comparisons. No associations were found between WML volume and IL‐7, IL‐15, IP‐10, MCP1, ICAM‐1, and VCAM‐1.

Conclusion

Neuroinflammation is associated with cerebrovascular injury in prodromal stages of AD, especially the markers of the VEGF family widely expressed in the vascular system.
Cognitive decline and cerebral vasoreactivity in asymptomatic patients with severe internal carotid artery stenosis
Authors: Marijana Lisak Marijana , Špiljak Bruno
Published: December 2020

Background

The aim of the study was to correlate cognitive decline and cerebral vasoreactivity in 150 asymptomatic right‐handed patients with severe ≥70 % unilateral internal carotid artery (ICA) stenosis and to evaluate the role of intracranial collateral circulation during cognitive testing.

Methods

Cognitive assessment was performed by means of Montreal Cognitive Assessment (MoCA) and Mini Mental State Exam (MMSE) scales. Cerebrovascular reactivity (CVR) and intracranial collateral circulation were evaluated by means of breath holding index (BHI) and transcranial color Doppler (TCD) sonography.

Results

The results were compared with 150 right‐handed controls matched for demographic variables and vascular risk factors. Patients with severe unilateral ICA stenosis had MMSE scores within a normal range, but MoCA scores were lower than normal. By examining the side of the observed stenosis, it has been noted that patients with left‐sided ICA stenosis had lower MoCA scores in categories of language and episodic memory performance, while patients with right‐sided ICA stenosis had lower MoCA scores in a category of visual–spatial skills. All patients had BHI values lower than normal. Subjects with a single intracranial collateral artery recruited had slightly better cognitive results than the patients with two or more collateral arteries activated.

Conclusions

Results of the study showed that altered cerebrovascular reactivity and cerebral hypoperfusion might be responsible for the reduction of specific cognitive functions ipsilateral to the ICA stenosis, therefore BHI and MoCA might be useful tools when screening for cognitive decline in asymptomatic patients with severe ICA stenosis.
Screening for gene mutation in early onset Alzheimer’s disease and frontotemporal dementia: Report from a Serbian tertiary referral center
Authors: Stojmenovic Gorana Mandic , Stefanova Elka , Novakovic Ivana , Dobricic Valerija , Stojkovic Tanja , Kostic Vladimir S.
Published: December 2020

Background

Early‐onset dementia (EOD) is conventionally considered to include patients with disease onset before 65 years of age. Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) are two most common forms of degenerative EOD. Our aim was to screen for known gene mutation status in consecutive degenerative EOD patients.

Method

Two hundred and eight consecutive patients diagnosed according to the current clinical criteria for AD and FTD spectrum were recruited from the Neurology Clinic, Clinical Centre of Serbia from 01.04.2012. until 01.04.2017. Patient from AD spectrum were tested for APP, PSEN1, GRN, MAPT and C9ORF72 gene mutation and FTD patients for GRN, MAPT, C9ORF72, VCP, ANG gene mutation.

Result

Gene mutations were identified in 3.9% of our AD patients: 2.3% patients had mutations in the PSEN1 gene and 1.5% patients in the APP gene. There was no MAPT, GRN and C9ORF72 mutations carriers in our AD cohort. Genetic mutations have been demonstrated in 10.3% of patients with FTD. The most frequent was the hexanucleotide expansion in C9ORF72 (6.4% of all FTD patients), following mutations in GRN, VCP and ANG with the same frequency of (1.3% FTD for each gene). No patient was a MAPT mutation carrier.

Conclusion

Gene mutations were rare causes in our AD cohort. The frequency of carriers was higher in FTD patients‐ mutations were identified in C9ORF72, GRN, VCP and ANG genes. No MAPT mutation carriers were identified in our cohort of patients with degenerative EOD.
Ultrasensitive blood biomarkers to predict cognitive decline and diagnose Alzheimer’s disease in the absence of AT(N) classification as the reference standard
Authors: Simrén Joel , Leuzy Antoine , Karikari Thomas K , Hye Abdul , Mattsson Niklas , Hansson Oskar , Schöll Michael , Mecocci Patrizia , Vellas Bruno , Tsolaki Magda , Kloszewska Iwona , Soininen Hilkka , Lovestone Simon , Aarsland Dag , Westman Eric , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J ,   AddNeuroMed Consortium
Published: December 2020

Background

In recent years, blood biomarkers for Alzheimer’s disease (AD) have attracted much interest. Technological advances have allowed quantification of markers for neurodegeneration (NfL), neurofibrillary tangles (p‐tau181) and amyloid‐β pathology (Aβ42, Aβ42/Aβ40), which perform well in cohorts stratified by cerebrospinal fluid and positron emission tomography (PET) biomarkers. Here, we aimed to investigate i) the diagnostic performance of blood biomarkers in the absence of CSF/PET modalities; ii) how these markers change longitudinally and relate to cognitive decline.

Methods

We evaluated cross‐sectional data for 307 participants (100 cognitively unimpaired (CU, Clinical dementia rating (CDR) score = 0) elderly and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) (CDR=0.5) and 106 AD dementia (CDR>0.5)) from the European multicentre AddNeuroMed cohort. 237 participants (76 CU, 161 CI) had longitudinal plasma biomarker and cognitive data (MMSE). Single molecule array (Simoa) assays were performed for NfL, t‐tau, Aβ42, Aβ40 and GFAp (all time‐points, single batch). P‐tau181 was measured using an in‐house Simoa assay. Cross‐sectional analyses were conducted using a generalized linear model for age‐adjustment, an ANOVA to compare biomarkers across groups, and correlation analysis to examine biomarker concentrations in relation to MMSE. Longitudinal analyses were performed using linear mixed models.

Results

At baseline, neuronal and astrocytic biomarkers were increased (p‐tau181, NfL, t‐tau, GFAp; P<0.001), whilst the amyloid marker (Aβ42/Aβ40 ratio) was decreased (P<0.001) in AD compared with CU. Significant differences were also observed between AD and MCI for p‐tau181, Aβ42/Aβ40, GFAp (P<0.001) and NfL (P<0.05). P‐tau181 (P<0.001) and NfL (P<0.05) were increased in MCI compared with CU. ROC curves revealed high accuracy for p‐tau181 in separating AD from CU (AUC=0.921) and MCI (AUC=0.816), and in separating CU from CI (AUC=0.843). Linear mixed models showed increases in all five measures in both CU and CI subjects; when assessing change in MMSE, the strongest associations were seen for GFAp in CU (standardized‐β=‐0.27, P<0.001) and for p‐tau181 in CI subjects (standardized‐β=‐0.34, P<0.001).

Conclusion

These results suggest that blood biomarkers have diagnostic potential for AD in the absence of AT(N) classification, and that longitudinally, levels of p‐tau181 have potential as a biomarker of cognitive decline.
Molecular events regulating axonal structure and function during injury
Authors: Devoto Victorio Martin Pozo , Lacovich Valentina , Carna Maria , Feole Monica , Texlova Katerina , Stokin Gorazd Bernard
Published: December 2020

Background

Axonal swellings (AxS) are focal enlargements of axons found in a range of biological and pathological settings, including traumatic brain injury. However, the development of AxS and their effects on axonal homeostasis are poorly understood. Here, using a novel in vitro experimental paradigm we describe cytoskeletal and molecular events responsible of AxS formation and its consequences to axonal homeostasis.

Method

Human neuronal progenitor cells were seeded into microfluidic chambers and terminally differentiated to neurons. In these chambers, axons grow into microchannels, which are crossed by a perpendicular channel that is connected to a syringe pump. A negative flow caused by the syringe pump subjects axons to bending stress. After full characterization of the axonal response to the stress, we established a protocol that causes injury without reaching axotomy. Detailed morphometric and structural analysis were performed to validate axonal injury.

Result

Structural analysis of the AxS showed disarrangement of microtubules and neurofilaments, with a disrupted periodicity of Actin and BII‐Spectrin rings underlying the axolemma. The functional impact of these changes was evidenced by the significant dysregulation observed in the axonal transport of APP vesicles during and after injury. Axonal membrane and calcium levels changes were analysed in real‐time, showing an increase in calcium levels that was concomitant to the formation of focal membrane enlargement. To understand the main source of axoplasm calcium increase during injury, extracellular and different intracellular stores of calcium were blocked. Activation of CaMKII derived from the local increase of Ca in the axon can lead to the regulation of multiple targets. We reasoned that myosins (one of CaMKII targets) could be regulating axolemmal changes by exerting a contraction force on the actin rings underlying the axolemma. By pharmacological and molecular intervention we uncover a physiological role of myosins in the regulation of the axonal shaft structure and the AxS formation.

Conclusion

We created a unique cell culture paradigm to study the response of axons to physical injury and provide novel insight into mechanisms responsible for axonal shaft structure and the formation of AxS.
An hiPSC‐based genetic screening system to model aggregation of tau protein allows the identification and validation of possible targets for Alzheimer’s disease therapies
Authors: Reinhardt Peter , Guillen Nathalie , Untucht Christopher , Ried Janina S. , Manos Justine , Geist Daniela , Korffmann Juergen , Cik Miroslav , Lakics Viktor
Published: December 2020

Background

One of the hallmarks of Alzheimer's Disease (AD), as with some other neurodegenerative diseases, is the misfolding and aggregation of proteins, such as amyloid‐beta and tau. Tau pathology is also believed to propagate trans‐synaptically from neuron to neuron. Either prevention of propagation, or the removal of aggregated tau, is a potential approach for AD modification.

Method

Deubiquitinating enzymes (DUBs) maintain ubiquitin homeostasis by removing ubiquitin modifications from target proteins, thereby altering protein function, stability, and signaling. We hypothesize that the modulation of the ubiquitin‐proteasome system with DUB inhibitors will lead to decreased tau aggregation either directly (by inhibiting the removal of ubiquitin from tau thereby increasing its degradation) or indirectly (via modulation of other relevant pathways, like autophagy). To select relevant DUBs, we developed a phenotypic assay to assess the effect of knocking down ∼100 DUBs on the clearance of tau aggregates in hiPSC – derived neurons, assayed using high content image analysis.

Result

We show that addition of recombinant tau seeds to hiPSC – derived cortical neurons expressing a fluorescent tau reporter construct, leads to formation of tau aggregates, which we can robustly and reproducibly reduce by knocking down specific DUBs.

Conclusion

The DUB enzymes revealed in our phenotypic screen have been validated in confirmatory studies and have the potential to become novel targets for the treatment of AD. In collaboration with Mission Therapeutics we will develop selective, potent DUB inhibitors for preclinical target validation.
What older adults do with results from a community‐based dementia screening program
Authors: Galvin James E , Tolea Magdalena I , Chrisphonte Stephanie
Published: December 2020

Background

Alzheimer’s disease and related dementias (ADRD), and mild cognitive impairment (MCI) are often under‐recognized in the community. Primary care providers are often responsible for the detection, diagnosis, and treatment of ADRD as the number of dementia specialists are not sufficient to meet the growing demands. MCI/ADRD screening could offer benefits such as early treatment, research participation, lifestyle modification, and advanced care planning. To date, there are no clear guidelines regarding the benefits vs. harms of dementia screening or what individuals who completed screening will do with their results.

Methods

A community‐based study was conducted to evaluate acceptability of MCI/ADRD screening, and how older adults would make use of the results and information provided to them. Measures of cognition, physical health, functionality, and mood were collected. Participants met with a health professional, were given screening results with recommendations, and then contacted 60 days later to determine what was done with the results.

Results

Participants (n=288) had a mean age 71.5+8.3y, mean education 13.3+4.8y, and were 70% female, 67% White, 26% Black, 48% Hispanic. After 60 days, 75% of participants were contacted; 54% shared results with family, 32% shared results with health care providers (HCPs), and 52% initiated behavioral change. Among participants sharing results, 51% reported HCPs did not follow‐up on the results, and 18% HCPs did not show any interest in the screening. Behavioral changes included lifestyle modification (58%), social engagement (10%), cognitive stimulation (5%) and advanced care planning (4%). Predictors of behavioral change were lower comorbidities (OR=0.62, 95%CI:0.39‐0.96), higher A1C (OR=3.24, 95%CI:1.32‐7.95), poorer self‐perceived emotional health (OR=4.67, 95%CI:1.17‐18.67) and increased age (OR=1.14, 95%CI:1.01‐1.29).

Conclusion

MCI/ADRD screening was well‐accepted in a diverse community sample. Participants showed interest in sharing the results with their family and HCPs and many attempted behavioral change. While HCPs did always not act on screening results, 25% ordered further testing and evaluation. Future efforts are needed to (1) increase self‐efficacy of older adults to discuss screening results with their HCPs, and (2) educate HCPs on the value of early detection of MCI/ADRD. Community dementia screening programs can increase MCI/ADRD detection, improving patient‐centered outcomes and medical decision‐making.
Functional changes and expression of inducible NO synthase in dentate gyrus of rats during modeling of depression and the possibility of their pharmacological correction
Authors: Ekova Maria , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich , Volotova Elena
Published: December 2020

Background

Depression is seen as the most common cause of disability, and is associated with chronic stress and neuroinflammation. The signaling pathway for the synthesis of nitric oxide plays a crucial role in the neurobiology of mild stress and depression.

Methods

3 groups were formed: group 1 — control rats (n = 10), group 2 — rats with experimental depression (n = 10), group 3 — rats with experimental depression (n = 10) receiving a compound with the laboratory cipher RSPU‐189 (salifen). The depressive state in animals was caused by exposure to stressful stimuli such as vibration, loud sound and pulsating bright light for 7 days (daily for 30 minutes). The experiment used rats at the age of 12 months. We evaluated the neuropsychiatric state of animals and expression of iNOS in the dentate gyrus.

Results

In animals of the 2 group, symptoms of depressive behavior were observed, having a pronounced phenomenological similarity to the clinical picture of depression: anxiety, behavioral correlates of despair, inactivity, anhedonia, as well as a decrease in tentative research activity. The use of salifen in rats of group 3 leveled these changes. When evaluating the results of immunohistochemical studies in rats with experimental depression, in contrast to animals of the control group, an increase in the expression level of iNOS‐IRM in granule cells and neuropil in inner polymorphic layer of dentate gyrus was noted. Pharmacological correction of experimental depression by salifen showed a decrease in the expression of iNOS‐IRM to values close to the expression level in the control group of animals.

Conclusions

When modeling a depressive state in rats of adulthood, an increase in iNOS expression in dentate gyrus is observed, the use of salifen leads to the correction of revealed changes, which may be associated with GABAergic modulation of neurotransmission in the hippocampus. The reported study was funded by RFBR and Administration of Volgograd region according to the research project № 19‐415‐340004∖19.
Neuropsychiatric symptoms correlated with functional trajectories among people living with Alzheimer’s disease dementia and Lewy body dementia
Authors: Borda Miguel German , Aarsland Dag , Oppedal Ketil , Giil Lasse Melvær , Vik‐Mo Audun Osland , Alves Guido , Tovar Diego , Gonzalez Maria Camila , Brønnick Kolbjørn
Published: December 2020

Introduction

Functionality is one of the most important markers of wellbeing in older adults. People with dementia lose functionality mainly because of cognitive impairment. However, little has been outlined regarding the independent association of Neuropsychiatric symptoms (NPS) on functional decline in this population, especially in those diagnosed with Lewy body dementia (LBD). The aim of our work is to study the association of NPS at time of dementia diagnosis and 5‐year longitudinal course with the 5 years’ trajectory of functional decline in people with Alzheimer´s disease (AD) and LBD.

Methods

This is a secondary analysis of the Dementia Study of Western Norway (DemWest) including a total of 196 patients with newly diagnosed AD (n=111) and LBD (n=85). Baseline information on NPS was obtained using the Neuropsychiatric Inventory (NPI), and activities of daily living (ADL) was assessed yearly during five years using the rapid disability rating scale (RDRS). The longitudinal functional trajectories were analyzed using linear mixed modeling, adjusting by Age, cognition, sex and comorbidity.

Results

Total NPI score at diagnosis was associated with functional decline for AD (Est 0.007 SE 0.002 p‐value 0.0014) but not for LBD (Est 0.002 SE 0.003 p‐value 0.4258). NPI score longitudinal course was associated with the functional decline trajectory in AD (Est 0.004 SE 0.001 p‐value 0.0002) and LBD (Est 0.005 SE 0.002 p‐value 0.0070).

Conclusion

NPS independently predicted the rate of functional decline in people with AD and LBD despite their cognitive status. These results highlight the relevance of early detection and intervention of NPS, which may also reduce functional decline.
Diffusion tensor imaging (tractography) in elderly people with mixed dementia and mild Alzheimer's disease
Authors: Mimenza Alberto Jose , Navarro Sara Gloria Aguilar , Albán Paulina Bombón , Samudio Alejandra , Ortega Jhonatan Ruvalcaba , Meléndez Oscar Marrufo , Funes José A Avila
Published: December 2020

Background

Cerebral tractography is a Magnetic Resonance Imaging technique that allows you to visualize the white matter fascicles that connect different parts of the brain. It is based on the diffusion of water in biological tissues, through which fiber tracts are evaluated in a three‐dimensional space, which allows to obtain the Anisotropy Fraction (FA) and Medium Diffusivity (DM). Tractography allows correlating the integrity of these pathways with cognitive function. The objective of our study was to identify anatomical regions with alterations in AF in mixed dementia compared to AD.

Method

16 patients were included; 8 with Mixed Dementia (DMix) and 8 with Alzheimer's Disease (AD). Mean, standard deviations and frequencies were used, as well as Chi‐square and Mann‐Whitney tests. A linear regression model was used to determine the association between Tractography and performance in cognitive domains, adjusted for age and educational level.

Results

The mean age of the participants was 85 ± 7.9 years (p ≤.57), 69% were women (p ≤.10) and the educational level was 11 ± 6.0 years (p ≤.87). Participants with AD had a worse cognitive performance (NEUROPSI: 68.5 ± 11.6 points, p ≤.02) compared to the DMix group. When analyzing by cognitive domains, patients in the DMix group had a worse performance in phonological verbal fluency (7.0 ± 3.5 words, p ≤.05). Regarding neuroimaging, significant differences were observed in participants with DMix in the Anisotropy Fraction (AF) in the following tracts: right cerebral peduncle (0.5557 ± 0.0121, p ≤.05), left cerebral peduncle (0.5476 ± 0.0121, p ≤0.01), right external capsule (0.3346 ± 0.0163, p ≤0.01) and left cingulate gyrus (0.3756 ± 0.0241, p ≤0.05) and mean diffusivity in the right thalamic posterior radiation (0.0010 ± 0.0000, p ≤ 0.03) and left external capsule (0.0012 ± 0.0001, p ≤0.03).

Conclusion

Tractography allows quantifying and differentiating anatomical regions with myelin damage in mixed dementia compared to AD.
Effects of cognitive rehabilitation intervention based on sensory activities on the perception, depression, and quality of life of the elderly with dementia in a care facility
Authors: Lee Hey Sig , Yang Min Ah
Published: December 2020

Background

We want to find out how the intervention of cognitive rehabilitation group programs based on sensory activities can affect the cognitive function, depression and quality of life for the elderly with dementia living in the facility.

Method

In this study, the cognitive rehabilitation group program based on the sensory activity of 20 cycles is applied to 10 the elderly with dementia facility to determine if it is effective by pre‐ and post‐evaluation of cognitive function, depression and quality of life. Cognitive function is evaluated as MMSE‐DS, depression as S‐GDS‐K, and quality of life as WHOQOL‐BREF.

Result

As a result of this study, the MMSE‐DS score increased by 3.20, the S‐GDS‐K score decreased by 4.32, and the WHOQOL‐BREF score increased by 7.05.

Conclusion

Therefore, sensory activity‐based cognitive rehabilitation programs are effective for the elderly with dementia living in the facility.
Finding a novel method to understand the role of salivary exosome in progression of cognitive impairment to Alzheimer's disease
Authors: Rastogi Simran , Rani Komal , Nikolajeff Fredrik , Kumar Saroj
Published: December 2020

Background

Cognitive impairment is an prominent aspect of aging and a common accomplice of dementia. Majority of dementia cases are dictated by Alzheimer’s disease (AD) pathology. There are many neuroimaging and molecular biomarkers to differentiate between cognitive impairment and dementia however, these are either invasive or expensive; also, for a patient without any cognitive complain, it is impractical to use these as an early diagnostic tool. Currently, extra‐cellular vesicles like exosomes are widely researched as they carry signals of disease pathology in there protein cargos. Its release and uptake in case of Parkinson’s and AD is already explored. In this study, we have demonstrated a novel method: nanoparticle tracking analysis to investigate how salivary exosomes concentration can elucidate the correlation between CI and AD and that could open a new way for early and cost‐effective screening of this disease.

Method

The exosomes were isolated from saliva using chemical precipitation. Total salivary exosomes concentration was measured by nanoparticle tracking analysis followed by exosomal cargo protein validation through automated western blot system using amyloid‐beta (Aβ) oligomer, monomer, phospho‐tau antibody.

Result

The exosome were validated using electron microscopy and exosomal surface marker CD63 [Figure 1 A & B] and its neuronal origin through, CD171 antibody [Figure 1 C]. We observed a significant difference in salivary exosomal concentration in cognitively impaired and AD patients (p=0.0001) [Figure 1 D] compared to age matched healthy control using NTA. We further validated and correlated our NTA findings by observing the protein expression level of oligomer Aβ, p‐tau. The Aβ oligomer/fibril abundance (p=0.0291) [Figure 2 A, B, C], p‐tau (p=0.0325) [Figure 2 D, E] and Aβ protein abundance (p=0.0198) [Figure 2 F, G] was significantly high in AD and CI patients in comparison to healthy control.

Conclusion

We demonstrated for the first time that the salivary exosome concentration as well as the expression level of hallmark proteins is higher in cognitively impaired and AD patient than healthy control as well is in accordance with the disease severity staging. This study has a potential to be developed as an early, cost‐effective screening method for detection of disease severity stage.