bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic screening of ANXA11 in Korean patients with Frontotemporal dementia syndrome
Authors: Kim Eun‐Joo , Ki Chang‐Seok , Kim Seung Hyun , Na Duk L , Seo Sang Won , Kim Hee Jin , Jung Na‐Yeon , Lee Sun Min , Moon So Young , Park Kyung Won , Kim Young‐Eun
Published: December 2023

Background

Pathogenic variants of ANXA11 have recently been identified in patients with ALS and ALS‐FTD in ALS cohorts. However, it is uncertain how prevalent the pathogenic variant of ANXA11 is in FTD syndrome. Thus, we performed genetic screening of ANXA11 in Korean patients with FTD to investigate the frequencies and clinical manifestations of ANXA11 mutations in Asian FTD population.

Method

We searched pathogenic variants of ANXA11 in whole exome database of Korean patients with FTD syndrome. Out of a total of 240 patients, 179 patients had been included in the previous Korean FTD genetic screening studies and the rest 61 patients have currently been enrolled in an ongoing longitudinal study of early onset dementia and family members‐FTD (LEAF‐FTD).

Result

One pathogenic variant in ANXA11, c.119A>G (p.D40G), was identified in three patients with right‐predominant svPPA. One of them has recently been reported elsewhere. They were all women and mean age of onset was 63 years old. Two of them had family history of dementia in first‐degree relatives. One patient showed dysarthria and motor weakness 3 years after the onset of symptoms who might have been presumed to have svPPA‐ALS, while the other two had no neurological deficits. Initial neuropsychological test results revealed selective impairments of naming and verbal memory. Brain MRIs demonstrated cortical atrophy in bilateral anterior temporal areas, worse on the right. One patient carried a pathogenic variant, p.V180I of PRNP as well as p.D40G of ANXA11, however, did not show any clinical features of CJD. Other than p.D40G variant, we found two variants of unknown significance of ANXA 11 in one patient with nfvPPA (c.1336‐6C>G) and the other with bvFTD (c.654G>A, p.T218 = ).

Conclusion

ANXA11 mutations account for 0.8% of familial and 1.7% of sporadic ALS in European populations. The p.D40G variant identified in this study (1.25%, 3/240) had already been reported in both familial and sporadic ALS. Although the phenotypic variation of ANXA11 in FTD or FTD‐ALS syndrome remains unclear, our results suggest that right‐predominant svPPA may be a common FTD or FTD‐ALS manifestation in p.D40G variant. Further genetic screening of ANXA11 in Caucasian FTD cohort is needed.
Behavioural Deficits and Regional Cerebral Perfusion Map in Cognitively Normal and Pre‐Dementia Stages
Authors: Vipin Ashwati , Soo See Ann , Zailan Fatin Zahra , Leow Yi Jin , Kumar Dilip , Lee Faith Phemie Hui En , Ghildiyal Smriti , Kandiah Nagaendran
Published: December 2023

Background

Our previous work has shown increased presence of early behavioural impairment in Asian than Western cohorts(Soo et al.,2021). Such impairments include mild behavioural changes, sleep disruptions and higher depression, anxiety and stress, in turn representing an at‐risk state which may predict later development of dementia(Müller‐Spahn,2003;Soo et al.,2021). Additionally, growing evidence illustrates that cerebrovascular changes are a key component in the pathological sequelae and may be detectable years before clinical presentation of dementia (de la Torre,2018). However, the influence of cerebral perfusion on behaviour, especially in pre‐dementia stages remains to be elucidated. Thus, we examined the association between regional grey matter perfusion and behaviour in cognitively normal(CN) and subjects with mild cognitive impairment(MCI) or subjective cognitive decline(SCD). We hypothesized that grey matter perfusion deficits would be related to behaviour impairment even in early stages of SCD/MCI.

Method

We studied 35 CN and 248 pre‐dementia (MCI/SCD) from a community‐based research cohort from the Dementia Research Centre (Singapore) with neuroimaging, neuropsychological and behavioural assessments(Table 1). We investigated the association between regional grey matter perfusion across 31 regions of interest spanning frontal, parietal, temporal and occipital lobes using 2D pulsed Arterial Spin Labelling and performance on the mild behaviour impairment‐checklist(MBI‐C), Pittsburgh Sleep Quality Index(PSQI) and Depression, Anxiety and Stress Scale(DASS). These associations were examined in CN and MCI/SCD groups separately and respective Pearson’s correlation matrices were derived.

Result

Overall, greater behavioural impairment on the MBI‐C, DASS and PSQI was associated with hypoperfusion across multiple grey matter regions. This association was stronger in CN than in the pre‐dementia group. Specifically, among CN, hypoperfusion in the frontal, parietal and occipital lobes related most strongly to greater behavioural impairment, especially MBI‐C and DASS depression(Fig.1). In the MCI+SCD group, only hypoperfusion in the frontal and temporo‐occipital regions related to worse behavioural impairment across the MBI, PSQI and DASS(Fig.2).

Conclusion

In this study, we illustrate differential associations between cerebral hypoperfusion and behavioural impairment in CN and MCI/SCD groups, with CN individuals showing more widespread and stronger associations between behavioural impairment and hypoperfusion across the brain. In SCD/MCI, hypoperfusion in frontal and temporo‐occipital regions were associated with behavioural impairment.
Dysbiosis of the Gut microbiota was improved after 24‐week multidomain intervention program to prevent dementia: Subgroup Analysis of SUPERBRAIN study
Authors: Kang Woorim , Park Yoo Kyoung , Jeong Jee Hyang , Moon So Young , Song Hong‐Sun , Lee Sun Min , Choi Muncheong , Park Kyung Won , Kim Byeong‐Chae , Cho Soo Hyun , Choi Seong Hye , Hong Chang Hyung , Na Hae Ri
Published: December 2023

Background

The stability of intestinal microbiota is critical to maintaining the integrity of epithelial barrier and immune homeostasis. Thereby, the disruptions to this balance and resulting dysbiosis are often associated with inflammation and compromised barrier function and may cause several kinds of diseases. There is growing evidence that people with Alzheimer’s may have different internal microorganisms than those who do not. We aimed to investigate gut microbiota changes after a 24‐week multidomain lifestyle intervention program in the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN).

Method

Participants without dementia and with at least one modifiable dementia risk factor, aged 60‐79 years, were randomly assigned to the facility‐based multidomain intervention (FMI) (n = 51), the home‐based multidomain intervention (HMI) (n = 51), and the control group (n = 50). Demographic and clinical factors were assessed as well as the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were evaluated as neuropsychological tests both at baseline and at the end of the study. Stool samples were collected for analysis of 16S rRNA gene sequencing, taxonomic profiling, and functional profiling.

Result

Participants who received either the facility‐based (5.4 ±7.7 increase) or home‐based (5.4 ±8.2 increase) intervention showed significantly increased RBANS scores compared to the control (0.03 ± 9.3 increase). The Beta‐diversity analysis showed significant differences in the microbial composition between the intervention group and control group. Also, participants who received multidomain intervention showed decreased proteobacteria abundance and increased abundance of Lachnospira, Parabacteroides.

Conclusion

In conclusion, the present study suggest that multidomain intervention in elderly with high risk of dementia not only showed beneficial effect on neuropsychological status but also improving the dysbiosis of gut microbiome
Adaptive immune response in Alzheimer’s disease: untangling the role of ApoE4
Authors: Halters Sem , Vries De
Published: December 2023

Background

The strongest genetic risk factor for developing late‐onset Alzheimer’s disease (AD), ApoE4, drives inflammation in the central immune system. However, it remains largely unkown whether ApoE4 also affects the adaptive immune response.

Method

First, we performed mass cytometry to identify an immune signature in splenocytes of human ApoE4‐TR and ApoE3‐TR mice. Following this, we used immunohistochemistry to check for brain infiltration of immune cells and BBB integrity.

Result

We identified an adaptive immune response in splenocytes of human ApoE4‐TR mice displayed by a shift from naïve and effector to memory CD8+ T cells. Futhermore, we found an increased number of CD8+ T cells in the brain of ApoE4‐TR mice. ApoE4 also has an effect on BBB integrity, as indicated by a decrease in the tight junction proteins, VE‐cadherin and claudin‐5, in ApoE4‐TR mice compared to ApoE3‐TR mice.

Conclusion

ApoE4 induces an adaptive immune response in mouse splenocytes resulting in brain infiltration of CD8+ T cells.
Comparative Pharmacokinetic Studies of One‐Month Donepezil IM Depot and Once Daily Oral Tablet in Healthy Male Volunteers
Authors: Seol Eunyoung , Lee Jinwoo , Lee Shin‐Won , Byun Jeongsu , Chung Jae‐Yong , Lee Heeyong
Published: December 2023

Background

This study is to evaluate the safety and tolerability of single dose of one‐month donepezil IM depot (GB‐5001) in healthy male volunteers and to compare pharmacokinetic parameters of 70mg donepezil IM depot and 10mg once daily oral tablet (Aricept®) in human.

Method

In this phase 1, a randomized, double‐blind, placebo‐controlled, dose‐escalation study, 48 healthy subjects were randomized to single dose of Aricept tablet or placebo or GB‐5001 (70mg or 140mg or 280mg) for 64 days. In this study, safety and tolerability of 70mg donepezil IM depot were examined by monitoring adverse events and vital signs. PK parameters such as AUCt, AUCinf, Cmax and Tmax were compared by measuring donepezil concentration after a single dose of 70mg IM depot and 10mg oral tablet.

Result

A single dose of 70mg donepezil IM depot showed no significant adverse events and was well tolerated in healthy male volunteers. In 70mg GB‐5001, all the subjects had measurable concentrations up to 1512 h post dose. The geometric mean of PK exposure parameters are 6482.82 h*ng/mL, 6604.01 h*ng/mL and 11.40 ng/mL for AUCt(0‐1512h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 432h post dose. In 10mg oral Aricept, all the subjects had measurable concentrations up to 240 h post dose. The geometric mean of PK exposure parameters are 656.84 h*ng/mL, 751.34 h*ng/mL and 17.68 ng/mL for AUCt(0‐240h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 2.25 h post dose.

Conclusion

A single dose of 70mg donepezil IM depot was found to be safe and well tolerated in healthy male volunteers. The pharmacokinetic results of 70mg donepezil IM depot showed stable donepezil blood concentration for more than one month without burst drug release, and showed comparable unit dose drug exposure not lower than that of once daily 10mg oral formulation. Through the PK results for additional higher doses and multiple PK simulations, optimal once monthly dose of donepezil IM depot could be suggested which will be bioequivalent to 10mg once daily tablet.
Premorbid musical experience influences socio‐emotional functioning in behavioural variant frontotemporal dementia
Authors: Hooft Jochum J. , Benhamou Elia , Herreros Claudia Albero , Jiang Jessica , Levett Benjamin , Core Lucy , Requena‐Komuro Mai‐Carmen , Hardy Chris JD , Tijms Betty M. , Pijnenburg Yolande A.L. , Warren Jason D
Published: December 2023

Background

While it is well established that musical expertise can shape brain structure and function, the potential of premorbid musical training to modify the clinical expression of neurodegenerative brain pathologies has been largely unexplored. In healthy subjects, long‐term musical exposure is associated with both enhanced emotion recognition and increased connectivity and functional integration in the salience network, a core target of the pathological process in behavioural variant frontotemporal dementia (bvFTD). Premorbid musical experience might therefore potentially affect socio‐emotional expression of bvFTD.

Methods

In 14 patients with bvFTD, premorbid musical experience (training and/or performing on an instrument), current musical listening habits and general socio‐emotional behaviours were scored using a bespoke semi‐quantitative musical survey and standardised functional scales administered to their primary caregivers. Patients were assessed on tests of pitch perception and melody recognition, referenced to a matched healthy cohort. Socio‐emotional behaviours were assessed using the Cambridge Behavioural Inventory (Revised) (CBI‐R), the Modified Interpersonal Reactivity Index (MIRI), and the Revised Self‐Monitoring Scale (RSMS). Higher CBI‐R scores reflect more behavioural impairments and higher MIRI and RSMS reflect better socio‐emotional functioning. Associations of musical scores with socio‐emotional functioning were assessed using a linear regression model adjusted for age, sex, educational attainment and overall cognitive severity.

Results

The bvFTD patients were matched to a healthy cohort on age, sex, education, peripheral hearing, musical experience, and music listening behaviour, but had worse performance on the pitch perception and melody recognition tests (Table 1). Greater premorbid musical experience (but not current listening habits or musical skill) was associated with significantly lower CBI‐R (β±SE = ‐16.5 ± 6.5; p = .03) and higher MIRI perspective‐taking scores (β±SE = 2.7 ± 1.1; p = .04) (Results are plotted with Pearson correlations in Figure 1).

Conclusions

Musical experience in earlier life may ameliorate socio‐emotional functioning in bvFTD. Future work in larger cohorts is required to substantiate the robustness of this association, establish its mechanism and evaluate its clinical potential.
The PPA Platform: A unique knowledge translation tool on PPA
Authors: Laforce Robert , Lafleur Philippe , Bédard Andréane , Drouin Marie‐Jeanne , Cyr Nancy , Parent Nancy , Sablonnière Justine De La , Poulin Elizabeth , Carrier‐Auclair Julie , Tastevin Maud , Lavoie Monica
Published: December 2023

Background

Very limited web‐based information is available for patients and families affected by Primary Progressive Aphasia (PPA). When accessible, it is often incomplete or worded in complex terminology. One of the objectives of the Research Chair on PPA – Fondation de la famille Lemaire (app‐ffl.ulaval.ca) is to educate the general population and healthcare professionals on PPA to promote earlier diagnosis and better care. We present the development of the PPA Platform, an innovative knowledge transfer tool.

Method

We carried out a focus group with patients and their relatives to understand their needs. We developed templates for ‘Patients/Relatives’ and ‘Health Professionals’ and adapted content and terminology for both sections. Content was then validated with experts in the field (neurologists, SLP). Videos were selected to illustrate the symptoms (eg, naming, repetition, etc.) and we included testimonials to further capture caregivers’ experience (eg, first symptoms, challenges, etc.). The French version of the platform was launched in 2020 and the English one in 2022.

Result

Since its inauguration, the PPA Platform has been consulted by more than 27 000 individuals in over 85 countries. Moreover, its content has been presented to approximately 500 healthcare professionals over training sessions either in person or by videoconference. Content is regularly updated and translation in other languages (Mandarin, Hindi, Spanish, Arabic and German) is ongoing.

Conclusion

The PPA Platform is an outstanding knowledge translation tool for patients, families and healthcare professionals. In a short amount of time, it positioned itself worldwide as a key reference on PPA.
Metformin and dietary restriction pathway are associated with neuroprotection in Alzheimer’s disease context. A key role for glial autophagy
Authors: Saravia Flavia Eugenia , Pomilio Carlos Javier , Gregosa Amal , Pérez Nicolás Gabriel González , Beauquis Juan
Published: December 2023

Background

The global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to premature brain aging. The inflammation and insulin resistance interplay represent a potential target to prevent neurodegeneration.

Method

We evaluated the effect of the antidiabetic drug metformin‐considered a dietary restriction (DR) mimetic‐ on patients enrolled in ADNI, an observational and longitudinal study including patients from all around the world. We employed data from patients diagnosed with mild cognitive impairment (MCI) due to AD and we performed a principal component analysis focusing on biomarkers associated to AD measured in cerebrospinal fluid.

We analyzed memory performance and hippocampal alterations in a model of AD, the PDAPP‐J20 transgenic mouse (Tg) and evaluated the effects of a periodic DR protocol (3 cycles of 40% DR for 5 days and ad libitum diet for 9 days).

Result

MCI metformin‐treated patients were characterized as subjects with a better CSF biomarkers profile than the mean population of MCI patients (p<0.05). Control subjects and T2D patients were paired by age, gender, ApoE allele and education, defining three groups: MCI, MCI+T2D and MCI+T2D+metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory/learning function. We found that MCI+T2D patients have a worse cognitive performance than MCI patients (p<0.01), but this effect was absent in MCI+T2D+metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume (p<0.001). Our study shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile and neuroanatomical measures in MCI due to AD patients.

We observed cognitive impairment, low adult neurogenesis and progressive Aβ deposition in the hippocampus of Tg mice. Periodic DR was associated to cognitive improvement, increased hippocampal neurogenesis, and reduced hippocampal amyloid load; we found that autophagy is modulated in Tg mice with a high proportion of LC3/Aβ colocalizing in astrocytes, probably contributing to the reduction in amyloid plaques associated to DR.

Conclusion

Our data suggest that metformin and DR may be potential interventions to promote healthy aging and prevent dementia.
The aftermath of boxing: Longitudinal changes of cerebral retention patterns of 18F‐florzolotau (18F‐APN‐1607) in the former professional boxers
Authors: Takahata Keisuke , Kubota Manabu , Tagai Kenji , Endo Hironobu , Miyata Mari , Saito Fumie , Tatebe Harutsugu , Matsuoka Kiwamu , Kurose Shin , Ichihashi Masanori , Kataoka Yuko , Hirata Kosei , Matsumoto Hideki , Seki Chie , Kokubo Naomi , Shinotoh Hitoshi , Oya Masaki , Sano Yasunori , Yamamoto Yasuharu , Kawamura Kazunori , Zhang Ming‐Rong , Tabuchi Hajime , Sahara Naruhiko , Tokuda Takahiko , Mimura Masaru , Higuchi Makoto
Published: December 2023

Background

Chronic traumatic encephalopathy (CTE), formerly known as “boxer’s encephalopathy” is a neurodegenerative disease associated with mild‐repetitive TBI. CTE is characterized by the deposition of hyperphosphorylated tau as neurofibrillary tangles around small blood vessels of the cortex, typically at the sulcal depths. Although tau PET studies on American football players reported findings consistent with neuropathological changes identified by postmortem brains, there are no reports of tau PET studies in boxers, and longitudinal changes of tau depositions following boxing remains unknown. The present study was aimed to characterize cerebral retention patterns of 18F‐florzolotau (18F‐APN‐1607) in the former professional boxers.

Method

Twenty‐nine former boxers (43.4 ± 10.3 years) and 27 age‐matched healthy control (HC) subjects underwent PET scans with 18F‐florzolotau and 11C‐PiB. Eleven former boxers underwent a second tau PET scan (average interval: 874days). Standard uptake value ratio (SUVR) with the optimized reference tissue was calculated. Regions of interest were defined on brain regions of the gray matter (GM), white matter (WM) and the gray‐white matter boundary (GWB). Association of regional SUVR values with neurocognitive symptoms and various indexes related boxing was investigated.

Result

One boxer was [11C]PiB positive. Former boxers showed higher 18F‐florzolotau retentions than HC subjects in the bilateral frontal GM, right parietal GM, bilateral frontal WM, right parietal WM (P < 0.001). There was a significant correlation between SUVR values in the whole GM and the total number of bouts (p = 0.07,r = 0.40). Subtyping using z‐score heatmap with predetermined criteria revealed heterogeneity in 18F‐florzolotau retention patterns in boxers. Of the 29 boxers, (1) 10 showed increased retention of 18F‐florzolotau in GM (GM dominant), (2) 4 showed increased accumulation mainly in WM (WM dominant), (3) 5 showed increased accumulation in GWB (GWB dominant), and (4) 10 showed no significant increased accumulation in the brain (No tau). These types vary in longitudinal changes of 18F‐florzolotau retention patterns, as well as in clinical features.

Conclusion

The present study not only supports pathological heterogeneity of late‐sequalae of professional boxing, but also suggests utility of 18F‐florzolotau PET in detection of late‐life neurodegenerative diseases following mild‐repetitive TBI.
Familiar olfactory stimulation related to self‐awareness in Alzheimer’s disease
Authors: Arbeláez María Alejandra Castro
Published: December 2023

Background

Alzheimer disease is extended everyday, Latinamerica is not an exception. Patients with AD have a decline about remembering events of general knowlage and past events about their life. Therefore episodic and semantic autobiographical memory is affected in patients with AD. This study shows how is that memory in Dominican Republic and Colombian Population. Also aim to see the difference after an olfactory stimulation with chocolate.

Method

Fifty people with mild and moderate A.D participated. The Control group, had an olfactory stimulation without familiar smell (placebo) and the experimental group, had an olfactory stimulation with familiar smell (chocolate). Before intervention post olfactory stimulation, of self‐consciousness, was made. After intervention an evaluation of autobiographical episodic memory and self‐consciousness was made. During intervention placebo stimulation with control group and an olfactory familiar stimulation with experimental group was incorporated. Afterwards, an evaluation of episodic autobiographical memory was conducted.

Result

Preliminary results shows that patients with AD improves their episodic autobiographical memory.

Conclusion

This findings shows a big impact for research because it will be a no farmacological trial that will help the patients with AD. Therefore it will be goood to their families, because it diminished the emotional impact of AD. Finally, will impacts the literature because is the first study in Caribbean region, a area in wich the research is not frequen because of the resources.
Analysis of persistence rate of cognitive enhancers in Alzheimer’s disease using the common data model
Authors: Jang Jae Won
Published: December 2023

Background

AchEIs are used by first‐diagnosed Alzheimer’s dementia patients. The effect of drug has been proven in safety and efficacy but it is known that the drug cannot be taken continuously due to side effects of about 10% in existing studies. However, studies report higher drug discontinuation rates. Cognitive function improvers or ‘nootropics’ such as choline alfocerate are used together with AchEI. Therefore, purpose of this study was to analyze the usage patterns of cognitive enhancers in Alzheimer’s patients and to confirm retention rate using a common data model.

Method

From 2010 to 2019, using the data of Alzheimer’s patients registered in the common data model server of Kangwon National University Hospital, we will investigate the prescription rate of cognitive function improving drugs (choline alfocerate) and drug analysis patterns such as ChEI and combination therapy. The analysis is conducted using the FeederNet‐based ATLAS WEB tool, and additional analysis is compared with the results obtained through the DBMS approach using SQL.

Result

As a result of the analysis of treatment trends and persistence for 10 years, among 2,658 newly diagnosed patients with Alzheimer’s disease, donepezil was prescribed the most with 1,518 patients (57.11%), choline alfocerate with 654 patients (24.6%), and memantine with 214 patients. (8.05%), rivastigmine in 74 (2.78%), and galantamine in 147 (5.53%) each. During observation, trend of increasing prescriptions was Donepezil (31.5% in 2010 to 68.7% in 2019), Nootropics (24.6% in 2010 to 34.2% in 2019), Memantine (3.7% in 2010 to 7.9% in 2019), and Rivastigmine(0.53% in 2010 to 3.32% in 2019), while galantamine decreased (12.2% in 2010 to 0.3% in 2019). Persistence was approximately 50% for donepezil and memantine and approximately 40% for rivastigmine, galantamine and choline alfocerate over 12 months

Conclusion

Comparing treatment trends of cognitive function improvers, donepezil, memantine, ribistigmine, and choline alfocerate showed a tendency to increase, whereas galantamine showed a tendency to decrease. Also, donepezil and memantine were associated with longer persistence than rivastigmine and galantamine and choline alfocerate. In particular, in case of Nootropics, a high rate of initial prescription is given to patients with dementia, but rate of continuous prescription is not high.
Xenon gas (Xe) treatment to restore microglial functions in Alzheimer’s disease (AD)
Authors: Brandao Wesley N , Yin Zhuoran , Kleemann Kilian , Zhang Xiaoming , Rosenzweig Neta , Jain Nimansha , Jones Mathew Blurton , Holtzman David M. , Ilin Ilya , Weiner Howard L , Butovsky Oleg
Published: December 2023

Background

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Emerging evidence shows that homeostatic dysregulation of the brain immune system orchestrated by microglia plays a significant role in the onset and progression of the disease. Our aim is to develop a therapy based on Xenon inhalation that addresses 1) penetration through the blood‐brain barrier, 2) microglial modulation, and 3) neuroprotection.

Method

Through a special chamber that can control the supply of Xenon gas in a closed‐circuit system, we evaluated the Xenon effect in microglia biology in models of acute and chronic neurodegeneration and humanized AD mice.

Result

We found that Xenon‐treatment can directly modulate the microglia phenotype, by increasing their phagocytic response and decreasing their proinflammatory signature. Weekly‐based Xenon inhalation decreased Ab‐plaque load and tauopathy and maintained microglial phenotype in an intermediated state associated with IFNg signaling and lipid biosynthesis signatures. Moreover, Xenon treatment also affects the peripheral immune response with a decrease in B cell and an increase in the tolerogenic signature in myeloid cells, which was validated by scRNAseq and FACS analysis. Importantly, Xenon treatment, directly modulated IPS‐derived microglia (iMGL) in vitro by suppressing their inflammatory signature and inducing lipid biosynthesis. Finally, treatment of humanized 5xFAD mice transplanted with iMGLs reduced Ab plaque load.

Conclusion

Xenon treatment modulates microglia and peripheral immune cells phenotype towards a reparative phenotype. This modulation is accompanied by reduction in Ab pathology in both mouse and humanized AD models, showing that Xenon inhalation can be used as a possible treatment for AD.
Alzheimer’s disease genetic risk score and neuroimaging biomarkers in the FINGER multidomain lifestyle randomized controlled trial
Authors: Hossain Gazi Saadmaan , Dalmasso Maria Carolina , Ramirez Alfredo , Hiltunen Mikko , Kemppainen Nina , Lehtisalo Jenni , Ngandu Tiia , Rinne Juha O. , Soininen Hilkka , Stephen Ruth , Kivipelto Miia , Solomon Alina
Published: December 2023

Background

A comprehensive genetic risk score (GRS) for Alzheimer’s disease (AD‐GRS) was recently developed based on 83 genome‐wide significant variants (Bellenguez et al. Nat Genet. 2022), excluding APOE. This study investigated AD‐GRS and APOE4 in relation to neuroimaging biomarkers in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER).

Method

FINGER included at‐risk individuals without dementia from the general population, aged 60‐77 years. Participants were randomized to either 2‐year multidomain lifestyle‐based intervention or regular health advice. At baseline, 132 participants underwent MRI scans, of which 48 also underwent PET scans (PiB/FDG). Two years later, 112 and 39 repeated their scans, respectively. MRI measures included hippocampus, total gray matter and white matter lesion volumes, and cortical thickness. Composite indices were calculated for PiB and FDG uptake values. We report preliminary results from linear regressions (standardized β‐coefficients, p‐values).

Result

At baseline, higher AD‐GRS tended to relate to lower hippocampus volume (β = ‐0.15, p = 0.07) and FDG‐PET index (β = ‐0.23, p = 0.08); this remained after APOE adjustment. APOE4 was associated with lower hippocampus volume (β = ‐0.27, p = 0.001) and higher PiB‐PET index (β = 0.48, p = 0.001). Overall, AD‐GRS was not related to the 2‐year change in neuroimaging measures, while APOE4 was related to decreasing hippocampus (β = ‐0.27, p = 0.01) and total gray matter (β = ‐0.25, p = 0.01) volumes, and cortical thickness (β = ‐0.28, p = 0.003). There were no significant interactions of AD‐GRS or APOE4 with randomization group in relation to neuroimaging changes. However, in analyses stratified by AD‐GRS (below vs above median), there was less PIB index increase in intervention vs control in the higher AD‐GRS group (β = ‐0.60, p = 0.03); no intervention control‐difference was found in the lower AD‐GRS group (β = 0.04, p = 0.86). In analyses stratified by APOE4, PIB index tended to increase less in intervention vs control in non‐carriers (β = ‐0.38, p = 0.078), with no intervention‐control difference in carriers (β = 0.05, p = 0.89).

Conclusion

Unlike APOE4, AD‐GRS was not related to 2‐year change in AD‐related neuroimaging measures. AD‐GRS and APOE4 may also have very different impact on potential intervention effects on amyloid, i.e. less accumulation in the higher‐risk group (AD‐GRS) vs lower‐risk group (APOE). However, these exploratory findings need to be verified in larger studies.
Single cell profiling of Microglia from PLCG2 and ABI3 Missense Variant Carriers in Alzheimer’s disease
Authors: Bergman Jeremiah , Is Ozkan , Wang Xue , Cherukuri Yesesri , Duvuuri Venkata N.S. , Quicksall Zachary , Atik Merve , Tutor‐New Frederick Q , Sotelo Katie , Nguyen Thuy , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilufer
Published: December 2023

Background

Alzheimer’s disease (AD) is a complex, multicellular disease with immunological and genetic components. Previous studies demonstrated associations between AD and the missense variants ABI3‐rs616338‐T and PLCG2‐rs72824905‐G. The perturbed expression of these genes has been demonstrated to disrupt microglial function. To date, the transcriptomic profiles of variant carriers in the context of microglial subtype and state have not been explored in human brain. This represents a knowledge gap in our understanding of AD risk and resilience. We have developed and optimized a single nucleus RNAseq (snRNAseq) approach to study the impact of ABI3 and PLCG2 variants on microglial enriched nuclei from frozen human brain.

Method

DOCK8 was identified as a nuclear microglial marker based on previous brain snRNAseq data. DOCK8 based microglial enrichment using fluorescent activated nuclei sorting (FANS) was validated using RT‐qPCR and snRNAseq in human cerebellum and temporal cortex (TCX), respectively. We are applying this enrichment and snRNAseq approach to TCX tissue from a cohort of 30 donors harboring ABI3 or PLCG2 missense mutations, or neither. Standard snRNAseq alignment and quality control pipelines will be applied, and nuclei annotated based on putative microglial markers. Differential gene expression will be assessed using pseudo bulk and MAST approaches, for association with ABI3 and PLCG2 genotype, diagnosis groups, risk factors, and pathology scores.

Result

DOCK8 has several commercially available antibodies, making it an ideal microglia‐selection marker. Using RT‐qPCR in microglia enriched nuclei, we demonstrated an enrichment of microglia marker genes and depletion of other brain cell type markers. This is further supported by snRNA‐seq data from DOCK8‐sorted TCX tissue that yielded a 5x increase in microglia proportion (56% vs. 11% in unselected nuclei), enabling analyses of microglia sub‐populations. Leveraging this approach, we will investigate affected genes and pathways and uncover the resilience and risk mechanisms within microglia sub‐populations in ABI3 and PLCG2 variant‐carriers.

Conclusion

Our study presents a novel method for enriching microglial nuclei from frozen human brains and enables transcriptomic profiling of microglial subpopulations in ABI3 and PLCG2 missense variant‐carriers. We expect these insights will reveal novel genes and pathways that may play a key role in microglial function in AD.
Activation of Wnt/β‐catenin pathway in the brain endothelium mitigates Aβ‐induced blood‐brain barrier dysfunction in Alzheimer’s disease
Authors: Yi Chenju
Published: December 2023

Background

Alzheimer’s disease (AD) is the leading cause of age‐related neurological and cognitive decline. As the mechanisms of this disease are yet to be fully understood, the treatments for AD pose a significant challenge. Dysfunction of the blood‐brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the disease. However, underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD.

Method

Here using both AD patients and APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB damage and the underlying molecular mechanism were examined.

Result

we showed dysfunctional BBB in AD patients indicated by perivascular accumulation of blood‐derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin‐5 and glucose transporter Glut‐1 in the brain endothelial cells (BECs). In the APP/PS1 mice, BBB dysfunction started at 4 months and became severe at 9 months. In the cerebral microvessels of APP/PS1 mice and Aβ‐treated BECs, we found suppressed Wnt/β‐catenin pathway triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switch to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signaling) to activate Wnt/β‐catenin pathway, Aβ‐inhibited BBB function was restored by promoting the barrier repair and preventing Aβ‐induced BEC impairments.

Conclusion

Targeting LRP6 in the Wnt/β‐catenin pathway in the brain endothelium can alleviate BBB dysfunction induced by Aβ, which may be a potential treatment strategy for AD.
The ReMember‐Me Cognitive Assessment Scale‐ReMCAS: Psychometric properties of a new digital tool to remotely assess cognitive function
Authors: Moza Sotiria , Sampanai Romina , Tziannarou Antonia
Published: December 2023

Background

The ReMember‐Me project, co‐funded by the AAL programme, proposes the ReMember‐Me Cognitive Assessment Scale (ReMCAS); a self‐administered and auto‐scored, digital instrument, to assess cognition remotely. The ReMCAS comprises of 19 tasks assessing temporal, spatial and personal orientation, naming, language, working, prospective and long‐term memory and executive function. It is administered via a tablet and is automatically scored, partially utilising artificial intelligence.

Method

50 older adults (M age = 74.16 years, 28 people categorized as cognitively fit, 15 male) participated in a two‐month study using serious games at home. The ReMCAS and the Mini Mental State Examination (MMSE) were administered at baseline (T0) and post‐study completion (T1). Half of the participants completed the ReMCAS digitally and half in hard copy to assess any technology‐related impact on performance.

Result

The ReMCAS showed good reliability (Cronbach’s a = .827) and consistency. All individual task scores correlated significantly with the ReMCAS total score, except for Task 7 (Naming) and Task 13a (recalling words with cues). The ReMCAS total score was associated with the MMSE total score both at T0 (r = .436, p = .004) and T1 (r = .720, p = <.001). The ROC Curve showed a good model fit (AUC = .910) and a 91.3% sensitivity/88.2% specificity in categorising people with cognitive decline (cut‐off score = 76.50/91 points). Independent sample t‐tests showed that participants’ performance did not differ significantly in the digital versus hardcopy administration of ReMCAS, either among cognitively fit (F(26) = 3.828, p>.05) or not‐fit (F(20) = .681, p>.05) individuals.

Conclusion

Despite the small sample of the present study, the preliminary findings indicated that the ReMCAS may be a helpful tool for the remote assessment of cognitive decline. Studies are currently being conducted through an intervention‐control group design to further evaluate the properties of the instrument.
All‐in‐Human Target Discovery in Alzheimer’s Disease and Resilient Brains
Authors: Martirosyan A , Chen W‐T , Lu A , Garcia D S , Craessaerts K , Vanheusden M , de Vries L , Pavie B , Corthout N , van Lieshout V , Misbaer A , Holstege H , Huitinga I , Dalby M , Fiers M , Plath N , Balice‐Gordon R , De Strooper Bart
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by neuropathological hallmarks including amyloid plaques and tau tangles and neurodegeneration in the frontal cortex. While there is a strong association of tau pathology with neurodegeneration and cognitive decline, around 30% of amyloid plaque‐carrying seniors remain cognitively healthy. We hypothesize that protective cellular mechanisms upstream of tau phosphorylation and neurodegeneration may underlie this resilience.

Method

We applied high resolution spatial transcriptomics and single nuclei RNA sequencing on postmortem frontal lobes from 10 demented and 10 non‐demented individuals with comparable degrees of amyloid pathology. We integrated the generated transcriptomics data with proteomics, genomics and drug action databases and interpret cellular transcriptome responses to pathology in the context of human specific protein‐protein interaction networks.

Result

Using spatial and single nuclei transcriptomics, we identify specific transcriptomic signatures and regulatory networks in cellular microenvironments around amyloid plaques and pTau pathology niches. Our results suggest that specific neuronal and glial subpopulations carry enriched vulnerability towards amyloid plaque and pTau depositions. We further find that certain cell death signaling pathways related to neurodegeneration are overrepresented in the context of pTau pathology. Finally, our multi‐omics database integration approach has led to the identification of potential drug targets for therapeutics addressing cellular mechanisms of neuroprotection.

Conclusion

Spatial transcriptomics from human brain tissue is a powerful approach to reveal cellular mechanisms of pathogenic lesions and enables us to identify neuroprotective mechanisms that may prevent the development of tauopathy and ultimately neuronal loss. The combination of single cell and spatial transcriptomics together with protein‐protein interaction networks provides a promising approach for the identification of novel therapeutic targets for AD.
Associations between Aβ‐PET, CSF pTau, and plasma GFAP, pTau181, pTau231 in memory clinic patients
Authors: Bluma Marina , Bucci Marco , Ashton Nicholas J. , Savitcheva Irina , Chiotis Konstantinos , Matton Anna , Molfetta Guglielmo Di , Grötschel Lana , Blennow Kaj , Zetterberg Henrik , Nordberg Agneta K
Published: December 2023

Background

Previous studies yielded contradictory findings regarding the association of plasma biomarkers with established biomarkers of tau and amyloid (Aβ) pathology. Here, we aim to examine the relationship between Aβ‐PET and CSF pTau with plasma biomarkers in a cohort of memory clinic patients.

Methods

Plasma GFAP, pTau181, pTau231, and CSF pTau181 were measured in 124 patients (age = 65±8(mean±SD), 69F/55M, MMSE = 25.6±3), admitted to the Memory Clinic,Theme Inflammation and Aging, Karolinska University Hospital, Stockholm,Sweden, and referred to [18F]flutemetamol Aβ‐PET after extensive clinical assessment.PET images were preprocessed with rPOP pipeline for PET‐only datasets. Plasma GFAP was measured using N4PE assay (Quanterix), whereas pTau181 and pTau231 with in‐house Single molecule array (Simoa) assays developed at the University of Gothenburg, and CFS pTau181 ‐ with commercial ELISA.To assess the relationship between the biomarkers we ran multiple linear regression (adjusted for sex and age,standardized variables),dominance analysis to compare the relative importance of the predictors, and mediation analysis to clarify interrelations between them.

Results

We found significant(p<0.05) associations of plasma GFAP(βAβ‐PET = 0.42,βpTau = 0.22), pTau231(βAβ‐PET = 0.38,βpTau = 0.39), and pTau181(βAβ‐PET = 0.35,βpTau = 0.3) with Aβ‐PET and CSF pTau, although when both Aβ‐PET and CSF pTau were added into the multivariate regression the effect of CSF pTau was attenuated by the effect of Aβ‐PET for GFAP(βAβ‐PET = 0.45) and pTau181(βAβ‐PET = 0.27), but not for pTau231(βAβ‐PET = 0.24,βpTau = 0.25). Dominance analysis showed that the relative importance of the variables (i.e., Aβ‐PET, demographics (sex, age), and CSF pTau) for prediction of GFAP values followed the order: Aβ‐PET>demographics>CSF pTau; of pTau181: Aβ‐PET>CSF pTau>demographics; and of pTau231: CSF pTau>Aβ‐PET>demographics. Mediation analysis revealed that the effect of CSF pTau on plasma GFAP and pTau181 was fully mediated by Aβ‐PET, whereas in case of pTau231 we could observe partial mediation, where both direct effect of CSF pTau and indirect effect through Aβ‐PET were significant.

Conclusion

In a clinical cohort of patients, we found differing associations between plasma GFAP, pTau181, and pTau231 with Aβ‐PET and CSF pTau.Amyloid burden contributed the most in explaining the variance in GFAP and pTau181, but not pTau231, where the contribution of CSF pTau was higher.These results suggest plasma GFAP and pTau181 as potential markers of pathological processes associated with amyloid pathology, whereas pTau231 ‐ with both amyloid and tau pathology.
Predictive Value of the Alzheimer Polygenic Risk Score on Cognitive Decline in Patients with Alzheimer’s Disease Dementia
Authors: Valero Sergi , García‐Gutiérrez Fernando , Marquié Marta , de Rojas Itziar , García‐González Pablo , Cano Amanda , Puerta Raquel , Olivé Clàudia , Alegret Montserrat , Pytel Vanesa Verónica , Rosende‐Roca Maitee , Tárraga Lluís , Boada Mercè , Ruiz Agustin
Published: December 2023

Background

Alzheimer’s disease (AD) is a complex disease conditioned by environmental and genetic factors. Over the last few years, Genome‐Wide Association Studies (GWAS) have gained increasing interest representing the basis of a personalized medicine that aims to facilitate interventions at the preclinical stages. In most studies, the integration of the high‐dimensional GWAS data is accomplished via polygenic risk scores (PRSs) representing a measure of the genetic risk associated with a given phenotype. For the first time, this study aimed to explore the predictive value of a PRS developed to predict conversion to AD in patients with mild cognitive impairment (MCI) (AD‐PRS) (Bellenguez et al., 2022) on cognitive decline once the AD dementia stage has been established

Method

The modulatory effect of genetics on cognitive decline was studied using a sample of 3921 subjects with AD dementia (clinical dementia rating (CDR) ≥1) evaluated at Ace Alzheimer Center Barcelona. Cognitive decline, operationalized as changes in Mini Mental State Examination (MMSE) scores over time, was modeled using multivariate regression models considering clinical and sociodemographic data, and the AD‐PRS. Interaction effects between the AD‐PRS and the other covariates were explored, and subsequently, mediation analyses were applied. Afterward, Machine Learning techniques were used to select the single nucleotide polymorphisms (SNPs) forming the AD‐PRS with the highest predictive value on cognitive decline.

Result

Multivariate regression models showed a significant interaction of the AD‐PRS with years of education (coef = .0006; p‐value = .005). Increased scores of AD‐PRS combined with higher formal education were found to be associated with greater cognitive decline. Furthermore, Machine Learning models identified 18 SNPs related to cognitive decline in AD, demonstrating that genetic information improves the predictive performance of the models.

Conclusion

This is the first study that demonstrates the predictive capacity of the AD‐PRS on cognitive decline in AD dementia. Years of education were shown to modulate, but not mediate, the effect of the AD‐PRS on cognitive progression. Additionally, a subset of SNPs comprising the AD‐PRS with the highest predictive value of cognitive decline in AD was identified. Altogether, these results provide new insights into the genetics of the disease.