bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic profiling of myeloid cells in Alzheimer’s Disease brain illustrates heterogeneity of microglia endolysosomal subtypes
Authors: Prater Katherine E , Green Kevin J , Sun Wei , Smith Carole L , Chiou Kenneth L , Mamde Sainath , Heath Laura M , Rose Shannon , Keene C. Dirk , Kwon Ronald Y , Snyder‐Mackler Noah , Blue Elizabeth E , Young Jessica E. , Logsdon Benjamin A , Shojaie Ali , Garden Gwenn A , Jayadev Suman
Published: December 2022

Background

Microglia‐mediated neuroinflammation contributes to disease progression in Alzheimer’s Disease (AD). Microglia demonstrate heterogeneous states with proposed beneficial, harmful, and disease‐specific subtypes. Defining the spectrum of microglia phenotypes is crucially important to the design of neuroinflammation‐modulating therapies.

Method

We performed single‐nucleus RNA‐seq on over 120,000 microglia nuclei isolated from dorsolateral prefrontal cortices collected from 12 AD and 10 controls. Nuclei were sorted for PU.1 expression using fluorescence activated nucleus sorting.

Results

We detected several microglia clusters that expressed features of “activation” as well as three previously unrecognized microglia transcriptomic subpopulations. These newly described subpopulations are defined by predominant endolysosomal gene expression patterns heterogeneous for metabolic and inflammatory signatures. One endolysosomal subtype is more abundant in AD individuals and uniquely enriched for transcripts involved in nucleic acid detection and interferon signaling. This population is distinct from a classic inflammatory subpopulation also present in our cohort, which upregulates NFKB, TLR and interferon related pathways but does not share the endolysosomal signature. Network analysis revealed subtype specific enrichment of IRF3 and IRF5 regulomes. AD individuals also exhibited increased expression of unfolded protein response and inflammatory genes in homeostatic microglia subpopulations.

Conclusion

We demonstrate significant heterogeneity in human brain microglia subtypes including identifying multiple endolysosomal subpopulations. Like neuroinflammation, alterations in the endolysosomal system have been identified as a key component of AD pathology; however, how endolysosomal dysfunction contributes to AD progression remains unresolved. Our study is the first to identify a subpopulation of microglia in human AD brain correlating endolysosomal activity and interferon pathway induction supporting a relationship between these two pathways in AD pathogenesis. These results highlight the heterogenous nature of the microglia response to AD pathology and inform efforts to target specific subtypes of microglia in the development of novel AD therapies.
Clinical validation of the Virtual Reality Functional Capacity Assessment Test – Short List (VRFCAT‐SLx) for assessment of iADL functioning in early symptomatic dementia: Baseline performance and associations with standard measures
Authors: Atkins Alexandra S , Schoemaker Dorothee , Abraham Chelsea , Flanagan Chloe , Evans Haley , Madsen Corrine , Sickel Nancy , Stevens Heather , Amaya Alexandra C , Plassman Brenda L , Loewenstein David , Welsh‐Bohmer Kathleen A. , Keefe Richard SE
Published: December 2022

Background

Clinical trials in preclinical and early symptomatic Alzheimer’s disease require increased precision for the assessment and monitoring of functional capacity. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a performance‐based assessment of function with the potential to serve this need. Prior work has demonstrated the VRFCAT’s validity and sensitivity as a measure of iADL functioning in subjective cognitive decline (Atkins et al., 2019), but pilot work in more cognitively impaired individuals indicated a risk of floor effects in some patients. The VRFCAT “Short List” (VRFCAT‐SLx) was developed to address this issue by modifying the test to reduce length and complexity. We present Baseline data from an ongoing clinical validation study of the VRFCAT‐SLx in participants with clinically characterized MCI/AD dementia

Method

At the time of submission, participants included 77 adults (32 male; mean age = 73.29, SD = 7.52) with established diagnoses of MCI or mild AD (NIA‐AA criteria) and CDR global scores of 0.5 or 1.0. Participants completed the tablet‐based VRFCAT‐SLx and other established measures (ADCS‐ADL‐MCI, MMSE, CDR, BAC cognitive tests) at Baseline and Follow‐up. At submission, 22 participants had completed follow‐up. Statistical analyses of baseline data, reported here, examined VRFCAT‐SLx task completion rates, the frequency of “floor” level performance, and baseline correlations with standard measures.

Result

Mean MMSE at Baseline was 27.47 (SD = 2.0). Cognitive performance reflected diagnoses of MCI, with the greatest impairments on verbal memory (1‐1.5 SD below the normative mean). All participants were able to complete the VRFCAT‐SLx at Baseline; 97.4% of participants (all but 2) met a priori set criteria for performance validity. VRFCAT‐SLx completion time (Total Adjusted Time) was significantly correlated with partner‐reported functioning on the ADCS‐ADL‐MCI (r = ‐.48, p<.001), the CDR‐SB (r = .37, p<.001), and BAC cognitive measures including Verbal List Learning (r = ‐.42, p<.001), Delayed Recall (r = ‐.40, p<.001), Tower of London (r = ‐.45, p<.001), and Symbol Coding (r = ‐.42, p<.001).

Conclusion

Baseline results support the use of the VRFCAT‐SLx as a performance‐based assessment of functioning in early symptomatic MCI/AD. Strong associations between VRFCAT‐SLx scores, partner‐reported functioning, clinical staging, and cognition replicate and extend earlier findings regarding the construct validity and clinical relevance of the tool.
Is the Long‐term Impact of a Multidomain Lifestyle Intervention on Cognitive Function Mediated by Changes in Leptin and Vascular Endothelial Growth Factor Concentrations?
Authors: Espeland Mark A. , Carmichael Owen T. , Evans Joni K , Hayden Kathleen M. , Johnson Karen C , Kahn Steven , Luchsinger Jose , Marvocina Santica , Neiberg Rebecca H.
Published: December 2022

Background

The 10‐year intensive lifestyle intervention (ILI) of the Look AHEAD study resulted in a legacy of relative deficits in cognitive function among participants who entered the clinical trial with a history of cardiovascular disease or current obesity, as compared to participants assigned to the diabetes support and education (DSE) intervention. We hypothesized that levels of two weight‐sensitive proangiogenic cytokines, leptin and vascular endothelial growth factor (VEGF), which have been previously reported to be associated with cognitive function, may have been altered by the ILI and account for this concerning finding.

Method

Concentrations of leptin and VEGF were determined using stored serum collected from 1,279 participants at Look AHEAD baseline, proximal to cessation of the intervention (Epoch 1), and an average of 4 years later (Epoch 2). Masked clinic staff conducted up to four standardized assessments of cognitive function at times ranging from 8 to 18 years after baseline. A composite score was derived from tests of attention, executive function, and memory. Mixed effects models were used to assess relative differences in leptin and VEGF concentrations between intervention groups and whether these accounted for changes in cognitive composite scores, overall and within subgroups defined by baseline history of cardiovascular disease or obesity.

Result

In both intervention groups, leptin concentrations increased from baseline to Epoch 1, and further between Epochs 1 and 2 (p<0.001). VEGF concentrations decreased between enrollment and Epoch 2 in both groups, and decreased substantially more between Epoch 1 and 2 in ILI than in DSE (p = 0.04). Overall, there was little evidence that leptin and VEGF concentrations were related to cognitive functioning. ILI‐DSE differences in VEGF, but not leptin, concentrations varied depending on baseline history of cardiovascular disease and obesity, but neither leptin or VEGF concentrations accounted for the relative decrements in cognitive function evident during long‐term follow‐up in participants assigned to ILI.

Conclusion

Among persons with type 2 diabetes and either a history of cardiovascular disease or obesity, long‐term relative deficits in cognitive function associated with intensive lifestyle intervention are not related to differences in two weight‐sensitive proangiogenic cytokines.
Education and Cognitive Function in the United States and Mexico
Authors: Saenz Joseph
Published: December 2022

Background

Education is associated with level of cognitive ability and may improve cognition by building cognitive reserve and improving health and socioeconomic status (SES) throughout life. This analysis evaluates consistency of associations between education and cognitive domains in the United States and Mexico and asks whether associations can be explained by late‐life health and SES.

Method

Data includes adults age 50+ from the MexCog in Mexico (n = 2,042) and the Harmonized Cognitive Assessment Protocol (HCAP) in the United States (n = 3,267). Associations between years of education and factor scores for several cognitive domain were estimated separately for each country, with and without adjustment for multiple chronic conditions, income, and wealth.

Result

In gender/age adjusted models, a year of education was associated with having 0.11 (memory), 0.14 (executive function), 0.14 (language), and 0.13 (visuospatial) standard deviations higher cognition in the MexCog and 0.12 (memory), 0.14 (executive function) and 0.13 (language) 0.10 (visuospatial), and 0.07 (orientation) standard deviations higher cognition in the HCAP. Further adjustment for chronic conditions, income, and wealth did not affect the size or statistical significance of estimates in either country.

Conclusion

Education positively related with cognition across all domains similarly in the United States and Mexico. Results suggest a direct effect of education on cognitive ability that is not eliminated by reducing educational disparities in later life health and SES.
Characterising heterogeneous spatiotemporal progression patterns of Alzheimer’s disease using Subtype and Stage Inference
Authors: Young Alexandra L.
Published: December 2022

Background

Alzheimer’s disease is heterogeneous in clinical syndrome, biomarker signature, and pathology. Disentangling this heterogeneity is challenging because multiple underlying factors contribute to the observed heterogeneity, including variability in disease subtype and disease stage.

Method

Subtype and Stage Inference (SuStaIn) is an unsupervised learning technique that combines clustering and disease progression modelling to identify subgroups of individuals (subtypes) with distinct progression patterns (stages) from cross‐sectional datasets. We describe the SuStaIn algorithm and recent enhancements and review previous studies using SuStaIn to analyse Alzheimer’s heterogeneity across a range of measures, including lobar and subcortical structural MRI volumes, tau PET, white matter hyperintensities, CSF and cognitive scores. We present new data applying SuStaIn to a more fine‐grained set of structural MRI features than has been used previously, extracting volumes from 34 cortical regions. 631 amyloid‐positive individuals based on PET or CSF at their most recent visit were selected from the ADNI dataset. 153 amyloid‐negative cognitively normal individuals were used as a control population. SuStaIn was used to estimate subtypes with distinct progression patterns, determine the optimal number of subtypes, and to subtype and stage individuals.

Result

Across previous studies SuStaIn identified three‐four subtypes depending on the choice of biomarkers. Across the 34 cortical regions included in this study, SuStaIn identified a hierarchical organisation of subtypes (Figure 1), with the optimal solution consisting of four subtypes (Figure 2): a ‘typical’ subtype (N=116), a ‘temporo‐parietal subtype’ (N=100), a ‘fronto‐temporo‐parietal’ subtype (N=66) and a ‘frontal’ subtype (N=19). We observed differences between the subtypes in age and number of APOE4 alleles (Table 1). Individuals assigned to the typical and frontal subtypes were older (p<0.001 typical; p<0.05 frontal), and individuals assigned to the temporo‐parietal and fronto‐temporo‐parietal subtypes were younger (p<0.001 temporo‐parietal; p<0.001 fronto‐temporo‐parietal). The temporo‐parietal subtype had the greatest number of APOE4 alleles (p<0.001), whilst the fronto‐temporo‐parietal subtype had the least number (p<0.05), potentially reflecting an atypical Alzheimer’s subtype. The subtype and stage assignments were longitudinally consistent (Figure 3).

Conclusion

Our results highlight the substantial heterogeneity of Alzheimer’s disease and demonstrate the utility of SuStaIn for identifying Alzheimer’s subgroups and their relationship with demographics, genetics, and cognition.
Clinical Implications of Internal Carotid Arterial Tortuosity in Patients with White Matter Hyperintensities
Authors: Sun Zhe , Li Chenyang , Muccio Marco , Masurkar Arjun V , Wisniewski Thomas , Ge Yulin
Published: December 2022

Background

White matter hyperintensities (WMHs) are observed frequently on MRI in elderly and associated with cognitive dysfunction. Many studies focused on intracranial small vessel disease (SVD), however, few studies linked WMHs with changes of extracranial large feeding arteries. We aimed to investigate the effects of internal carotid artery (ICA) tortuosity changes through quantitative MR Angiography.

Method

Fifty‐seven patients (age: 72.98±5.62; 32 females/25 males) with WMHs were included. WMHs lesions were semi‐automatically segmented on FLAIR images. ICAs were segmented on the TOF images to generate tortuosity quantitative metrics, including tortuosity index (TI), inflection count metric (ICM), and ICA angle (Figure 1). According to the Fazekas scores, patients were categorized into mild, moderate and severe groups as summarized in Table 1. One‐way ANOVA analyses were applied to reveal the difference of averaged bilateral ICAs' tortuosity measurements. Pearson's correlation coefficients were calculated to quantitatively investigate the relationship between tortuosity and volumes of lesions that are apart from the ventricle in subcortical white matter, i.e., deep white matter lesions (DWMLs), as well as the lesions attached with the ventricular system, i.e., periventricular white matter lesions (PVWMLs).

Result

Patients with higher Fazekas scores have higher TI and ICM, indicating higher tortuosity (Figure 2). The correlation results showed that TI and ICM were positively correlated with DWMLs volumes (r = 0.33, P< 0.05; r = 0.4, P< 0.01), however, they did not show associations with PVWMLs. While there's no correlation between averaged bilateral ICA angles and DWMLs or PVWMLs, we found significant correlations between left ICA angles and DWML volumes on left brain (r =0.56, P < 0.005) as well as between right ICA angles and DWML volumes on right brain (r = 0.49, P < 0.05) (Figure 3).

Conclusion

Tortuosity measurements derived from TOF images showed that subjects with higher degree of ICA tortuosity had higher lesion volumes of DWMLs not PVWMLs, indicating DWMLs may have different etiologies such as ischemic origin. The findings also highlight the importance of ICA angle as a risk factor for WMHs development which might be associated with the local hemodynamic shear stress at the bulb, where the ICA plaques are often developed.
Sema6D Promotes TREM2‐dependent Phagocytosis in Human iPSC‐derived Microglia
Authors: Finan Gina M. , Kwak Chulhwan , Hyun‐Woo Rhee , Kim Tae‐Wan
Published: December 2022

Background

Microglia mediate key functions in inflammation and phagocytic clearance central to Alzheimer’s disease (AD). Semaphorins and their receptors, plexins and neuropilins, are best known for their role in axon guidance, but emerging roles include the regulation of innate immunity. Semaphorin receptors are highly expressed in microglia, including those encoded by AD risk genes discovered through genome‐wide association studies (e.g. PLXNA4 and PLCγ2). We investigate the function of semaphorin 6D (Sema6D) and interacting receptors in human iPSC‐derived microglia (iMG).

Method

We generated TREM2 knockout (KO) human iPSCs using CRISPR/Cas9. Following differentiation to iMG, we used a proximity labeling approach to demonstrate the interaction of known Sema6D receptors (Plexin‐A1 or Plexin‐A4) with TREM2. WT and KO cells were treated with Sema6D to assay (i) phagocytosis activity via live‐cell imaging and (ii) secretion of inflammatory cytokines via multiplex immunoassays (iii) downstream signaling events.

Result

We demonstrated that Sema6D promotes phagocytic uptake of oligomeric Aβ, and human synaptosomes, as well as significantly increases secretion of several inflammatory cytokines including IL‐1β, IL‐6, TNF‐α and IL‐8. TREM2 KO abrogates Sema6D‐induced cellular changes in iMG. Plexin‐A1 and Plexin‐A4 interact with TREM2 in the intact cell.

Conclusion

Sema6D is a novel ligand for microglial Plexin‐A1and Plexin‐A4 and likely mediates signaling via a co‐receptor complex harboring TREM2. Sema6D is a regulator of microglial phagocytosis and cytokine release in a TREM2‐dependent manner, suggesting a Sema6D‐Plexin/TREM2 pathway as a novel therapeutic target for AD.
Alzheimer’s Disease Preclinical Efficacy Database (AlzPED): Optimizing the Scientific Rigor and Reproducibility of Preclinical Research in Alzheimer’s Disease
Authors: Chakroborty Shreaya , Martin Zane , Yuan Jean , Petanceska Suzana S , Refolo Lorenzo M
Published: December 2022

Background

Assessments of preclinical animal studies in Alzheimer’s disease (AD) highlight the lack of methodological rigor and inadequate reporting practices as contributive to the preclinical to clinical translation gap in AD therapy development. The Alzheimer’s Disease Preclinical Efficacy Database (AlzPED), a searchable and publicly available knowledgebase developed by the National Institute on Aging aims to illuminate key elements of experimental design and reporting practices of preclinical efficacy testing studies for researchers, funding agencies, and the public. The database is missioned to improve transparency in reporting, increase awareness of the need for greater rigor in study design, and identify critical experimental design elements and methodology missing from studies that make them susceptible to over‐interpretation and reduce their reproducibility and translational value.

Method

Using key word‐driven literature searches published studies are acquired and curated by two experts for bibliographic details, funding source, study goals and principal findings, data on relevant translational criteria like therapy type, therapeutic agent, therapeutic target, animal models, and AD‐related outcome measures, prior to publication in the database. Rigor in study design and methodology is evaluated with a Rigor Report Card consisting of a standardized set of expert‐recommended study design elements.

Result

AlzPED hosts curated summaries from nearly 1200 published preclinical therapeutic studies in AD animal models, and data related to 225 therapeutic targets, 1019 therapeutic agents, 195 animal models, more than 2000 AD‐related outcome measures, and thousands of principal findings. Evaluation of Rigor Report Cards from each study demonstrates significant under‐reporting of critical elements of methodology such as power/sample size calculation, blinding, randomization, balancing for sex, animal genetic background, and inclusion/exclusion criteria, these being reported by fewer than 30% of the nearly 1200 curated studies.

Conclusion

Our analysis of curated studies demonstrates serious deficiencies in reporting critical elements of methodology. These deficiencies diminish the scientific rigor, reproducibility, and translational value of the preclinical studies. Adopting a standardized set of best practices like those proposed by AlzPED can improve the predictive power of preclinical studies in AD animal models and promote the effective translation of preclinical drug testing data to the clinic.
Lifespan diffusion MRI reveals structural abnormalities in the 5xFAD model of Alzheimer’s Disease
Authors: Noarbe Brenda P , Jullienne Amandine , Silvola Rebecca , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Persohn Scott C , Territo Paul R , Obenaus Andre , AD MODEL
Published: December 2022

Background

The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium has been established to develop the next generation of Alzheimer’s disease (AD) models based on human genomic findings. As new models are developed, phenotypic data are compared to established models, including the 5xFAD mouse model. We undertook measurements of diffusion metrics to characterize the temporal alterations in brain structure in male and female 5xFAD mice, including connectivity analysis between the hippocampus and infralimbic prefrontal cortex (PFC).

Method

5xFAD mice were compared to age‐matched littermates (C57BL/6J, WT) at 4, 8, and 12 months (mo). Mice underwent high resolution diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) at 9.4T (5 B0, 30 directions b=3000 mm2/sec) to assess regional white and gray matter. Regional tissue features were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps. Tractography was performed based on the AMBMC mouse atlas. 18F‐AV45 PET was performed in a separate cohort at 4, 6, and 12mo to quantitate amyloid β (Aβ) load.

Result

Elevated FA within hippocampal CA1 was first observed in 5xFAD males at 8mo, but at 12mo 5xFAD females had increased FA in bilateral CA1 compared to WT mice. Connectivity between CA1 and PFC found 12mo 5xFAD females had significantly increased RD along the tract with concomitant increases in MD and AxD. AV45‐PET uptake was increased at 6mo (∼20%) and remained elevated at 12mo (∼25%) in the PFC in male and female 5xFAD compared to WT. In the hippocampus there was a ∼20% increase in AV45 binding at 6mo, that then declines by 12mo in 5xFAD mice.

Conclusion

Phenotyping of mouse models using DTI identifies altered brain connectivity and regional tissue modifications that may be indicative of increasing Aβ deposition. These data support that increasing Aβ deposition results in altered DTI metrics and connectivity using clinically relevant imaging modalities.
Assessment of High Risk for Alzheimer’s Disease Using Plasma Biomarkers in Subjects with Normal Cognition in Taiwan: A Preliminary Study
Authors: Hu Chaur‐Jong , Yang Shieh‐Yueh
Published: December 2022

Background

In Alzheimer’s disease (AD), cognitive impairment begins 10‐15 years later than neurodegeneration in the brain. Plasma biomarkers are promising candidates for assessing neurodegeneration in people with normal cognition. It has been reported that subjects with the concentration product of plasma amyloid β 1‐42 and total Tau protein, i.e. Aβ1‐42 x T‐Tau, higher than 455 pg2/ml2 are assessed as having a high risk of amnesic mild impairment (aMCI) or AD, denoted as high risk of AD (HRAD). The prevalence of high‐risk for dementia in cognitively normal controls is explored by assaying plasma biomarkers.

Method

In this work, 422 subjects aged 20 to 89 years were enrolled in seven cities around Taiwan. All enrolled subjects were clinically diagnosed with normal cognition. Plasma Aβ1‐40, Aβ1‐42 and T‐Tau levels were assayed for each subject using immunomagnetic reduction to assess the risk of dementia.

Result

The results in this study showed that 4.6% of young adults (age: 20‐44 years), 8.5% of middle‐aged adults (age: 45‐64 years) and 7.3% of elderly adults (age: 65‐90 years) had HRAD. The percentage of individuals with HRAD dramatically increased in middle‐aged and elderly adults compared to young adults.

Conclusion

The percentage of HRAD in cognitively normal subjects are approximately 10%, which reveals that the potentially public‐health problem of AD in normal population. Although the subject having abnormal levels of Aβ or Tau is not definitely going on to develop cognitive declines or AD, the risk of suffering cognitive impairment in future is relatively high. Suitable managements are suggested for these high‐risk cognitively normal population. Worth noting, the attention should be paid to preventing cognitive impairment due to AD, not only in elderly adults but also middle‐aged adults. More subjects should be enrolled in the future to validate the percentage of people with normal cognition with HRAD.
SUVN‐I7016031: A Novel M1‐receptor Positive Allosteric Modulator (M1‐PAM) for the treatment of Parkinson's Disease Associated Dementia
Authors: Grandhi Venkata Ramalingayya , Ganuga Narender , Medapati Rajesh Babu , Tadiparthi Jayaprakash , Jayarajan Pradeep , Shinde Anil K , Badange Rajesh Kumar , Nirogi Ramakrishna
Published: December 2022

Background

Parkinson's disease (PD) patients experience progressive cognitive decline over the time and as the disease progresses. Drug‐induced Parkinsonism (DIP) is the second‐most‐common etiology of parkinsonism in the elderly after Parkinson's disease. DIP is indistinguishable from pathological PD as the symptoms are similar for both conditions. Haloperidol is a classical antipsychotic, known for its propensity to cause parkinsonism, which can be accompanied with the cognitive impairment, due to the blockade of striatal dopamine D2 receptors and further the downstream antagonism of M1 receptors in the signaling cascade. Therapeutic potential of SUVN‐I7016031 was evaluated in an animal model reflecting PD associated dementia.

Method

Haloperidol was supplied in water feeder bottles at 2 mg/kg, p.o. to induce PD associated dementia. Following one week of haloperidol supplementation, treatment with either SUVN‐I7016031 (0.3, 1, 3 and 10 mg/kg, p.o.) or rivastigmine (0.3 mg/kg, s.c.) was began and the treatments were continued up to 37 days. Social recognition task (SRT) was conducted on day‐13 and day‐37. In SRT, familiarization and recognition trials were conducted with a trial delay of 30 min. Social investigation time by adult rat with either familiar or novel juvenile rat was assessed during recognition trial and compared, along with discriminative index. Statistical analysis is carried out using GraphPad Prism software (Version 7.02).

Result

Animals treated with haloperidol did not discriminate the novel juvenile from the familiar juvenile and showed cognitive impairment on day‐13 and day‐37. Rivastigmine reversed haloperidol‐induced PD dementia on day‐13 and day‐37. SUVN‐I7016031 at 10 mg/kg, p.o., reversed haloperidol‐induced PD dementia on day‐13 of testing. However, on day‐37, SUVN‐I7016031 reversed haloperidol‐induced PD dementia at 1, 3 and 10 mg/kg, p.o. which resulted in dose‐dependent positive efficacy. Further, rivastigmine and SUVN‐I7016031 treatment also resulted in significant improvement of discriminative index relative to haloperidol control on day‐37. Effects observed with SUVN‐I7016031 are more prominent on day‐37 relative to day‐13.

Conclusion

SUVN‐I7016031 showed positive efficacy in an animal model reflecting PD associated dementia, which could be a future promising therapeutic strategy in improving health related quality of life (hQOL) in PD patients.
A Trait‐like Component of Subjective Memory Concern in Men from Average Age 38 to 67 Years
Authors: Bell Tyler Reed , Beck Asad , Franz Carol E , Gillespie Nathan A. , Reynolds Chandra A. , Williams McKenna E. , Kremen William S.
Published: December 2022

Background

Subjective memory concern is a risk factor for dementia in older adults, yet it also appears to be stable over time. Few studies examine memory concern starting in midlife in cognitively normal adults or the role of genetic influences on memory concern. We focused on the stability of subjective memory concern from early midlife into older adulthood and its association with objectively assessed episodic memory and depressive symptoms. Using a classical twin design, we assessed genetic and environmental influences on longitudinally‐assessed subjective concern and its overlap with episodic memory and depressive symptoms.

Method

We examined 1,334 community‐dwelling men assessed in the Survey of Health and the Vietnam Era Twin Study of Aging, who were assessed for subjective memory concern at average ages 38, 56, 62, and 67. Objective episodic memory and depressive symptoms were assessed at 56, 62, and 67. Biometric twin models were used to estimate genetic and environmental influences over time, and correlated genetic and environmental influences between measures.

Result

Subjective memory concern was highly stable after average age 38 and not significantly associated with age. Phenotypic models showed that subjective memory concern was more related to depressive symptoms (β = .46) than with episodic memory (β = ‐.12) within timepoint, as shown by non‐overlapping confidence intervals. There were no significant lagged associations of subjective memory concern with episodic memory or depressive symptoms. Heritability of subjective memory concern was 51% and remained stable over time; 49% of the variation was attributed to unshared environmental influences. There were also significant genetic correlations between subjective memory concern and both episodic memory and depressive symptoms.

Conclusion

Subjective memory concern was stable from age 38 to age 67, and over half of the variance was explained by genetic influences. There was also significant genetic overlap with depressive symptoms and episodic memory. The stability and heritability results provide strong support for a trait‐like component of subjective memory concern. To be most useful as an indicator of imminent cognitive decline and increased risk for dementia, it will be important to differentiate dynamic aspects of subjective concern from its trait‐related dimension.
Sex‐specific mediational effects of microglial activation on Alzheimer’s disease proteinopathy in older adults
Authors: Casaletto Kaitlin B , Nichols Emma , Aslanyan Vahan , Simone Stephanie M. , Rabin Jennifer S. , La Joie Renaud , Brickman Adam M. , Dams‐O'Connor Kristen , Palta Priya , Kumar Raj G. , George Kristen M. , Satizabal Claudia L , Schneider Julie A , Pa Judy
Published: December 2022

Background

Women show disproportionate burden of Alzheimer’s disease (AD) pathology and higher AD dementia prevalence compared to men, yet the mechanism(s) driving these vulnerabilities are unknown. There is sexual dimorphism in immunologic functioning and neuroimmune processes are implicated in AD genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex.

Method

187 decedents (64% female; 89 years‐old at death; 62% non‐demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid‐β, and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA‐DP‐DQ‐DR) and morphological staging (stage I, II, or III). Amyloid and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modeling, we estimated the mediational effect of microglial activation on the amyloid to tau relationship in the whole sample and stratified by sex (amyloid→ microglial activation→ tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation→ amyloid→ tau).

Result

Microglial activation significantly mediated 67% (95%CI 32‐90) of the relationship between amyloid and tau in the whole sample; however, stratified analyses suggested this effect was stronger and only statistically significant in women. 57% (95%CI 20‐100) of the effect of amyloid‐β on tau was mediated through microglial activation in women, compared to 19% (95%CI 0‐62) in men. Secondary models suggested that mediational effects were driven by cortical versus subcortical microglial activation. Alternative models suggested that in women, microglial activation was a significant exposure both preceding the amyloid‐β to tau relationship (50%, 95%CI 22‐89) and directly related to tau burden (50%, 95%CI 11‐78). In contrast, in men, only the direct effect of microglial activation to tau reached significance (74%, 95%CI 34‐99) (mediational effect: 25%, 95%CI 1‐66).

Conclusion

Our models suggest a reciprocal, bidirectional relationship between amyloid‐β and microglial activation that accounts for tau burden in women. In men, direct independent (non‐mediational) relationships between microglial activation or amyloid‐β with tau were observed. Microglial activation may be disproportionately important for AD pathogenesis in women.
Sex Differences in the Effects of High Fat Diet on Neuroinflammation in a Mouse Model of VCID
Authors: Salinero Abigail E , Abi‐Ghanem Charly , Mansour Febronia , Kordit David , Riccio David , Venkataganesh Harini , Kelly Richard D , Robison Lisa S , Gannon Olivia J , Kopec Ashley , Zuloaga Kristen L
Published: December 2022

Background

Neuroinflammation plays a central role in the progression of vascular contributions to cognitive impairment and dementia (VCID). Unfortunately, anti‐inflammatory therapeutics have proven insufficient so far at ameliorating the progression of VCID. This may be because broadly suppressing inflammation prohibits its beneficial functions. Instead, supporting endogenous inflammation resolving programs may prove more effective. Mid‐life metabolic disease is a major risk factor for VCID, particularly in women. Therefore, we examined neuroinflammation at middle‐age in both males and females with VCID. We modeled metabolic disease via long‐term administration of a high fat (HF) diet, and VCID via unilateral carotid artery occlusion surgery which results in chronic cerebral hypoperfusion. We hypothesized that metabolic disease would lead to more adverse cognitive and neuroinflammatory effects in middle‐aged females compared to males in a mouse model of VCID.

Method

8.5 month old male and female C57BL/6J mice were placed on a HF or control diet for 7 months. At month 3, they received VCID or sham surgery. At month 6, cognitive function was assessed. Half of the brains were collected for histology while the other half were flash frozen for qPCR analysis of pro‐inflammatory and pro‐resolving mediators.

Result

Hippocampal‐dependent spatial memory was impaired in VCID males, regardless of diet; however, in females, both HF diet and VCID (or a combination of the two) impaired spatial memory. In males, HF diet increased microglial activity in the hippocampus. Additionally, HF diet in combination with VCID surgery increased expression of pro‐inflammatory markers as well as pro‐resolving mediators in males. However, females on a HF diet experienced a suppression of microglia activity in the hippocampus. HF‐fed females, regardless of surgery, had decreased expression of both pro‐inflammatory markers as well as pro‐resolving mediators.

Conclusion

In line with clinical findings, these data suggest that metabolic disease increases cognitive deficits to a greater extent in middle‐aged females than males. Further, our data suggest VCID with metabolic disease increases neuroinflammation and its resolution in males, while metabolic disease suppresses neuroinflammation and its resolution in females. This highlights the need for a better understanding of the sex differences in neuroinflammation following vascular injury.
The Utilization of Nature‐Based Virtual Reality (VR) Practice for the Wellbeing of Older Adults with Dementia
Authors: Kim Yongseop , Lee Jungjoo , Nuseibeh Betsey Zenk , Jung Miyeon J , Kim Junhyoung
Published: December 2022

Background

Despite abundant evidence supporting the health benefits of nature‐based programs and activities, older adults with dementia experience practical limitations to their participation in these nature‐based activities. Utilizing a Nature‐based Virtual Reality (VR) Program can be a good alternative to outdoor nature activities by minimizing physical and structural barriers that older adults with dementia often encounter. Thus, the purpose of this study was to assess the changes in the emotional health and health‐related quality of life among older adults with dementia after the Nature‐based VR program participation.

Method

This study used a single‐group pre‐post design. Six participants were contacted for recruitment from a memory care unit and five were enrolled. Inclusion criteria were as follows: (a) clinically diagnosed with dementia, (b) have no prior VR experience, (c) basic communication skills, and (d) age between 65‐90 years old. Five participants engaged in the Nature‐based VR program which was offered twice a week for 20‐30 mins during the 5 weeks for a total of 10 sessions. Emotional health and health‐related quality of life were assessed at baseline and immediate‐post intervention. Emotional health was assessed using the Observed Emotion Rating Scale. Caregiver‐observer assessed the levels of five emotions by marking one of six pre‐defined time intervals. Health‐related quality of life was assessed using Alzheimer’s disease‐related quality of life. These items constitute four domains, physical health, mental health, social, and financial domains, and are measured with a 4‐point scale. The summed score of the scale ranges from 13 to 52, and a higher score indicates a higher quality of life for the care recipients.

Result

From paired t‐test analysis, increased emotional wellbeing was detected. Specifically, the mean score of alertness increased from 4.50 points in pre‐intervention to 5.00 in post‐intervention while anger decreased from 1.67 to 1.00 and anxiety scores decreased from 1.50 to 1.00 points, respectively. Health‐related quality of life improved after the intervention. The QOL‐AD mean scores changed from 38.8 to 41.2 and median value was shifted from 38.5 to 44.0.

Conclusion

This study provides preliminary evidence that the Nature‐based VR program may improve emotional health and health‐related quality of life.
Visualization of tau oligomers in TauP301L‐BiFC transgenic mice exhibits the progression of tauopathy
Authors: Lim Sungsu , Pae Ae Nim , Kim Yun Kyung
Published: December 2022

Background

Accumulation of abnormal tau aggregates in the brain is a pathological hallmark of multiple neurodegenerative disorders including Alzheimer’s disease (AD). Increasing evidence suggests that soluble tau aggregates play a key role in tau pathology as neurotoxic species causing neuronal cell death and act as prion‐like seeds mediating tau propagation. Despite the pathological relevance, there is a paucity of methods to monitor tau oligomerization in the brain. Therefore, we have developed a novel tau transgenic mouse model as a tool to monitor tau self‐assembly in the brain.

Method

We introduced bimolecular fluorescence complementation (BiFC) technique to human tau containing a P301L mutation to generate a novel tau transgenic mouse, named TauP301L‐BiFC. Tau self‐assembly, represented by BiFC fluorescence was monitored and quantified in the brain of transgenic TauP301L‐BiFC mice. Behavior and biochemical differences were assessed between 3 and 12 months for the characterization of TauP301L‐BiFC mice. In vivo efficacy of methylene blue, a tau aggregation inhibitor, was evaluated for further validation of TauP301L‐BiFC mice as an in vivo model of tauopathy.

Results

TauP301L‐BiFC mice showed soluble tau oligomerization from 3 months, showing significantly enriched BiFC fluorescence in the brain. Then, massive tau fragmentation occurred at 6 months showing dramatically decreased TauP301L‐BiFC fluorescence. The fragmented tau species served as a seed for insoluble tau aggregation. In a result, insoluble TauP301L‐BiFC aggregates co‐aggregated with endogenous mouse tau accumulated in the brain, showing subsequently increased BiFC fluorescence from 9 months. Neuronal degeneration and cognitive deficits were observed from 12 months of age. Administration of methylene blue significantly reduced tau‐BiFC fluorescence in the brain of TauP301L‐BiFC mice, presenting a significant decrease in the level of matured tau‐BiFC complexes in the soluble brain lysates. TauP301L‐BiFC mouse model demonstrated that methylene blue reduced the amount of soluble tau oligomers in the brain, resulting in the prevention of cognitive impairments.

Conclusion

The tau oligomerization was able to monitor and quantify in the brain of TauP301L‐BiFC mice. Thus, we assure that TauP301L‐BiFC mice are a bonafide animal tool to monitor pathological tau oligomerization in AD and other tauopathies.
Characterising the prodromal phase of dementia with Lewy bodies
Authors: Jensen Clara Mellergaard , Waldemar Gunhild , Vogel Asmus , Frederiksen Kristian Steen
Published: December 2022

Background

Three subtypes of prodromal dementia with Lewy bodies (DLB) have recently been proposed. This study investigates the frequency of symptoms in the prodromal phase of DLB.

Method

Patients diagnosed with DLB between the 1st of February 2017 and 1st of February 2021 were retrospectively identified and matched to a group of patients with Alzheimer’s disease (AD). Patient case files were reviewed identifying the first symptoms and symptoms in the prodromal phase (cognitive impairment, psychiatric symptoms, delirium/acute confusional episodes, RBD, motorsymptoms indicative of Parkinson’s disease, anosmia, and autonomic dysfunction).

Results

A retrospective cohort of 166 DLB patient and 168 AD patients were included. Of the proposed subtypes in patients diagnosed with DLB, 30% presented with cognitive impairment at onset in isolation, 6% with psychiatric symptoms, and 2% with delirium/acute confusional episodes (Figure). Eighty‐three percent of DLB patients had two or more non‐cognitive symptoms in the prodromal phase. Further, 82 % had at least one psychiatric symptom, and 33 % had an episode with delirium/acute confusional episode in the prodromal phase. Of other possible subtypes, Rapid eye movement sleep Behaviour Disorder was found at onset in 22% with a mean prodromal length of 8.4 years (as opposed to 4.3 years in DLB generally)

Conclusion

We found no supportive evidence of the proposed clinical subtypes of prodromal DLB. Our findings indicate that RBD subtypes may exist, but further research is needed.
Delays and underdiagnoses of dementia in the LMICs: Pathways and factors
Authors: Ellajosyula Ratnavalli , Narayanan Jwala , Hegde Soumya , Kamath Vikram , Murgod Uday , Easwaran Vandana , Seetaram Raghavendra , Srinivasan Murali , Watson Peter
Published: December 2022

Background

Two thirds of people with dementia live in low and middle income countries (LMICs)but only about 10% of these persons are estimated to receive a dementia diagnosis. Reasons are multiple and complex. Early diagnosis is essential for initiating treatment, referral for care services, and planning for the future. There is a paucity of data on the pathways to dementia diagnosis in LMICs. We investigated the pathways and factors contributing to delay in diagnosis in a specialist memory clinic from urban India.

Method

Consecutive patients and their carers attending the specialist memory clinic in Bangalore, India with cognitive complaints underwent a detailed clinical assessment, neuropsychological testing, neuroimaging, and blood tests. Details of symptom onset, visits to various medical providers, diagnoses made were captured on a proforma. Effect of education, gender, dementia subtype, and age of onset on time to diagnosis were examined using univariate analysis of covariance.

Result

879 out of 1212 patients had dementia. Only 24 (2.39%) received a dementia diagnosis elsewhere. Approximately 20% of the patients were on dementia‐specific medications but the family and the patient were unaware of the diagnosis. The median time to diagnosis was 24 (range 3 to 180) months. 43% of the patients were diagnosed 24 months after symptom onset. Patients with young onset dementia, Alzheimer’s disease, and Frontotemporal dementia were diagnosed significantly later as compared to those with vascular dementia and dementia with Lewy bodies. Education and gender did not have an effect on the time to diagnosis.

Conclusion

Both delay and lack of communication about the diagnosis of dementia appear to be important issues that need to be addressed to improve the early detection of dementia in India. Training of health providers appears an essential component in improving the early diagnosis of dementia. Findings from our study will be compared to literature from other LMICs and a comprehensive framework to improve early diagnosis of dementia in LMICs will be discussed.
Supporting Youth With A Parent Who Is Living Younger‐Onset Alzheimer’s: A Crucial Component In Integrated Care
Authors: Cose Diana Shulla
Published: December 2022

Supporting Youth With A Parent Who Is Living Younger‐Onset Alzheimer's: A Crucial Component In Integrated Care Lorenzo's House, a nonprofit in Chicago, focuses on a transformative approach that supports children and young adults who are living with a parent with younger‐onset Alzheimer's. Youth are often affected by a parent's diagnosis at a neurobiologically vulnerable time in their lives. Youth frequently don't know how to explain their experience as a care partner with their peers, leaving them isolated and managing the ongoing change by themselves. By creating spaces specifically catered towards these young care partners, we are radically shifting the journey of what younger‐onset Alzheimer's looks like for children and young adults.

We focus on the relationship between the parent diagnosed and their children, what children need as care partners, and what issues and struggles they face at a variety of ages in this journey. Our three youth programs focus on innovation to support youth living with a parent with younger‐onset Alzheimer's: Lorenzo's Camp, a camp designed by youth care partners, therapists, medical professionals ‐ intended to share common stories and build an alliance; the Light Club, a virtual youth care partner group injected with team building and relationship development; and lastly youth‐led advocacy work. Our model shifts the narrative for how youth experience being a member of a family that is navigating a younger‐onset Alzheimer's diagnosis.
PROGRESS IN DEVELOPING A LIGHT‐STABLE 4R TAU PET IMAGING AGENT: APN‐1701 FIH
Authors: Tempest Paul , Lin Yih‐Shyan , Tai Chin‐Yin , Ono Maiko , Russell David S , Sandiego Christine M , Carroll Vincent , Gunn Roger N , Margolin Richard A , Higuchi Makoto , Jang Ming‐Kuei
Published: December 2022

Background

The need for a light stable 4R tau PET tracer for use in diverse tauopathies is widely appreciated. We aimed to assess the initial human imaging profile of [18F]APN‐1701 as such a tracer and to compare its imaging profile to the well‐established but light‐sensitive tracer [18F]‐APN‐1607 that can detect 4R aggregates as well as 3R and mixed 3R/4R aggregates. [18F]APN‐1607 has progressed to a multicenter Phase 2 clinical trial for Alzheimer’s disease (AD); therefore, prior imaging data with it was considered valuable for comparison.

Method

One cognitively normal (CN) subject (male, 73yo) and one AD subject (female, 58 yo), who had undergone prior amyloid profiling using [18F]florbetapir PET and subsequent imaging with [18F]APN‐1607 in a proof‐of‐concept study and a test‐retest study, respectively, participated in the current study. Dynamic imaging with [18F]APN‐1701 was performed over 180 min to obtain kinetic data.

Result

Overall, for both subjects [18F]APN‐1701 generally matched [18F]APN‐1607 findings, i.e., peak SUV values reached similar levels. The CN subject, who was amyloid negative, had slight, uniform cortical [18F]‐APN‐1701 uptake and more substantial uptake in the pallidum, pons and midbrain. SUVr images for the AD subject showed retention in similar brain regions for both tau tracers with the same rank order of regional SUV/SUVr. Notably, for this subject [18F]APN‐1701 continued to accumulate up to the end of image acquisition.

Conclusion

[18F]APN‐1701 demonstrates cortical uptake generally similar to [18F]APN‐1607 but its slow kinetics are unfavorable for further development.