bluuebunny/crossref_metadata_2025 huggingface dataset:
Moral emotions in neuropsychiatry : testing FTD and Schizophrenia patients with the MEA scale.
Authors: AUGER Raphaëlle LEROUX , Mouchabac Stephane , Daigmorte Chloé , GALLARDA Thierry , Hamisultane Jessica , Azuar Carole
Published: December 2022

Background

Moral emotions have a key role in human prosocial behaviors. Impaired moral emotion processing can lead to disrupted decision‐making and behavioral adaptation.

Better knowledge about moral emotion processing in neuropsychiatric diseases is necessary to facilitate diagnosis and patient care.

The aim of this study was to investigate and to compare moral emotion processing in patients with neurodegenerative diseases ‐behavioral fronto temporal dementia (FTD) and Alzheimer’s disease (AD)‐ and patients with schizophrenia.

Method

We investigated 22 FTD, 15 AD, 30 schizophrenia patients and a control group with validated task, the Moral Emotions Assessment (MEA). This tool consisted in 42 scenarios exploring positive and negative moral emotions such as admiration, gratitude, shame or anger. Subjects had to choose between several emotions the most appropriate to the context of the scenario. To control for moral specificity, we contrasted the 42 moral scenarios with 18 extra‐moral scenarios eliciting the emotions without involving any inter‐human moral context.

Result

FTD patients and Schizophrenia patients were significantly impaired in moral emotion processing, when compared to healthy controls, whereas AD patients were not impaired. There was a specific impairment of moral emotions in FTD, (73.1% of correct answers VS 95.1% in control group p<0,001) and the most impaired emotion was guilt. AD patients didn’t show impairment in moral emotion processing compared to healthy controls. In Schizophrenia patients, moral emotion processing was significantly impaired (85,8% of correct answers VS 95,9% in control group, p<0,001), and the most impaired emotions were anger and shame.

Conclusion

Moral emotions processing seemed significantly impaired in FTD patients and schizophrenia patients, with different patterns of deficits, whereas AD patients seemed to have preserved moral cognition. These results provide a better understanding of the behavioral changes observed in FTD and schizophrenia patients.
Bibliographic Analysis of Aging Anxiety and Lifestyle
Authors: Park Sun Ha , Lim Young Myoung , Kim Mi Kyeong , Lee Ha Min , Park Hae Yean
Published: December 2022

Background

With the recent increase in the older adults population, interest in successful aging is increasing. Aging anxiety, a psychological mechanism that affects successful aging, refers to the inability to feel stable due to worry or fear in old age, which negatively affects the older adult‘s feelings of depression and quality of life. According to a study on successful aging and aging anxiety, it was recently reported that aging anxiety can be prevented by realizing healthy aging through lifestyle intervention. To date, studies analyzing aging anxiety and lifestyle from a macro perspective are insufficient. To compensate for these limitations, bibliographic analysis methods that derive the characteristics of academic literature from bibliographic information are used. Since it is essential to understand research trends from a macroscopic point of view at a time when the need for research on aging anxiety and lifestyle is emphasized, in this study, the flow of research on aging anxiety and lifestyle is identified to prepare basic data for future research.

Method

Among the bibliographic analysis methods, first a citation analysis method that identifies the association based on the number of citations. Second a simultaneous appearance word analysis method that identifies the association based on the number of keywords appeared was used. VOSviewer was used to cluster and chart the analyzed information.

Result

The frequency of published papers by year showed a gradual increase until 2017 and a rapid increase from 2018. In the field of research paper study, research was most actively conducted in the field of psychiatry. In the citation analysis, the United States, Australia, and the United Kingdom showed high correlation with each other, and as a result of conducting simultaneous word analysis on major keywords, words with high association with ‘aging anxiety’ were found to be ‘depression’.

Conclusion

This study is meaningful in that it grasped the flow of aging anxiety and lifestyle research from a macroscopic point of view using a bibliographic analysis method. Based on this, it is expected to understand the importance of lifestyle from the preventive point of view of aging and to be used as basic data for intervention and related education.
How well is Brazil prepared for a disease‐modifying Alzheimer’s treatment?
Authors: Mattke Soeren , Filho Otelo Corrêa dos Santos
Published: December 2022

Background

While the majority of patients with Alzheimer’s disease resides in low and middle‐income countries, little is known of their preparedness for emerging disease‐modifying treatments. We analyze the preparedness of Brazil, one of the most populous middle‐income countries, from a capacity and institutional preparedness perspective.

Method

Desk research and 12 interviews for background and capacity data. Markov model to estimate wait times for access to treatment.

Result

Brazil has no national dementia strategy or established pathway for evaluation of cognitive concerns, and dementia is typically diagnosed late if at all. While members of private health plans have ready access to elective specialty care, wait times in the public sector are long. Assuming potentially treatment‐eligible patients are referred from primary to specialty care based on a brief cognitive exam and a blood test for the Alzheimer’s pathology, available capacity will not be sufficient to match the projected demand (Figure 1). The biggest obstacle is availability of dementia specialist visits, and the effect of population growth and ageing means that the wait list for specialist appointment will continue to grow from around 400,000 in 2022 to over 2.2 million in 2040. We do not project substantial wait times for confirmatory biomarker testing and treatment delivery but note that this is a consequence of patients waiting for their specialist appointments. These queues will result in estimated persistent wait times for treatment of around two years on average with substantial differences between the public and private sectors, as capacity growth is insufficient to keep up with increasing demand.

Conclusion

Our findings suggest that Brazil is ill‐prepared to provide timely access to an Alzheimer’s treatment with predicted wait times of about two years, largely because of a limited number of dementia specialists. Access is likely to be unequal based on socioeconomic status and geographic location. Closing this gap will be challenging because of high public debt and chronic underinvestment, leaving a focus on prevention and on use of scalable technologies, such as digital cognitive and blood tests for Alzheimer’s disease as viable option. A national dementia plan with an implementation strategy would be an important first step.
Family care partners experiences of delirium in caring for a person with dementia: Qualitative descriptive study
Authors: Shrestha Priyanka , Fick Donna Marie , Boltz Marie , Loeb Susan J , High Andrew C
Published: December 2022

Background

Delirium in persons with dementia is common, distressing, and associated with poor outcomes not only for the older adults, but also for their family care partners. There is a practice and science gap in understanding the role care partners’ may play in the prevention, recognition, and management of delirium in persons with dementia, as well as care partners’ needs, necessary to inform co‐designed interventions to improve the lives of the dyad. This study explored family care partners’ understanding and experience related to delirium as well as their preferences in terms of need for education, support, and resources.

Method

Qualitative descriptive design was employed. Data were collected from 16 family care partners (age x̄ = 65, SD = 13.2) of persons with dementia using demographic questionnaires and semi‐structured in‐depth interviews [telephone (N = 7); Zoom video conference (N = 9)]. Demographic data of the sample were described. Qualitative thematic analysis revealed patterns and themes. The reporting of this study followed the criteria for reporting qualitative studies in the (COREQ) 32‐item checklist.

Result

Six themes emerged: : (i) distressing sentiment; (ii) unexpected manifestation of delirium, (iii) unfamiliarity with delirium; (iv) changing roles; (v) complexities of delirium and dementia management; and (vi) longing for support.

Conclusion

Balancing the care needs relating to pre‐existing dementia, while simultaneously identifying and managing delirium is difficult for family care partners. Challenges were related to communication, differentiating signs of delirium from dementia, lack of resources, and uncertainty and fear about the future. Providing education about delirium to family care partners through trained clinicians exhibits a promising approach, but utilization of existing community resources should also be encouraged. Care partner experiences should be valued and future research should involve family care partners in co‐designing therapeutic interventions to promote family care partners’ well‐being and to boost their confidence and efficiency in their caregiving role. Implications for practice, research, and policy will be discussed.
Post‐mortem assessment of retinal phosphorylated tau and amyloid beta in a cohort of neurodegenerative diseases.
Authors: de Ruyter Frederique J. Hart , Morrema Tjado , Gase Gina , den Haan Jurre , de Boer Johannes , Scheltens Philip , Rozemuller Annemieke J.M. , Verbraak Frank D. , Bouwman Femke H. , Hoozemans Jeroen J.M.
Published: December 2022

Background

The retina provides an opportunity for development of a screening tool to detect early stages of AD. Studies showing the presence of Aβ and p‐tau in AD retina are contradictory, and their characterization in a large, neuropathologically confirmed cohort with different neurodegenerative diseases is scarce. In this study we assessed the presence of different tau isoforms and Aβ (4G8) in the retinas of AD cases, control cases, as well as other neurodegenerative diseases, and correlated these directly to cortical cerebral tau and amyloid pathology loads.

Method

Post mortem eyes (N = 62) with both clinical history and post‐mortem neuropathological reports available were collected through the Netherlands Brain Bank. Donors included AD, PSP, CBD, FTLD, PD(D), DLB, MSA, ALS, MS and controls, with and without cerebral cortical p‐tau. Superior‐temporal quadrants were cut in 10 µm sections. Sections were immunostained using antibodies directed against p‐tau (AT270, AT100, AT8, pS422) and Aβ (4G8). Linear mixed models were used to analyze between‐group differences and the relation between brain and retina.

Result

Tau appeared as a diffuse neuritic staining, and in some cases as somatodendritic‐like staining and was mainly present in the plexiform layers of the retina. AT8, AT100 and AT270 immunoreactivity showed a predilection in the far periphery. AT8 was generally found in tauopathy cases as opposed to non‐tauopathy cases. A strong correlation was found between retinal AT8 and brain cortical tau pathology. 4G8 appeared sporadically as extracellular structures, mainly present in the retinal nerve fiber layer, ganglion cell layer and near blood vessels. 4G8 did not differ between control and disease cases, and no group differences or relation with cortical amyloid load was found.

Conclusion

P‐tau measured with AT8 in the retina correlates with the presence of tau pathology in cortical brain areas. In contrast, Aβ (4G8) immunoreactivity is sporadically present in the retina, is not specific for AD and does not correlate with cortical amyloid load in a large cross‐disease cohort. Our study shows that p‐tau detected in the retina by AT8 is a potential biomarker candidate for tauopathies.
Psychosocial Stress‐Accelerates Alzheimer’s Disease Progression via the Xanthine Oxidase Pathway
Authors: Burrage Emily , Prabhu Saina , Oudomvilay Crystal , Simpkins James W , Kelley Eric E , Chantler Paul D
Published: December 2022

Background

Vascular contributions to cognitive impairment and dementia are a key pathology associated with Alzheimer’s disease (AD). We have shown that chronic stress induces cerebrovascular dysfunction due to a pro‐oxidative environment, a phenotype similar to that noted with AD. Epidemiological studies also suggest a link between chronic stress and dementia. We tested the hypothesis that chronic stress accelerates the AD pathology via the xanthine oxidase (XO) pathway.

Methods

Wild type (WT) and Triple transgenic (AD) mice were separated into 1) WT control, 2) WT+UCMS, 3) AD control, 4) AD control+Feb, 5) AD+UCMS, 6) AD+UCMS+Feb. At 4 months‐of‐age, dependent upon group, the unpredicted chronic mild stress (UCMS) model with or without Febuxostat (Feb) treated water (50mg/L) began for 8 weeks. Mice were either euthanized at 6 or 9 months‐of‐age. The middle cerebral artery (MCA) was removed for pressure myography. Brains were homogenized to extract soluble and insoluble fractions of tau proteins using Western blot normalized to GAPDH or B‐actin.

Results

At 6 months‐of‐age, AD mice displayed a 72% impaired MCA dilation to acetylcholine compared to WT control mice (p<0.05). WT and AD mice that underwent UCMS displayed similar MCA dysfunction compared to AD control mice. UCMS accelerated total and phosphorylated tau protein expression by 83% (p<0.05) and 350% (p<0.001), respectively, compared to AD controls. Treatment with Feb prevented MCA dysfunction in AD control mice, WT UCMS mice, and AD UCMS mice. Feb prevented the increased expression of phosphorylated tau and lowered the total tau protein expression in the AD‐UCMS group. However, total tau protein expression remained higher compared to AD control levels. At 9 months‐of‐age, the majority of these trends persisted with the one exception being a significant impairment in the AD UCMS group compared to both AD control or WT UCMS mice. Tau levels have yet to be processed for 9‐months.

Conclusion

Overall, these data suggest that chronic stress accelerates cerebrovascular pathology with AD and via a pro‐oxidative state driven by activation of the XO pathway. We will further explore Aβ1‐42 and XO in 3xTg brain homogenates at 6 and 9 months‐of‐age, to better understand how stress accelerates AD pathology.
Detecting genetic loci for preservation of cognition in the Midwestern United States Amish
Authors: Main Leighanne R. , Song Yeunjoo E. , Laux Renee A. , Miskimen Kristy L. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Osterman Michael D. , Lynn Audrey , Dorfsman Daniel A. , Caywood Laura J. , Prough Michael B. , Adams Larry D. , Clouse Jason E. , Herington Sharlene D. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L.
Published: December 2022

Background

Alzheimer’s Disease (AD) is the most common form of dementia and has limited treatments. While AD risk has a large genetic component, under 50% of the genetic risk has been identified. By focusing on identifying genetic variants that delay or prevent the onset of AD, our goal is to identify new associated genes and variants. To detect such loci, we studied cognitive preservation in the Midwestern Amish, a genetically and culturally isolated population of European descent.

Methods

We studied 946 Amish individuals (ages 76‐95) from Ohio and Indiana. Participants were classified as cognitively impaired (33.8%) or cognitively unimpaired (66.2%) by consensus review of cognitive examinations. These individuals were all connected in a 15‐generation 8,222‐person pedigree. This pedigree was divided into 104 sub‐pedigrees via PedCut for linkage analysis. MERLIN was used for autosomal linkage analysis, while MINX was used for X‐chromosome linkage analysis. The association analysis, corrected for genetic relationship, used GENESIS for autosomes and XWAS for the X chromosome.

Results

Over 250,000 SNPs were used for association and two‐point linkage analyses, and a subset of 5,294 uncorrelated SNPs was used for multipoint linkage analyses. on 15 different chromosomes, with the highest two‐point heterogeneity LOD score (HLOD = 5.85) on chromosome 2 (∼79Mb) and highest multipoint HLOD (3.55) on chromosome 12 (∼25Mb), neither overlapping with known AD genes. Two linkage results overlapped with known AD genes (Chr 6: CD2AP; Chr 11: PICALM) and do not overlap with association results. Significant (p ≤ 6.4x10‐7) and suggestive (p ≤ 1x10‐4) thresholds for association were determined using SimpleM. While no significant associations were found, suggestive associations were found for 103 SNPs (11 loci) across 10 chromosomes. Three of these (chr 11: MS4A2; chr 14: SLC24A4; chr 16: IQCK) fall near known AD genes. These significant and suggestive regions are being followed up currently with fine mapping.

Conclusion

Preliminary analyses suggest that using cognitive preservation as our phenotype of interest identifies both known AD loci and novel regions that warrant further evaluation and may lead to a further understanding of both AD and cognitive preservation.
Targeting neuroinflammation reduces synaptic, neuronal and cognitive loss in 5xFAD Alzheimer mice.
Authors: Lecca Daniela , Yung Yoo Jin , Scerba Michael T , Tweedie David , Hsueh Shih Chang , Hoffer Barry , Kim Dong Seok , McDevitt Ross A , Greig Nigel H
Published: December 2022

Background

Neuroinflammation is a consistent characteristic of Alzheimer’s disease (AD); however, whether its development drives disease progression or is an epiphenomenon remains unknown (Gyengesy et al., 2020). In this study, we evaluated how treatment with the Immunomodulatory imide drugs (IMiDs) Pomalidomide (Pom) and more potent novel analog 3,6’‐dithioPomalidomide (3,6’‐DP) affects neuronal and synaptic loss as well as cognitive impairment in a 5xFAD transgenic mouse model of AD, by targeting neuroinflammation. These mice are known to develop neuroinflammation consequent to excessive amyloid‐b (Ab) peptide generation.

Method

As a first step, Pom and 3,6’‐DP neuroprotective and anti‐inflammatory potential were characterized on primary cell cultures challenged with Ab. 5xFAD mice were evaluated over a 4‐month period, during which cognitive deficits develop. Behavioral tests were performed to establish whether selective resolution of neuroinflammation could mitigate cognitive impairment. Pom and 3,6’‐DP effects were assessed on markers of neuronal death, microglial activation, astrogliosis, and expression of PSD‐95 post‐synaptic protein. Changes in levels of inflammatory cytokines and Ab in hippocampus and cortex 5xFAD mice were also measured. Lastly, the teratogenic potential of both compounds was appraised by a cereblon/BRD3 binding FRET assay.

Result

Pom and 3,6’‐DP reduced neuronal and neurite network loss, as well as microglial cell activation in primary cortical cultures challenged with Ab. In hippocampus and cerebral cortex of 5xFAD mice, 3,6’‐DP, in particular, mitigated elevated expression of Iba1, TNF‐a and GFAP proteins, markers of microglial and astrocyte activation. This was accompanied by reductions in synaptic and neuronal cell loss as well as mitigation of behavioral impairment but, notably, no alteration in either Ab plaque or peptide generation. Both 3,6’‐DP and Pom bound cereblon; however, 3,6’‐DP did not lower Ikaros, Aiolos or SALL4, which are key downstream neo‐substrates involved in the anticancer and teratogenic actions of the IMiD drug class. Hence, 3,6’‐DP could represent a potentially safer drug to lower TNF‐a levels.

Conclusion

Mitigating neuroinflammation in the absence of actions on Ab generation to alleviate neurodegeneration and behavioral impairment indicates that neuroinflammation is a primary causative event in the Ab‐mediated pathological cascade leading to neuronal loss/cognitive impairment. Targeting neuroinflammatory mediators with IMiDs represent a promising AD therapeutic strategy.
PROPOSING THE NEUROGENESIS HYPOTHESIS FOR ALZHEIMER’S DISEASEWITH A CASE STUDY‐ PHASE 2 CLINICAL TRIALS OF NA‐831
Authors: Tran Lloyd , Kurkinen Markku
Published: December 2022

Background

In the hippocampus, new neurons are generated throughout life via a process called adult hippocampal neurogenesis (AHN). In mild cognitive impairment (MCI) and mild to moderate AD (early AD), AHN is reduced suggesting that AHN impairment compromises hippocampal functions. Augmenting AHN could help prevent or slow cognitive decline in MCI and early AD. The neurogenesis hypothesis is supported by the results of a Phase 2 randomized, double‐blind, placebo controlled clinical trial of NA‐831.

Method

NA‐831 is a small drug molecule, which activates synaptic AMPA receptors, and increases the expression of brain derived neurotrophic factor (BDNF), which is crucial in synaptic plasticity, learning and memory formation in the hippocampus. NA‐831 restores neurogenesis by increasing the number of DCX+PCNA+ neuroblast cells. The study was conducted in 56 patients with MCI, mild and moderate Alzheimer’s disease, who received 10mg to 30 mg of NA‐831 or placebo orally per day for 24 weeks.

Result

NA‐831 provided a significant delay in cognitive decline in MCI as measured by ADAS‐Cog‐13, an average score difference of 3.4 compared to placebo (p = 0.01; ITT) after 24 weeks of treatment. Similarly, NA‐831 delayed cognitive decline in early AD, an average score difference of 4.1 com‐pared to placebo (p = 0.001; ITT). CIBIC‐Plus showed 78% of the study participants receiving NA‐831 improved (p = 0.01; ITT). NA‐831 was well‐tolerated at 30 mg/day for 24 weeks, and no serious adverse events were observed.

Conclusion

The Neurogenesis Hypothesis, and details of the Phase 2 clinical trials will be presented and discussed.
In vivo cholinergic system integrity and cognition using [18F]‐FEOBV PET in healthy postmenopausal women: a pilot study
Authors: Conley Alexander C , Castellano Tonnar , Boyd Brian , Begnoche John Patrick , Rosenberg Adam J , Shokouhi Sepideh , Dumas Julie , Newhouse Paul A
Published: December 2022

Background

Women are at a higher risk of developing Alzheimer’s disease (AD), and a possible reason for this may be the effects of estrogen depletion and cholinergic system activity following menopause. The investigational radiotracer [18F]‐fluoroethoxybenzovesamicol (FEOBV) can assess in vivo cholinergic integrity, as the tracer binds to the vesicular cholinergic transporter at the synapse. FEOBV has previously shown cholinergic system decline in AD patients. The present study is an investigation of cholinergic system integrity in a sample of cognitively normal postmenopausal women, aged 50‐70 years that were part of a larger study examining cholinergic compensation following menopause. We predicted that higher FEOBV standardized uptake value ratios (SUVR) would be associated with larger basal forebrain cholinergic volumes, lower levels of amyloid SUVR, and better cognitive performance as measured by the RBANS.

Methods

Ten postmenopausal women (mean age: 57.3 ± 5.1 years) completed an FEOBV PET scan (6.5 mCi dose), MRI and cognitive assessments. The FEOBV PET images were co‐registered to the participant’s structural MRI data. FEOBV SUVR was normalized in reference to the supraventricular white matter to avoid partial volume effects from ventricular tissue. Preliminary analyses focused on associations between FEOBV SUVR and the key outcome variables.

Results

Preliminary analyses showed a positive relationship between FEOBV SUVR and the gray‐matter volume of the cholinergic basal forebrain of both hemispheres (L: r=0.51, R: r=0.65). Two participants were amyloid positive, and their FEOBV SUVR values were lower compared to the amyloid negative participants. A positive relationship was also seen between FEOBV SUVR and the RBANS total score, with higher SUVR associated with better cognitive performance (r=0.43).

Conclusions

In a small sample of cognitively normal postmenopausal women, greater FEOBV uptake was positively associated with both basal forebrain volume and cognitive performance. The results of this pilot sample show the importance of cholinergic system integrity in cognitive performance following menopause, supporting the idea that cholinergic integrity may be linearly related to performance and amyloid aggregation. Deterioration of cholinergic integrity post‐menopause may increase the risk of future cognitive decline and development of AD.
VGL101 Rescues CSF1R Dysfunction in Human Microglia And Macrophages: Evaluation of In Vitro Trem2 Agonism in Models Of A CSF1R‐Dependent Leukodystrophy
Authors: Larson Kelley C. , Gergits Frederick , Tchessalova Daria , Renoux Abigail , Figley Matthew , Fisher Richard , Papapetropoulos Spyros , Mirescu Christian
Published: December 2022

Background

Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal dominant primary microgliopathy caused by kinase loss‐of‐function mutations in the CSF1 receptor (CSF1R). The cardinal features of ALSP include demyelination, axonopathy, and symptoms ranging from frontal temporal dementia‐like behavior, movement disorders, epilepsy, and psychiatric manifestations. Many of these hallmarks further resemble Nasu‐Hakola disease, another rare leukoencephalopathy associated with homozygous mutations in triggering receptor expressed on myeloid cells 2 (TREM2) or its tyrosine kinase binding adaptor (TYROBP) which result in complete loss‐of‐function of TREM2 or its signaling partner DAP12. Following binding to its cognate ligands, IL‐34 or CSF‐1, CSF1R dimerization initiates a signaling cascade both through its kinase domain and through DAP12, which together activate SYK to promote myeloid cell survival, proliferation, and morphological changes. While analogous to CSF1R in cellular expression and interaction with DAP12, TREM2 lacks intrinsic signaling capacity and therefore requires DAP12 to translate extracellular damage‐associated cues and orchestrate a constellation of intracellular and functional responses which phenocopy CSF1R activation. Accordingly, we hypothesize TREM2 activation may rescue CSF1R loss‐of‐function and ameliorate ALSP‐associated pathology.

Methods

To test whether TREM2 gain‐of‐function could compensate for CSF1R loss‐of‐function, we developed multiple approaches to model ALSP in human myeloid cells by CSF‐1/IL‐34 depletion or CSF1R kinase inhibition using PLX‐5622 and explored functional intervention via a human TREM2 agonistic antibody, VGL101, currently in Phase‐1 clinical development. Rescue for CSF1R was quantified using a combination of live‐cell morphology captured via automated longitudinal microscopy, viability monitored by ATP Cell‐Titer Glo, and apoptosis quantified by Caspase‐3/7 fluorogenic‐imaging.

Results

In vitro phospho‐SYK profiling of VGL101 in iPSC‐derived microglia is consistent with its agonist profile (EC50: 0.77 ± 0.08 nM), while the absence of pSYK induction in TREM2‐knockout microglia demonstrates exquisite on‐target selectively. In both CSF‐1/IL‐34 depletion and CSF1R kinase inhibition paradigms of ALSP, VGL101 demonstrated full rescue of microglial and monocyte‐derived macrophage viability, inhibited apoptosis, and promoted morphological changes resembling intact CSF1R activation.

Conclusion

Collectively, our studies support the hypothesis that TREM2 agonism can compensate for CSF1R dysfunction and highlight the therapeutic potential for treating ALSP with TREM2 agonism via VGL101 passive immunotherapy.
How white matter hyperintensities impacts Alzheimer's disease and frontotemporal dementia across underrepresented Latin American samples
Authors: Campo Cecilia Gonzalez , Fraile‐Vazquez Matias , Ibáñez Agustin
Published: December 2022

Background

White matter hyperintensities (WMH) are frequently observed on MRI scans of older people. Usually interpreted as a sign of cerebrovascular disease (CVD), they are also associated with increased risk of cognitive impairment and dementia. While WMH and CVD are highly prevalent in Alzheimer's disease (AD), this has been less studied in behavioral variant frontotemporal dementia (bvFTD), letting alone their study in underrepresented populations with increased CVD. Here, we investigated WMH in AD and bvFTD patients in Latin America (Argentina, Chile and Colombia), a region with high prevalence of CVD. We analyzed total volume and regional distribution of WMH and its association with cognitive impairment and brain lacunes, a marker of CVD.

Method

A total of 66 patients (43 AD, 23 bvFTD) and 66 controls (CN) from the ReDLat consortium underwent high‐resolution brain MRI and neuropsychological examination. WMH were extracted from Flair images using automated segmentation algorithms to perform analyses of total volume and spatial distribution. Brain lacunes were visually quantified from T1 and Flair images. Group differences in total and regional WMH volume and associations with different cognitive domains, age, and brain lacunes were examined.

Result

Total and regional WMH volumes were significant larger in AD patients compared to CN and to bvFTD. No differences were found between CN and bvFTD. Only in AD, regional WMH load correlated with worse performance in a particular executive functioning task. No differences were found in the proportion of lacunes among groups nor in the total load of WMH of subjects with or without lacunes. In CN and AD, but not FTD, there was a positive correlation between total WMH volume and age, with a differential topographic distribution with a selective involvement of the bilateral cingulum‐hippocampus bundle in AD.

Conclusion

Enhanced WMH was observed in AD but not in FTD. WMH loading in specific brain regions contribute to domain‐specific cognitive deficits in AD. WMH could be partially independent of vascular pathology (it was unrelated to brain lacunes) suggesting a specific neurodegenerative origin in AD. The typical earlier onset of brain abnormalities in FTD could mask the age‐related increase in WMH.
Exercise‐Associated Modulation of Neuroinflammation in Alzheimer's Disease
Authors: Birnbaum Allison , Nobles Amber C , Banks Macy Teya , McGraw Megan , Cortes Constanza J
Published: December 2022

Background

Exercise promotes powerful systemic and central nervous system anti‐inflammatory effects, even during aging. Exercise also limits neuroinflammation in models of Alzheimer's disease (AD), thereby inhibiting disease progression and promoting other well‐documented neuroprotective effects such as supporting neuronal plasticity, stimulating adult neurogenesis, and enhancing cognitive function. However, exercise is not always accessible to aging populations that are most at risk for developing AD.

Method

We have recently derived transgenic mice that moderately overexpress Transcription Factor EB (TFEB), a lysosome biogenesis promoter, in skeletal muscle (cTFEB;HSA‐Cre mice) which resulted in enhanced muscle proteostasis, similar to what is observed with long‐term exercise regimes. These mice were then bred with 5xFAD AD‐model mice and evaluated for CNS hallmarks of AD, hippocampal neuroinflammation, and CNS amyloid beta plaque accumulation, at two time points (age=4 months, 8 months).

Result

cTFEB;HSA‐Cre;5xFAD mice were observed to have similar inflammatory expression patterns as plaque‐free controls compared to 5xFAD mice. Preliminary analysis also indicates lower amyloid beta plaque load in cTFEB;HSA‐Cre;5xFAD mice. We are currently performing Nanostring analysis with the AD nCounter panel and neuroinflammation nCounter panel to identify transcriptional changes in neuroinflammatory signaling and ameliorating mechanisms associated with skeletal muscle TFEB overexpression.

Conclusion

We have identified an exercise‐regulated pathway through which AD‐associated neuroinflammation can potentially be ameliorated and plaque burden modulated. These results support the discovery of an exciting therapeutic intervention against AD progression that eliminates the need for strenuous exercise. We are currently identifying essential exercise‐associated cytokines that can reduce AD‐associated neuroinflammation and prevent disease progression, as well as establish a therapeutic exercise mimetic to combat amyloid beta‐associated neurodegeneration.
Association of acetylcholinesterase inhibitor and memantine treatment with cognitive function in patients with clinical dementia syndrome with and without post‐mortem Alzheimer pathology
Authors: Rosen Jurij , Jessen Frank
Published: December 2022

Background

Acetylcholinesterase inhibitors (AchE‐I) and memantine are licensed and recommended for the treatment of dementia of Alzheimer type (DAT). Between 10 and 20 % of patients with DAT, however, do not have Alzheimer’s disease (AD) pathology. It remains unclear, if these patients also benefit from treatment. This project aims to examine the association of AchE‐I and memantine use with cognitive function in patients with DAT with and without evidence of AD pathology at autopsy.

Method

This study is based on The National Alzheimer‘s Coordinating Center‐Uniform Data Set (NACC‐UDS). Inclusion of participants for this analysis was based on the following criteria: 1) Diagnosis of DAT, 2) information on the extent of AD‐neuropathological change at autopsy (ABC score high/intermediate/low/not), 3) follow‐up time ≥ 6 months, 4) ≥ 2 Mini‐Mental State Examinations (MMSE) during follow‐up.

Result

1483 participants with 3.8 ± 1.7 visits met inclusion criteria. Of these, 1009 participants showed an ABC score of “high”, 265 of “intermediate” and 209 of “low/not”. Use of AD‐medication was more common in participants with pronounced AD pathology (ABC score “high”: 89 %, “intermediate”: 66 %, “low/not”: 53 %). Follow‐up time was 41 ± 23 months in participants with medication compared to 36 ± 24 months in participants without medication. In the group of participants with an ABC score of “high” and “intermediate”, those with treatment showed a baseline MMSE score of 23 ± 5 and a decline of 8 ± 6 points, while those without treatment scored 26 ± 4 at baseline with a decline of 4 ± 6 points. In the cohort of participants with an ABC score of “low” and “not”, both groups with and without medication showed a baseline MMSE score of 26 ± 4 points with a decline in those with medication of 6 ± 6 points and of 3 ± 4 points in those without medication.

Conclusion

The present descriptive analysis does not provide evidence for a clear association of treatment with AD medication and the presence of AD pathology in patients with DAT. Modelling analyses including covariates will be presented.
Microglia‐specific Alzheimer’s disease polygenic risk score is associated with amyloid‐β, tau, and microglial activation
Authors: Yang Hyun‐Sik , Teng Ling , Kang Daniel , Menon Vilas , Ge Tian , Finucane Hilary , Schultz Aaron P. , Properzi Michael J , Klein Hans‐Ulrich , Chibnik Lori B. , Schneider Julie A , Bennett David A , Hohman Timothy J. , Mayeux Richard , Johnson Keith A. , De Jager Philip L , Sperling Reisa A.
Published: December 2022

Background

Genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have implicated microglia in AD pathogenesis, and microglia is a promising cellular therapeutic target in AD. However, it remains unclear when and how AD genetic risk localizing to microglia contributes to AD pathophysiology.

Method

Participants are from two community‐based cohorts (Religious Orders Study, the Rush Memory and Aging Project [ROSMAP]; n = 299 deceased; age 88.9±7.1, female 67%) and the screening phase of an AD prevention trial (the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s study [A4]; n = 2919 cognitively unimpaired; age 71.4±4.8, female 60%). We quantified post‐mortem Aβ and tau in ROSMAP, and used PET to quantify Aβ (florbetapir cortical composite standardized uptake value ratio [SUVR]) and tau (flortaucipir temporal composite SUVR; subset n = 302) in A4. In a subset of ROSMAP participants (n = 31), we evaluated the proportion of activated microglia (PAM) in post‐mortem neocortex. We combined AD GWAS summary statistics with cellular gene expression profiles from human brain single nucleus sequencing, to derive cell‐type‐specific ADPRS (excluding APOE region) in ROSMAP and A4. We assessed the association of each (standardized) cell‐type‐specific ADPRS with AD pathology (linear regression; adjusting for APOE genotypes, age, sex, and first 10 genotype principal components), and examined the correlation between the microglial ADPRS and PAM (Pearson’s correlation). We used Bonferroni‐corrected p‐value threshold, p<6.25×10−3.

Result

Microglial, astrocytic, and endothelial ADPRS were associated with higher Aβ and tau in ROSMAP (Figure 1A‐B). In A4, microglial ADPRS showed the strongest association with Aβ (beta = 0.017, p = 1.6×10−7; Figure 1C), while the association of all other cell‐type‐specific ADPRS with Aβ were no longer significant once adjusted for microglial ADPRS (all p>0.05). Microglial ADPRS showed a suggestive association with temporal composite tau (beta = 0.033, p = 0.012; Figure 1D), even after additionally adjusting for Aβ (beta = 0.024, p = 0.048). Microglial ADPRS was positively correlated with PAM in ROSMAP (Figure 2).

Conclusion

Genetic risk of AD localizing to microglial genes may contribute to Aβ and tau accumulation and microglial activation, likely starting from the preclinical (cognitively unimpaired) stage. These findings directly connect aggregate microglial AD genetic risk with Aβ and tau accumulation, and provide a genetic rationale to test microglia‐specific interventions in AD prevention trials.
Evaluating the relationship between endostatin and cognition in mild cognitive impairment (MCI), coronary artery disease (CAD), and Alzheimer’s disease (AD)
Authors: Song Bing Xin , Herrmann Nathan , Gallagher Damien , Rapoport Mark J. , Charles Jocelyn , Papneja Purti , Rajji Tarek K. , Andreazza Ana C. , Oh Paul I. , Marzolini Susan , Kiss Alex , Swardfager Walter , MacIntosh Bradley J. , Vieira Danielle , Koo Grace KY , Lanctôt Krista L.
Published: December 2022

Background

Endostatin is an endogenous angiogenesis inhibitor that can regulate pro‐and anti‐angiogenic factors, notably vascular endothelial growth factor. Research shows that endostatin levels in the brain are associated with amyloid plaque formation in Alzheimer’s disease (AD), and may contribute to AD pathogenesis. Hence, endostatin may be relevant to the broad range of cognitive impairments, namely people with mild cognitive impairment (MCI), AD, and/or coronary artery disease (CAD) who are at risk for cognitive impairment. We examine associations between serum endostatin and global cognition.

Methods

Participants with MCI, AD, or CAD (with or without MCI) were recruited. Serum endostatin concentrations were measured and analyzed using enzyme‐linked immunosorbent assays. MCI was diagnosed using either the Petersen criteria or the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) criteria. AD was diagnosed using DSM‐5 criteria. CAD was defined as at least 1 of previous hospitalization for acute myocardial infarction, coronary angiographic evidence of ≥ 50% blockage in ≥ 1 major coronary artery or a prior revascularization procedure. Global cognition was assessed by the Montreal Cognitive Assessment (MoCA). Linear regression analyses were used to assess the association between endostatin levels and global cognition with and without covariates. Endostatin levels were log‐transformed prior to analyses due to significant departure from normality in Shapiro‐Wilk tests.

Results

In 119 participants, 94 (79.0%) were male, 102 (85.7%) had CAD, and 23 (19.3%) had MCI or AD; the mean(SD) age was 65.6(7.5), years of education were 16.4(3.3), and endostatin levels were 156.3(38.6) ng/mL. Endostatin was associated with global cognition alone [F(1,117) = 11.39, p <.001, R2 = .089] and also when considering covariates: age, sex, body mass index (BMI), education, MCI/AD diagnosis, and CAD diagnosis [F(7,111) = 11.27, p< .001, R2 = .415]. All variables except age, sex, BMI, and CAD diagnosis added significantly to the association (p< .05). Controlling for other variables, one log endostatin unit was associated with a total MoCA score 5.08 (SE= 2.52) points lower.

Conclusion

In this sample, lower serum endostatin concentrations were associated with higher cognitive performance. This relationship may support the involvement of endostatin in cognitive functions and neurodegenerative diseases.
Associations between cognitive function and endogenous levels of estradiol and testosterone in adults with Type 2 diabetes?
Authors: Robusto Brian Andres , Espeland Mark A. , Bahnson Judy , Bennett Wendy , Cook Delilah R. , Hayden Kathleen M. , Howard Marjorie , Hugenschmidt Christina E , Johnson Karen C , Luchsinger Jose A , Yasar Sevil , Yassine Hussein N.
Published: December 2022

Background

Type 2 diabetes mellitus (T2D) accelerates cognitive decline in women and men. Among older women, prior reports suggest that higher endogenous estradiol levels may further accelerate the cognitive decline associated with T2D and increase risks for cognitive impairment. Testosterone may interact directly with cognitive decline in T2D, or through its conversion to estradiol via the aromatase enzyme.

Methods

Estradiol (E2) and total testosterone (TT) concentrations were determined using stored serum from 996 individuals, mean (±SD) age 69±6 and not receiving hormone therapies, collected at two times (averaging 4 years apart). Serum was collected during follow‐up years 8‐18 of the Look AHEAD cohort, a randomized controlled clinical trial of a 10‐year behavioral weight loss intervention in individuals with T2D and overweight or obesity at trial enrollment. One to four standardized assessments of attention, executive function, memory, and verbal fluency were collected during follow‐up years 8‐18. Mixed effects models were used to assess associations that E2 and TT concentrations had with current body mass index (BMI) and cognitive function.

Results

Greater current BMI was associated with higher E2 concentrations in women and men, and greater TT concentrations in women, but lower TT concentrations in men (all p<0.001). The weight loss intervention did not leave a legacy of differences in E2 and TT concentrations. E2 concentrations were not associated with cognitive function in women or men. TT concentrations were not associated with cognitive function in women, but greater TT concentrations were associated with better verbal fluency in men (p<0.001), most strongly among those carrying the APOE‐e4 allele (interaction p = 0.02). While the weight loss intervention left a legacy of relatively lower cognitive functioning among women, this was not mediated by current concentrations of E2 and TT.

Conclusions

Contrary to prior reports, we found no evidence that higher endogenous E2 concentrations were related to worse cognitive functioning in women with T2D. Higher TT concentrations were associated with better verbal fluency in men, but not women. The legacy of modestly lower cognitive function in women left by a 10‐year weight loss intervention was unrelated to any long‐term alterations in E2 or TT concentrations.
Are infections the missing elements in predicting Alzheimer’s disease?
Authors: Rheault Sylvie , Belleville Sylvie , Duchesne Simon
Published: December 2022

Background

Alzheimer’s disease (AD) begins many years before its clinical expression. Therefore, an important goal is accurate long‐term prediction, especially for prevention trials and when evaluating the impacts of early intervention. Yet, current efforts still fall short, which is indicative of missing information in the modelling. Recently, the Epstein‐Barr virus has been shown to trigger the development of multiple sclerosis, years after infection. Similarly, some studies have reported odds ratios for AD that were almost as high as age for some chronic infections, such as those caused by either the herpes simplex virus or cytomegalovirus. We aim to review the literature on prediction models to examine whether infection load has been sufficiently studied as an early biomarker of AD.

Method

We used the same strategy employed in previous reviews by Stephen et al. (2010), Tang et al. (2015), and Hou et al. (2018) to perform a systematic review of the literature published between January 2018 to May 2021 for the prediction of AD in cognitively intact individuals from the general population. We examined the type of model and input data as well as the performance of the prediction models in the selected articles with a particular focus on infection load.

Result

Our initial search yielded 18,915 articles. Artificial intelligence was found to be the most widely used technique for prediction model computation. Most models included chronological age, and long‐term prediction accuracy was mainly determined by this parameter. Of note, models with a measure of amyloid beta misfolding were highly predictive of the progression to AD. Only one model included data exploring the contribution of infection.

Conclusion

Long‐term prediction models for AD in the general population of cognitively intact older adults were mostly driven by age. Despite the growing literature associating specific infectious agents with the pathophysiological development of AD, only one model used infection load as a parameter to predict AD. The potential of serological infection status as a parameter to improve prediction models in the general population must therefore be further explored.
Differential roles of ApoE isoforms in regulation of inflammatory cytokine expression
Authors: Arsenault Ryan , Li Qiao , Zhang Wandong
Published: December 2022

Background

ApoE Ɛ4 has long been known as a top genetic risk factor in the development of late‐onset Alzheimer’s disease (LOAD). More recently the genetic variants of the innate immune receptor TREM2 such as R47H, which confers a similar risk as ApoE4 in LOAD, have been identified as genetic risk factors in the development of many neurodegenerative diseases with dysregulated neuroinflammation. TREM2 is expressed highly on microglia and macrophages and plays key roles in inflammation regulation. Our previous study (Dorey et al. 2017) has shown that ApoE isoforms play differential roles in Aβ‐induced inflammatory response. Atagi et al (2015) identified that ApoE is a ligand for TREM2. Given the physiological relationship between ApoE and TREM2 while also considering the three isoforms of ApoE, it is crucial to investigate and understand the mechanisms underlying the possibility differential ApoE isoform signaling through TREM2 surface receptor.

Method

THP‐1 (human monocytic leukemia cell line) cells were differentiated into macrophages (M0) using PMA and subsequently polarized to M1 and M2 using IFN‐γ/LPS and IL‐4/IL‐13, respectively. Following differentiation, 3uM of ApoE2, E3, or E4 was added to polarization media. RNA was extracted following 2 day polarization and used for RT‐qPCR in relative gene expression quantification.

Result

ApoE2 strongly stimulated the expression of anti‐inflammatory cytokines IL‐10 and TARC/CCL17 in M1 and M2 macrophages as compared to control, ApoE3 and ApoE4. While ApoE4 showed a massive reduction in these same transcripts in M0 and M2 macrophages. In contrast, ApoE4 strongly promoted the expression of pro‐inflammatory cytokines IL‐1β and TNF‐α in M0, M1, and M2 macrophages as compared to control, ApoE3 and ApoE2.

Conclusion

The ability for ApoE2 to promote the expression of anti‐inflammatory cytokines in macrophages, suggests that ApoE2 may play a neuroprotective role; while ApoE4’s ability to promote inflammatory cytokine expression indicates its pro‐inflammatory role. Both ApoE2 and ApoE4 may play their roles via interacting with TREM2.