bluuebunny/crossref_metadata_2025 huggingface dataset:
Mediation effect of WMH on the associations of dementia risk with cognition and AD‐related brain changes
Authors: Wang Yan‐li , Sun Mengfan , Zhang Yuan , Jia Ziyan , Li Runzhi , Jiang Jiwei , Xu Jun
Published: June 2023

Background

The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, a validated tool estimating dementia risk, has been suggested to be associated with accelerated brain atrophy but the imaging biomarkers and AD pathologies remains to be elucidated. We aimed to explore the relationships of CAIDE score with cognition and AD‐related brain changes, including beta‐amyloid (Aβ) deposition and glucose metabolism and the mediation effect of the WMH on these associations.

Method

A sample of 1,285 participants underwent CAIDE dementia risk assessment, of these, 958 individuals had a CAIDE score of less than or equal to 8. Memory and executive function were used to measure cognitive performance. We analyzed data using linear mixed‐effects and mediation.

Result

CAIDE score was significantly associated with WMH volume, and also had significant association with Aβ deposition, AD‐metabolism, and memory and executive function. WMH volume mediated 6.04%, 12.87%, 6.93% and 7.92% of the total association of CAIDE score with memory, executive function, FDG‐PET and AV45‐PET, respectively.

Conclusion

Memory, executive function, AD‐metabolism and Aβ deposition are strongly associated with dementia risk. Besides, the associations could be mediated by WMH volume and whether this represents a causal relationship remains to be determined.
The value of heart rate variability in autonomic nervous function evaluation and diagnosis of fatal familial insomnia
Authors: Wu Liyong , Cui Yue , Huang Zhaoyang
Published: June 2023

Background

Fatal familial insomnia (FFI) is a rare autosomal dominant inherited prion disease characterized by prominent organic sleep‐related impairment accompanied by a series of symptoms with strong clinical heterogeneity in a rapid progression. As the most significant clinical feature and the potential diagnostic marker of FFI, progressive sympathetic symptoms were lack of a objective noninvasive quantitative method to detect.

Method

From May 2013 to August 2020, nine patients with FFI, eight patients with Creutzfeldt‐jakob disease (CJD) and nine normal control (NC) with matched sex and age were recruited in this study. All the participants underwent a nocturnal video‐polysomnography included a lead II electrocardiography (ECG). Heart rate variability analysis with successive 5 min (in time domain methods, frequency domain methods and non‐linear measurement) was performed during quiet wake before sleep and in the following N2, N3 and REM of the first sleep cycle.

Result

In FFI group, the continuous increased heart rate with the relatively decreased amplitude of the oscillations compared with NC and CJD group, revealed the axis of equilibrium shifts towards sympathetic activation. Furthermore, the RMSSD and HF during sleep stage in FFI were significantly lower than in NC group, which reflected the decreased activation of parasympathetic nervous system. The significant abnormal LF/HF ratio and SD1/SD2 ratio in combination with the lower values of correlation dimension D2 in FFI group supported its unbalanced autonomic nervous function.

Conclusion

Dysfunctions of autonomic nerve system in patients with FFI may be affected by parasympathetic hypofunction partly except sympathetic activation, and HRV is expected to become a method in diagnosis for FFI.
Specific structuro‐metabolic pattern of thalamic subnuclei in fatal familial insomnia: A PET/MRI imaging study
Authors: Xie Kexin , Chen Yaojing , Chu Min , Cui Yue , Chen Zhongyun , Liu Li , Wu Liyong
Published: June 2023

Background

Dysfunction of the thalamus has been proposed as a core mechanism of fatal familial insomnia. However, detailed metabolic and structural alterations in thalamic subnuclei are not well documented. We aimed to address the multimodal structuro‐metabolic pattern at the level of the thalamic nuclei in fatal familial insomnia patients, and investigated the clinical presentation of primary thalamic alterations.

Method

Five fatal familial insomnia patients and 10 healthy controls were enrolled in this study. All participants underwent neuropsychological assessments, polysomnography, electroencephalogram, and cerebrospinal fluid tests. MRI and fluorodeoxyglucose PET were acquired on a hybrid PET/MRI system. Structural and metabolic changes were compared using voxel‐based morphometry analyses and standardized uptake value ratio analyses, focusing on thalamic subnuclei region of interest analyses. Correlation analysis was conducted between gray matter volume and metabolic decrease ratios, and clinical features.

Result

The whole‐brain analysis showed that gray matter volume decline was confined to the bilateral thalamus and right middle temporal pole in fatal familial insomnia patients, whereas hypometabolism was observed in the bilateral thalamus, basal ganglia, and widespread cortices, mainly in the forebrain. In the regions of interest analysis, gray matter volume and metabolism decreases were prominent in bilateral medial dorsal nuclei, anterior nuclei, and the pulvinar, which is consistent with neuropathological and clinical findings. A positive correlation was found between gray matter volume and metabolic decrease ratios.

Conclusion

Our study revealed specific structuro‐metabolic pattern of fatal familial insomnia that demonstrated the essential roles of medial dorsal nuclei, anterior nuclei, and pulvinar, which may be a potential biomarker in diagnosis. Also, primary thalamic subnuclei alterations may be correlated with insomnia, neuropsychiatric, and autonomic symptoms sparing primary cortical involvement.
Amyloid PET in patients with carotid occlusive disease: Preliminary results of the AMYCODE study
Authors: Starmans Naomi LP , Tolboom Nelleke , Leeuwis Anna E , Viol Sebastiaan L Meyer , Golla Sandeep S.V. , Boellaard Ronald , Biessels Geert Jan , Kappelle Jaap , van der Flier Wiesje M. , Connection Heart‐Brain
Published: June 2023

Background

Carotid occlusive disease (COD) is a risk factor for cognitive decline. One of the proposed underlying mechanisms is that cerebral hypoperfusion may result in accelerated accumulation of amyloid‐β in the brain. We hypothesized that patients with longstanding, unilateral COD have an asymmetrical burden of cerebral amyloid‐β, with more amyloid‐β in the hemisphere ipsilateral to the COD than in the contralateral hemisphere.

Method

The AMYCODE study is a cross‐sectional observational study. Inclusion criterion is a unilateral occlusion of the internal carotid artery. Exclusion criteria are: a contralateral stenosis of > 70% and a history of vascular reconstructive surgery. All patients underwent a neuropsychological assessment, MRI‐scan and dynamic 18F Florbetaben positron emission tomography scan (PET). Global relative perfusion (R1) and binding potential (BPND) were determined from the PET‐images using PMOD and a simplified reference tissue model with the cerebellar grey matter as reference region. Distribution Volume ratio (DVR) was calculated as BPND + 1. We performed Wilcoxon signed‐rank tests to examine differences between hemispheres within subjects.

Result

To date, we included eight participants (seven males, age 66.1±7.3 years, MMSE score 28.1±2.0; inclusion ongoing, target n = 20). Mean global DVR was 1.03±0.03 in the ipsilateral hemisphere (i.e. side of the occlusion) and 1.04±0.02 in the contralateral hemisphere (p = 0.064). Mean global R1 was 0.89±0.06 in the ipsilateral hemisphere and 0.91±0.05 in the contralateral hemisphere (p = 0.033).

Conclusion

Preliminary analyses suggest that patients with unilateral COD had similar amyloid‐β distribution, despite lower cerebral perfusion in the hemisphere ipsilateral to the COD than in the contralateral hemisphere.
MR Nano‐Radiomics for Detection of Amyloid Plaques in Alzheimer’s Disease
Authors: Starosolski Zbigniew , Badachhape Andrew A , Devkota Laxman , Srivastava Mayank , Tanifum Eric , Annapragada Ananth , Ghaghada Ketan
Published: June 2023

Background

Amyloid plaques are a pathological hallmark of Alzheimer’s disease (AD). In a recent pre‐clinical study, we showed an amyloid‐targeted liposomal macrocyclic gadolinium (Gd) contrast agent, ADx‐001, for in vivo MRI‐based detection of amyloid plaques in mouse. Although ADx‐001 showed high sensitivity at a high dose (0.2 mmol Gd/kg), the performance was sub‐optimal (<70%) at lower doses (0.1 and 0.15 mmol Gd/kg). In this work, we investigated if nano‐radiomics (radiomic analysis of nanoparticle contrast‐enhanced images) would increase sensitivity of ADx‐001 at lower dose levels.

Method

In vivo studies were performed in the APP/PSEN1 mouse model of amyloid pathology. The efficacy of ADx‐001‐ enhanced MRI was studied at three dose‐levels: 0.10, 0.15, and 0.20 (mmol Gd/kg). Pre‐ and post‐contrast MRI was performed in transgenic (n = 6/dose) and wild‐type mice (n = 6/dose) using a T1‐weighted spin‐echo sequence. Semi‐automatic 3D segmentation of hippocampal and cortical regions was performed using a mouse brain MR atlas (Fig.1). Radiomic analysis was executed on the hippocampus and cortex regions of ADx‐001‐enhanced MR images 900 radiomic features (RFs). RF selection was completed using a non‐parametric neighborhood component method. 5‐fold cross‐validation was performed using a set of linear and non‐linear classifiers to confirm the accuracy of group separation.

Result

Seven RFs (three RFs for cortex and four RFs for hippocampus) were identified that differentiated amyloid‐positive transgenic mice from amyloid‐negative wild‐type mice based on ADx‐001‐enhanced MRI. The best performing nearest‐neighbor classification model was trained simultaneously on all ADx‐001 dose groups. Nano‐radiomic analysis of ADx‐001‐enhanced MRI demonstrated 100% accuracy, specificity, and sensitivity for dose levels of 0.2 and 0.15 mmol Gd/kg. For low dose level (0.1 mmol Gd/kg), radiomics achieved accuracy of 91.6% and sensitivity of 83.3%, while maintaining specificity at 100%. The new results were superior when compared to previously reported results based on global signal enhancement analysis.

Conclusion

Nano‐radiomic analysis of ADx‐001‐enhanced MRI improved sensitivity of ADx‐001 at lower dose levels for the detection of amyloid pathology and demonstrated excellent for intermediate and high dose. Our study demonstrates that radiomic analysis of contrast‐enhanced MR images could boost the performance of targeted molecular imaging agents for early detection of AD.
Community research liaison role in increasing participation of African Americans in cognitive research: A case study
Authors: Brangman Sharon A , Royal Kathy , Dillenbeck Colleen , McNamara Sarah , Smith Nancy , De Rosa Eve , Anderson Adam , Riley Elizabeth
Published: June 2023

Background

Racial and ethnic underrepresentation in aging research and need for effective recruitment strategies is well documented. A Community Research Liaison (CRL) role created under a NIA award is demonstrating the value of embedding staff from underrepresented communities in the research infrastructure.

Methods

The role and qualifications for a CRL were developed with individuals from an African American community. The CRL hired from this community is engaging in outreach to understand barriers to and discuss the value of research with community members. Through the CRL, community input is being translated into changes in recruitment methods that reflect the concerns, interests and needs of potential African American participants. This case study reports on recruitment outcomes for a study on markers of cognitive decline in older adults requiring 2 hours in an MRI, 5 for testing, and 3 for travel. Recruitment data are compared 6 months before and 3 months after the CRL was engaged.

Result

In the 6 months prior to the CRL’s involvement, 309 individuals passed an initial screening and 156 were found potentially eligible after a second screening. Five (3.2%) of the 156 were African American. Of these, one was found ineligible, one was lost to follow‐up and the 3 participated in the study. In the first 3 months after the CRL was engaged, 35 were referred to the study after recruitment by the CRL. All were African American, 15 (43%) were eligible and enrolled, 9 (26%) were ineligible, and 9 (26%) are still in the screening process.

Conclusion

The case study demonstrates the promise of a CRL who is a member of an African American community in increasing African American participation in research. The CRL dramatically increased the number of older African Americans recruited despite potential participation barriers. The increase was due in large part to the CRL’s understanding of and recognition as a trusted member of the community and to changes she recommended to promotional materials and logistics based on community feedback. Data on recruitment effectiveness are continuing to be evaluated across a range of aging research studies and clinical trials in which the CRL is engaged.
Integrating Serious Illness Care into Primary Care Delivery for persons with dementia: CARIÑOS En Su Casa – Care for you at home
Authors: Patel Neela K. , Liu Jia , de Erausquin Gabriel A.
Published: June 2023

Background

The patient‐centered medical home (PCMH) as a model of primary care transformation has the potential to improve the quality, safety, and efficiency of care and reduce costs, particularly during the COVID‐19 pandemic for persons with dementia. However, the effects of adopting the PCMH are lack of clinical and economic support, let alone the challenge of applying it in ethnically and culturally diverse patient populations.

Method

To address the limitations of the traditional PCMH model, the CARIÑOS approach, a patient‐driven, comprehensive, coordinated, and multi‐site care model, was developed by the University of Texas (UT) Health San Antonio Geriatrics and Supportive Care Practice to meet the healthcare needs of patients in an underserved, primarily Hispanic community, who are often frail and have complex medical and care needs between various healthcare settings. Early outcomes on costs were collected to demonstrate its economic effects.

Result

Overall, the implementation of the CARIÑOS approach reduced total costs per patient per year by comparing six practices affiliated to the UT Health San Antonio Accountable Care Organization (ACO) – Regional Physicians Network. They serve similar underserved areas in the first and second Quarters of 2021. After adopting the CARIÑOS approach ($45,705), the costs were lower than 4 out of the 6 ACOs practices. In comparison, the Hierarchical Condition Category (HCC) score of the patients seen at the Geriatrics and Supportive Care Practice (HCC = 1.45) was higher than those seen at the other six practices (average = 1.15) during the same period of 2021.

Conclusion

The CARIÑOS approach provides an innovative and comprehensive perspective delivering culturally congruent care for persons with dementia and support for their families.

The main learning objectives of the session will be

1. To enlist the elements of the CARINOS Approach for person centered care.

2. To describe strategies that can be used to implement this approach in dementia care of underserved and Hispanic families.

3. List the ways to engage promotores or community health workers as a bridge between the healthcare team and patient and family to improve patient experience.

Key words – person centered, dementia care
Assessing trust and relationship quality in families with cognitively impaired family member
Authors: Patel Neela K. , Liu Jia , de Erausquin Gabriel A.
Published: June 2023

Background

Relational factors play a critical role in the experience and outcomes of persons with Alzheimer’s Disease and related dementias (AD+RD).Complex and bi‐directional association of relational factors and cognitive decline using the Postiive Affect Index‐ PAI in Spanish.

Method

Semi‐structured interviews were conducted for 20 dyads – 20 persons with dementia and 20 caregivers for total of 40 interviews. Patients were asked, “How did [caregiver] come to be your caregiver?”, and “What is their role when you go to the doctor and why do they play that role?”. Caregivers were asked, “How did you come to be the caregiver for [patient]?”; and “What is your role when they go to the doctor and why do you play that role?” Responses were recorded, transcribed, and analyzed using thematic analysis to describe overarching themes in patient and caregiver responses.Patients were asked about the quality of their relationship with their caregiver, and caregivers were asked about the quality of their relationship with the patient. Items in the 5‐item questionnaire are evaluated using a 6‐point Likert scale (1 = not close to 6 = extremely close) examples are “How is communication between yourself and this person—how well can you exchange ideas or talk about things that really concern you?” and “Taking everything into consideration, how close do you feel in your relationship with this person?” The PAI was orally administered, with patients being asked about the quality of their relationship with their caregiver and caregivers being asked about the quality of their relationship with the patient. Relationship quality scores were compared between patient and caregiver and as they relate to trust.

Results

Conventional content analysis techniques were also used to identify and classify the existence and prevalence of factors for caregiver selection and to examine perceived roles and reasons for roles in the medical encounter. The data is derived from both the patient and caregiver perspective, and comparisons are made to determine whether and how accounts differ between patient and caregiver.

Conclusion

The findings help elucidate the role of patient‐caregiver‐physician relational factors in AD + RD care, experience, and trajectory specific to underserved Hispanic dyads
Neuropsychiatric symptoms in mild cognitive impairment and Alzheimer’s disease: Relation with disease stage, sex, and daily function impairment
Authors: Zhang Wenbo , Lü Yang , Yu Weihua
Published: June 2023

Background

To reveal the relations between neuropsychiatric symptoms (NPS), stages of cognitive impairment, sex, and daily function impairment in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).

Method

1,154 patients with MCI and AD were enrolled from 2014 to 2021 from the Memory Clinic, The First Affiliated Hospital of Chongqing Medical University. Mini‐mental State Examination (MMSE) was used to assess the cognitive function, and Clinical dementia rating scale (CDR) was used to evaluate the disease severity of patients. NPS and function of patients’ daily life were evaluated by Neuropsychiatric Inventory (NPI) and activities of daily living (ADL) respectively.

Result

Psychosis symptoms displayed the highest prevalence in MCI (43.3%) and mild AD stage (62.2%), while in moderate and severe AD, behavior symptoms showed its dominance (86.7% and 96.4%, respectively). Delusion, apathy, AMB and sleep disturbance were the discriminant symptoms across the spectrum of cognitive decline (all P <0.05). Depression was more prominent in female (26.1% vs. 14.9% in MCI; 40.2% vs. 21.0% in AD, all P< 0.05) while male patients presented higher prevalence in apathy (27.0% vs. 18.6% in MCI; 54.1% vs. 42.8% in AD, all P< 0.05). Physical self‐maintenance was negatively impacted by apathy and sleep disturbance at mild AD stage, while instrumental activity of daily living was significantly influenced by aberrant motor behavior in MCI and mild AD (all P< 0.05).

Conclusion

The prevalence of NPS is correlated with sex, the stage of cognitive impairment and daily living function. Revealing their relations can allow he development of better prevention and treatment strategies for patients with cognitive impairment.
European adaptation of the Harmonized Cognitive Assessment Protocol: Methodological lessons learned from SHARE‐HCAP
Authors: Otero Marcela , Douhou Salima , Pettinicchi Yuri , Sommer Elena , Ludmark Vania Panes , Rieckmann Anna , Börsch‐Supan Axel
Published: June 2023

Background

Alzheimer’s disease and related dementias pose a major epidemiological challenge worldwide. A key impediment to dementia research is the availability of internationally comparable cognitive assessments that are socio‐culturally adapted and language appropriate. The Survey of Health, Ageing and Retirement in Europe‐ Harmonized Cognitive Assessment Protocol (SHARE‐HCAP) study aims to use multistage translation and pre‐statistical harmonization procedures to develop an in‐depth neuropsychological battery that assesses cognition in a population‐based survey administered across Continental Europe.

Method

SHARE‐HCAP will assess cognitive functioning using the HCAP – an hour‐long neuropsychological test battery and informant interview developed for the Health and Retirement Study and similar population‐based ageing surveys. The survey will be implemented in five European countries (Czech Republic, Denmark, France, Germany, Italy) in a stratified study sample of 2,500 SHARE panel respondents. SHARE‐HCAP’s adaptation procedures include the a) development of socio‐culturally appropriate recruitment strategies and interview techniques, b) translation of HCAP content, including study documents, test materials, and informant interview by a team of multi‐lingual researchers and clinicians, c) pre‐statistical harmonization of the HCAP test battery, including administration and scoring, and d) development of comprehensive training of local survey interviewers who were inexperienced in cognitive assessment. SHARE‐HCAP adaptations were assessed in two small‐scale preliminary data collections. Descriptive statistical analyses of neuropsychological test scores were conducted.

Result

To date, we have developed lingo‐culturally adapted HCAP documents (e.g., informed consent, recruitment materials), and neuropsychological test content and interviews for five SHARE countries. Descriptive statistics suggest that SHARE‐HCAP pre‐test data behave similarly to neuropsychological test data of two English‐language HCAP studies (i.e., USA and England).

Conclusion

As the first HCAP sub‐study conducted cross‐nationally, SHARE‐HCAP’s cultural and linguistic adaptations can provide valuable insights into the collection of cognitive health data in population‐based surveys in multi‐national contexts. Preliminary results support the comparability of SHARE‐HCAP to English‐language HCAP batteries. Assessing cognitive functioning in population studies, such as SHARE‐HCAP, leverages the international variation of health and life circumstances to identify the bio‐medical and socio‐economic conditions that contribute to cognitive health over the life‐course.
The effect of education on ATN biomarkers of Alzheimer’s disease according to the presence of APOE4
Authors: Kim Yeshin , Jang Hyemin , Jang Jae‐Won
Published: June 2023

Background

As a proxy of cognitive reserve, education is known to have a protective effect against the cognitive decline in Alzheimer’s disease. It is explained that those who have higher education would resist pathologic burdens through other mechanisms such as changes of functional networks of the brain. However, it is not well known whether there is an association between education and the pathologic burden. APOE is the important genetic risk factor, and the presence of the ε4 allele is associated with biomarkers. This study aimed to evaluate the association between education and ATN biomarkers in Alzheimer’s disease according to the presence of APOE4.

Method

We analyzed 1,076 Alzheimer’s Disease Neuroimaging Initiative participants’ data (336 cognitively normal (CN), 279 early aMCI, 279 late aMCI, 182 AD). The values of CSF amyloid β1‐42, CSF phosphorylated Tau (p‐Tau), and 18F‐fluorodeoxyglucose‐positron emission tomography (FDG PET) brain metabolism were used as ATN biomarkers. We analyzed the association between education and ATN biomarkers in each group, according to the presence of APOE ε4 allele, using a multiple linear regression model after controlling age and sex.

Result

Higher education was related to lower CSF p‐Tau in the early aMCI group only when APOE4 was positive (β = ‐1.3, p = 0.013). Other than the early aMCI group, we could not find any association between education and ATN biomarkers.

Conclusion

This finding suggests that education could have a protective effect on the pathologic tau burden in the presence of APOE4, especially at the early aMCI stage.
Head‐to‐head comparison of Relative Cerebral Blood Flow derived from [18F]florbetapir and [18F]flortaucipir in subjects with Subjective Cognitive Decline
Authors: Tuncel Hayel , Visser Denise , Timmers Tessa , Wolters Emma E , Ossenkoppele Rik , van der Flier Wiesje M. , van Berckel Bart N.M. , Boellaard Ronald , Golla Sandeep S.V.
Published: June 2023

Background

Several studies validated R1 as a marker for relative cerebral blood flow (rCBF). However, the similarities or differences of R1 estimates obtained from different PET tracers has never been investigated.

Aim

The aim of the current study was head‐to‐head comparison of R1 estimates, derived from dynamic [18F]florbetapir and [18F]flortaucipir PET scans.

Method

Fifty subjects with subjective cognitive decline (Aβ‐;N = 31, Aβ+;N = 19) underwent both [18F]florbetapir and [18F]flortaucipir PET (interval: 50.6 ± 34.7 days). Receptor parametric mapping (RPM) was used to generate R1 maps with cerebellar grey matter as reference. For voxel‐wise analyses, Statistical Parametric Mapping software (SPM12) was used. Furthermore, different regions‐of‐interest were assessed (in subject‐space). Paired t‐tests, coefficients of determination (r2) and ICC were used to compare R1 estimates from [18F]florbetapir and [18F]flortaucipir PET.

Results

Voxel‐wise analysis revealed only a few small significant clusters in part of the thalamus, insular gyri, midbrain and part of the cerebellum with higher R1 estimates for [18F]florbetapir and higher R1 estimates in the hippocampus, vermis, midbrain and calcarine sulcus for [18F]flortaucipir in Aβ‐ subjects (Figure 1a & 1b). In Aβ+ subjects, [18F]florbetapir showed higher R1 estimates only in part of the thalamus and [18F]flortaucipir showed higher R1 estimates in the hippocampus and striatum (Figure 1c & 1d). Despite the small amount of significant voxels, [18F]florbetapir R1 showed good correlation and excellent ICC with [18F]flortaucipir for whole brain (Aβ‐:r2 = 0.76, ICC:0.92; Aβ+:r2 = 0.60,ICC = 0.87).

Conclusion

To conclude, [18F]flortaucipir and [18F]florbetapir showed similar R1 estimates in cortical regions, illustrating that R1 is a robust marker for flow independent of tracer of interest.
The QSP model of TREM2 influences on inflammatory state of microglia in Alzheimer’s disease
Authors: Lerner Stepan , Karelina Tatiana
Published: June 2023

Background

Inflammation is one of the critical components in the development of neurodegenerative diseases. Microglia is the resident of macrophages of the central nervous system. In the AD brain, microglial cells are found in close association with amyloid beta deposits. Histological examination of AD brains as well as cell culture studies have shown that the interaction of microglia with fibrillar amyloid beta leads to their phenotypic activation. It increases the activation of microglia cells and switches them from resting (M0) to activating (M1 or M2) state and the release of cytokines. The role of microglia in AD progression is unclear with conflicting reports regarding their detrimental or protective contribution to the disease. The QSP model was developed to investigate influence of TREM2 on inflammation of microglia.

Methods

The model describes microglia resting state, phagocytosis, TLR, P2×7 and TREM2 receptors, kinases, intracellular signaling pathways, apoptosis of microglia cells, response of microglia to LPS, oligomeric and fibrillar amyloid and cytokines (IL6, IL1b, TNFa), distribution of cytokines from the brain into cerebrospinal fluid and blood.

Results

The model correctly describes decreased phagocytosis, increased cytokine and pro‐inflammation factors with influence of amyloid beta and TREM2 KO during LPS‐induction. It demonstrates that: 1) TREM KO leads to decrease of phagocytosis [1] 2) Ab influence on TREM2 leads to increase of inflammatory cytokine level [2] 3) Inhibitor of PI3K (LY294002) decreases phagocytosis in signaling pathway (PI3K/FoxO/phagocytosis) [3].

Conclusions

This QSP model can be used to predict the response of microglia to various conditions caused by neurodegenerative diseases and therapies targeting microglial state.

[1] – PMID: 30548312

[2] – PMID: 33065553

[3] – PMID: 28842601
Photobiomodulation in human neuroblastoma under oxidative stress
Authors: Rossato Rafaella Carvalho , Salles Geisa Rodrigues , de Albuquerque Amanda Lira Gurgel , Pacheco‐Soares Cristina
Published: June 2023

Background

With the increase in life expectancy, the number of people with neurodegenerative diseases such as Alzheimer’s Disease (AD) is rising rapidly. Considering the pathways of AD, one of its fundamental processes is oxidative stress, affecting the central nervous system and cell regeneration. Interestingly, in the last decades, photobiomodulation has shown positive effects on neural cells that are compromised by AD. Studies have demonstrated that LED (light emitting diode) irradiation regulates cell function, stimulating cell proliferation, promoting biomodulation in the cytoskeleton, and reducing apoptosis. To contribute with the elucidation of the importance of photobiomodulation in AD, this study aims to evaluate its neuroprotective effect, comparing different energy density of LED irradiating in SH‐SY5Y cells (human neuroblastoma) under the effect of oxidative stress induced by hydrogen peroxide (H2O2).

Method

SH‐SY5Y cells (human neuroblastoma) were cultivated in DMEM/F12 medium (Dulbecco’s modified Eagles medium ‐ Gibco), supplemented with 10% fetal bovine serum and 1% antibiotic and antimycotic, at 37°C, in an atmosphere of 5% CO2. Cells were plated in 24‐well plates. After cell adhesion, cells were irradiated with LED at 660 nm (LED Biopdi/Irrad‐Led5), at energy densities of 1 J/cm2, 3 J/cm2, 5 J/cm2 and 10 J/ cm2. 24 h after irradiation, oxidative stress was induced with 200 μM H2O2 for 24h (this parameter had been previously determined by ROSSATO, R. C. et al, 2021).

Result

Once cells are irradiated and stressed, a considerable statistic difference is observed for all energy densities evaluated, compared to the stressed‐only group (H2O2). Importantly, the energy density of 3 J/cm2 was the lowest one that obtained better statistical increase in mithocondrial activity (p < 0.0001).

Conclusion

It was possible to determine and compare the energy densities of LED irradiation to promote cellular photobiomodulation, inducing mithocondrial activity on neubroblastoma. Importantly, this study demonstrated the neuroprotective effect of LED in an in vitro model of AD oxidative stress, approaching novel concepts and a preventive tool.

ROSSATO, R. C. et al. Neuroprotective effects of taurine on SH‐SY5Y cells under hydrocortisone induced stress.

Research, Society and Development, v. 10, n. 9, p. e55510918426‐e55510918426, 2021
Review of assessment methods for dementia
Authors: Parsapoor Mahboobeh , Menard Pierre‐Andre , Boulianne Gilles
Published: June 2023

Background

More than 50 million people worldwide live with various types of dementia, which incorporates a progressive decline in patients' cognition. Early detection of dementia in older adults is crucial and helps them apply for intervention programs. Numerous assessment methods have been developed to be used in clinical practice and help clinicians accurately detect dementia and diagnose its types. The recent advancement in the artificial intelligence domain has revolutionized the early detection of dementia and allowed clinicians to use AI‐based assessment technologies for detecting dementia at its very mild decline stage. The AI community aims to develop valid, efficient, practical, reliable, and accurate AI‐based assessment technologies to detect dementia; thus, to help the community, this paper reviews clinical assessment methods and recently developed AI‐based assessment technologies, particularly AI‐based language and speech assessment techniques. Moreover, it collects information about available datasets, python libraries for developing AI assessment methodologies to detect dementia.

Method

We have extracted around 300 peer‐reviewed articles from PubMed and MEDLINE related to AI‐based assessment technologies (i.e., focusing on automated language and speech‐based assessment methods) and cognitive, behavioral, neurophysiological, functional assessment methods.

Result

By reviewing more than 50 various clinical and AI assessment methods, we listed the advantages and limitations of clinical and AI assessment methods and available machine learning datasets, python scripts, and libraries to develop AI assessment methods to detect dementia.

Conclusion

The paper could provide valuable information for the AI community to have better progress in developing quick, accurate, multicultural, practical assessment technologies with high specificity and sensitivity. The paper can be beneficial for mental health clinicians to learn about known AI‐based assessment methods to detect dementia.
Autopsy‐confirmed minimally invasive biomarker identifies Alzheimer’s Disease even in the presence of co‐morbid pathologies
Authors: Chirila Florin , Xu Guang , Fontaine Daniel , MacTurk William , Khan Tapan , Alkon Daniel L
Published: June 2023

Background

There are currently no FDA‐approved tests that are highly sensitive and highly specific for Alzheimer’s disease (AD). Diagnostic Accuracy has been even more difficult due to recent findings that >50% of AD brains show co‐morbid pathologies such as multi‐infarct dementia and Frontal Lobe Dementia. Here, we describe an autopsy‐confirmed AD Biomarker that identifies AD pathology even with co‐morbid brain pathology.

Method

A Morphometric Imaging (MI) assay was previously shown to correlate the dementia and presence of AD pathology in the brains of AD patients (Chirila et al., 2013) with abnormalities of skin fibroblasts isolated with routine punch biopsies (∼3mm). Cells were cultured on a thick layer of 3‐D Matrigel matrix and subjected to image analysis. AD cell lines formed large aggregates in contrast to non‐AD dementia (non‐ADD) or non‐demented control (NDC) cell samples. Typically skin fibroblasts formed “networks” analogous to networks formed by neurons isolated in cell culture and AD networks were slower and less connected Quantitative image analyses enabled the calculation of average unit aggregate area (A) in terms of ln(A/N). Samples were collected with a double‐blind protocol for demented patients > 55 years old who eventually reached blinded autopsy examination. NDC samples were collected for Biomarker assay only.

Result

The total fibroblast patient sample (N = 74) consisted of AD (N = 26) patients and non‐ADD (N = 21) patients (all were autopsy confirmed and had blinded biomarker data); and NDC, N = 27 that had biomarker data. The cut‐off value of ln(A/N) = 6.98 was determined from the biomarker values for NDC patient samples. For the Biomarker AD vs. Non‐ADD data, True Positive = 26, False Negative = 0, False Positive = 0, with Sensitivity and Specificity calculated as 100 and 100, respectively. (AD vs. Non‐ADD, p < .000001). The NDC MI assay values closely superimposed with the non‐ADD sample values.

Conclusion

In these autopsy‐confirmed results, the MI Biomarker distinguished AD from Non‐ADD patients and correctly diagnosed AD even in the presence of other co‐morbid pathologies at autopsy. This highly, accurate, minimally invasive AD biomarker, therefore, was validated by rigorous reference to the NIH gold standard criteria for an AD Diagnosis, dementia in life and the presence of plaques and hyperphosphorylated tau at autopsy.
Implementing and evaluating the driving and dementia roadmap (DDR) during the COVID pandemic
Authors: Naglie Gary , Stasiulis Elaine , Sandhu Harvir , Gallucci Christina E. , Rapoport Mark J.
Published: June 2023

Background

To address the gap in evidence‐based interventions and resources to support people living with dementia (PWD) and family/friend carers (FCs) through the challenging process of driving cessation, we developed a web‐based educational resource called the Driving and Dementia Roadmap (DDR). An implementation evaluation, which took place during the COVID pandemic, was conducted to explore the delivery, acceptability, adaptability, preliminary benefits and limitations of the DDR.

Method

The DDR was delivered to Alzheimer Society (AS) clients by staff from six organizations in four Canadian provinces from December 2020 to September 2021. Semi‐structured interviews were conducted with 19 AS staff, eight PWD and 13 FCs. In addition to questions about their experiences of delivering and using the DDR, participants were asked about the impact of COVID on using the DDR. Data were examined using a thematic analysis approach.

Result

AS staff reported that client concerns about driving cessation and the need for the DDR were less than anticipated due to COVID. They attributed this to other pressing issues such as the need to stay safe from COVID, a lack of access to services and activities, caregiver burnout and PWD’s isolation. FCs and PWD also indicated that driving was not an immediate concern because they were driving less in the pandemic. However, AS staff expressed apprehensions about increased driving risk in the aftermath of COVID due to reports of PWD’s profound cognitive decline and lack of driving experience during the pandemic.

Conclusion

Although COVID’s impact on driving cessation initially lessened PWD’s and FCs’ urgency in attending to this issue, the longer‐term implications of neglecting this issue may be considerable for PWD and FC. The need for resources, such as the DDR, to support PWD and FCs in the decision‐making and transition to non‐driving will be particularly critical post‐COVID.
Association of HbA1c trajectory and variability with cognitive function
Authors: Mongraw‐Chaffin Morgana , Evans Joni K , Bancks Michael P. , Schaich Christopher L. , Shappell Heather M , Espeland Mark A. , Hayden Kathleen M.
Published: June 2023

Background

Type 2 diabetes (T2D) is an important modifiable risk factor for cognitive decline, and increasing evidence suggests that worse glucose control, in addition to a diagnosis of T2D, may play a role in cognitive function in later life. Despite this increasing concern, evidence regarding the relative contributions of poor glucose control and higher glucose variability to cognitive dysfunction among individuals with overweight or obesity is limited, mostly due to lack of repeated measures in many studies.

Method

Look AHEAD MIND Study participants, aged 45‐76 years at baseline (2001‐04) with T2D and overweight or obesity, were randomized to an intensive lifestyle intervention focused on weight loss or a diabetes support and education condition, which were discontinued after ∼10 years. HbA1c levels were evaluated at years 1‐4, 6, 8, and 10. Cognitive function was evaluated up to four times between years 8‐18 with a cognitive battery that assessed memory, attention, and executive function domains. Cognitive scores were binned into four groups based on relative timing of cognitive assessments (8‐9; 10‐11; 12‐14; and 15‐18 years). We classified HbA1c variability according to: Variability Independent of the Mean (VIM), Average Real Variability (ARV), and data‐driven latent trajectories. Mixed linear regression models for standardized composite cognitive scores were adjusted for: repeated measures, order of cognitive test, years from randomization, randomization arm, age, sex, race/ethnicity, years of education, CVD history, and APOE ε4.

Result

Four HbA1c trajectories were identified: increasing, decreasing, stable‐high, and stable‐low. Composite cognitive scores were significantly lower for increasing, decreasing, and stable‐high HbA1c trajectories ‐compared to stable‐low HbA1c (Table). In multivariable analysis, higher baseline HbA1c, ARV, and VIM were associated with lower composite cognitive scores, and differences between groups were similar by years since randomization. Estimates for ARV and VIM were attenuated when adjusted for baseline HbA1c (not shown). Estimates were similar for tests from all cognitive domains, with little heterogeneity by randomization arm.

Conclusion

Among individuals with T2D, higher HbA1c at baseline and greater HbA1c variability over 10 years were significantly associated with lower cognitive scores, suggesting that maintaining glucose control may be useful for the prevention of cognitive decline.
Improved SUVR calculation for [18F]‐AV45 amyloid pet imaging using a novel reference region approach
Authors: Pfeil Julia , Drzezga Alexander , van Eimeren Thilo , Bischof Gerard N
Published: June 2023

Background

Utilization of a data‐driven approach to find a more sensitive reference region (RR) for [18F]‐AV45 PET imaging that differentiates the spectrum of Alzheimer’s disease (AD) and improves especially longitudinal study designs.

Method

Data of 283 participants (135 amyloid‐negative cognitively normal (CN), and 148 amyloid‐positive AD) from the ADNI database (http://adni.loni.usc.edu/) was used. All [18F]‐AV45 scans were co‐registered, normalized, and skull‐stripped. The dataset was split into a training‐and test‐dataset. Voxel‐wise group comparisons were performed in the training‐set (75 CNs, 77 ADs) to identify a RR that is void off on‐target tracer uptake. Potential clusters were used to extract mean global SUVRs in the test‐dataset (60 CNs, 70 ADs). Effect sizes between novel and commonly used RRs were compared. Baseline and follow‐up data of 19 CNs, 36 participants with mild cognitive impairment, and 26 ADs was used to test whether the newly identified RR is more sensitive to assess longitudinal change than common RRs. Effect sizes of change in SUVR between baseline and follow‐up were used as metric of sensitivity.

Result

The training dataset yielded two novel RRs in the brainstem and the cerebellar white matter. These new RRs showed higher effect sizes compared with commonly used RRs. However, no significant differences in the effect sizes were observed when examining longitudinal change in SUVR compared with commonly used RRs.

Conclusion

The data‐driven approach did not improve SUVR measurements for [18]‐AV45 imaging. However, our analyses proved that the commonly used RRs are also longitudinally stable and sensitive to differentiate clinical from non‐clinical groups.
Role of Amyloid Precursor Protein in Astrocytes in Alzheimer´s Disease.
Authors: Jauregui Gretsen Velezmoro ,   Translational Neuroscience and Aging Program (TAP)
Published: June 2023

Background

Astrocytes are specialized glial cells that when exposed to inflammatory factors go through a process known as reactive astrogliosis. Reactive astrocytes are a neuropathological feature of Alzheimer’s disease (AD). The etiology of AD is often explained by the accumulation of β‐amyloid peptides, a proteolytic product of the amyloid precursor protein (APP). However, inflammation also plays a prominent role in the development of AD. How reactive astrocytesparticipate in the pathogenesis of AD remains poorly understood

Method

To elucidate the role of astrocytes in the pathogenesis of AD we exploited different in vitro and in vivo models to investigate the role of Amyloid Precursor protein in setting the immune response of astrocytes.

Result

Our results show that overexpression of APP in human cortical astrocytes induces reactive phenotype, similar to astrocytes found in brains of AD patients. These reactive astrocytes produce significantly increased levels of INF‐g in comparison with control astrocytes. Similar positive correlation between APP levels and INF‐g is found also in astrocytes from AD transgenic and traumatic brain injury mice models.

Conclusion

Our data indicate that astrocytes are activated by high levels of APP, which promotes production and secretion of interferons and recapitulates salient features of astrocytes in AD.
Brain‐derived neurotrophic factor genes are associated with neuropsychiatric symptom progression in dementia. The Cache county dementia progression study
Authors: Matyi Joshua , Drewel Mikaela , Schwartz Sarah , Rattinger Gail B. , Gonzalez Hector Leonardo , DeBerard Scott , Buhusi Mona , Lyketsos Constantine G. , Tschanz JoAnn T
Published: June 2023

Background

Polymorphisms in genes coding for the neurotrophin, brain‐derived neurotrophic factor (BDNF) or its receptors, have been associated with Alzheimer’s disease and related disorders (ADRD), with sex‐dependent effects. Associations with neuropsychiatric symptom (NPS) progression after dementia onset has been largely unexplored. In a population‐based cohort, we examined the relationships between BDNF gene single‐nucleotide polymorphisms (SNPs) and NPS progression after dementia onset.

Method

880 participants [61.3% female; mean (SD) age = 82.0 (71) years] with dementia [68.2% AD; 13.5% Vascular Dementia (VaD); 18.3% other dementia (OD)] were assessed on the Neuropsychiatric Inventory (NPI) every six‐to‐18 months. Mean(SD) baseline dementia duration was 2.9(2.7) years. The following SNPs were examined as predictors of NPI scores over time in linear mixed‐effects models: rs6265 (BDNF G196A/Val66Met), rs56164415 (BDNF C270T), rs2289656 (NTRK2 receptor TrkB), and rs2072446 (NGFR p75NTR). Covariates included age of dementia onset, education, apolipoprotein E genotype, and dementia type and duration at baseline.

Result

Sex‐dependent effects were found for two SNPs. Compared to those with major alleles, males with the rs56164415 minor allele exhibited a lower initial Apathy score, that increased over time (C/t*sex*time2:b = ‐0.063, SE = 0.029, p = .033); by contrast, females showed no differences by SNP alleles. Females homozygous for the rs2289656 minor allele exhibited a rapid increase in Anxiety that decreased over time (t/t*sex*time2: b = ‐0.145, SE = 0.054, p = .0073). For both sexes, presence of minor alleles for BDNF polymorphisms rs6265 (G/a*time2: b = ‐0.017, SE = 0.004, p < .001; a/a*time2: b = ‐0.035, SE = 0.013, p = .006) and rs56164415 (C/t*time2: b = 0.019, SE = 0.005, p < .001) was associated with increased NPI Agitation/Aggression well after baseline. Rs6265 minor allele homozygotes (a/a*time2: b = ‐0.049, SE = 0.013, p < .001) and rs2072446 minor allele carriers (Ct/tt*time2: b = ‐0.012, SE = 0.005, p = .025) exhibited initial increases in Delusions, which diminished approximately 5 years thereafter.

Conclusion

Specific BDNF genotypes were associated with NPS presentation after dementia onset, with some sex‐dependent effects. Future research on enhancing BDNF signaling may present possible targets for intervention.