bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitigating chronic neuroinflammation in Alzheimer mice by novel immunomodulatory imide drugs (IMiDs) conserves neuroplasticity and cognitive function and also alleviates neurodegeneration‐behavioral impairments in TBI‐challenged mice
Authors: Greig Nigel H , Lecca Daniela , Hsueh Shih Chang , Tweedie David , Scerba Michael T , Hoffer Barry , Wang Jia‐Yi , Sambamurti Kumar , Lahiri Debomoy K. , Kim Dong Seok
Published: December 2023

Background

Neuroinflammation is an invariable characteristic of chronic neurodegenerative disorders, such as Alzheimer’s disease (AD), and acute ones, epitomized by traumatic brain injury (TBI). However, whether neuroinflammation development drives disease progression or is an epiphenomenon remains unknown.

Methods

To test the hypothesis that, once initiated, AD‐associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline irrespective of changes in amyloid‐β (Aβ) peptide generation, a new class of immunomodulatory imide drugs (IMiDs) was developed on the backbone of thalidomide/pomalidomide to reduce proinflammatory cytokine generation and resulting inflammation, but lacking action on SALL4 – a key protein implicated in thalidomide teratogenicity. (i) 5xFAD mice, known to develop neuroinflammation consequent to excessive Ab generation, were evaluated over a 4‐month period during which cognitive deficits develop, and (ii) wild type mice subjected to TBI and impacted with motor and cognitive impairments were evaluated to assess whether selective resolution of neuroinflammation by novel IMiDs could mitigate behavioral declines.

Results

Pomalidomide (Pom) and the more potent novel analog, 3,6’‐dithioPom (3,6’‐DP), which does not impact SALL4 levels, were administered to reduce microglial cell activation ‐ as confirmed in primary cortical cultures challenged with Aβ and RAW 264.7 cells challenged with lipopolysaccharide (LPS). 3,6’‐DP, in particular, decreased microglial and astrocyte activation in hippocampus and cerebral cortex of 5xFAD mice. This was accompanied by reductions in synaptic and neuronal cell loss, and behavioral impairment in the absence of changes in Aβ plaque or peptide generation. In TBI challenged mice, 3,6’‐DP, likewise, mitigated neuroinflammation and resulted in reduced neuronal loss and behavioral impairments.

Conclusions

AD‐associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aβ generation provides a means to mitigate AD‐associated cognitive/behavioral impairments, and provides a new drug candidate to alleviate other neurodegenerative disorders, such as TBI.
Education, wealth, and survival after dementia diagnosis
Authors: Chen Yi , Crimmins Eileen M. , Zissimopoulos Julie M
Published: December 2023

Background

The relationship between socio‐economic status (SES) and length of life after dementia diagnosis may vary by specific aspects of SES. Education and wealth, two widely used measures of SES, may extend life expectancy via greater efficiency of health investment and better access to care. However, according to the cognitive reserve hypothesis, education protects against dementia pathology and thus when dementia symptoms manifest, individuals with higher education have more advanced atrophy, likely shortening their post‐dementia life expectancy. This paper examined education and wealth disparities in 1) timing of dementia diagnosis, 2) length of life after diagnosis, and 3) use of healthcare after diagnosis as a potential mechanism through which education and wealth differentially influence survival.

Method

Data was extracted from the Health and Retirement Study (HRS) linked to Medicare claims. From claims we identified 2,377 individuals with incident dementia diagnosis between 2000 and 2016 and followed them for up to 18 years. Using Cox proportional hazard models, we estimated relationships between education, household wealth, and mortality, adjusting for demographics, comorbidity, function, and cognition at the time of dementia diagnosis. To test whether SES disparities were driven by healthcare utilization, we ran linear regressions on the number of emergency room (ER) visits, inpatient admissions, and office visits after diagnosis with the same set of predictors.

Result

Individuals with higher education and wealth exhibited less functional and cognitive impairment at dementia diagnosis. The protective effect of higher education on mortality was absorbed by controlling for wealth. In the fully adjusted model, ranking in the top quartile of wealth was associated with a 17% reduction in mortality risk (HR = 0.83, 95% CI: 0.72‐0.96), relative to the bottom quartile. Wealth was not associated with ER visits, hospitalization, or office visits.

Conclusion

More intact function and cognition at incident diagnosis did not confer longer survival for the highly educated. In contrast, the most affluent experienced a lower mortality risk, which was unrelated to healthcare utilization. While more research is warranted to understand pathways, these disparities inform opportunities for achieving health equities among persons living with dementia, by targeting at those with limited financial resources.
Characterizing cerebral microhemorrhage associations in dementia subtypes in the UK Biobank
Authors: Haddad Elizabeth , Sheikh‐Bahaei Nasim , Jahanshad Neda
Published: December 2023

Background

Cerebral microbleeds (CMBs) are associated with neurodegenerative diseases (Charidimou, 2011) and have been identified as an adverse amyloid‐related imaging abnormality event (ARIA‐H) related to amyloid clearing medications (Sperling, 2011). Identifying risk factors for CMBs can help refine inclusion criteria for clinical trials and mitigate the risk of ARIA‐H. CMBs are readily detected on T2*‐GRE MRI sequences, including susceptibility weighted imaging (SWI) – a modality used to detect magnetic field distortions caused by paramagnetic products like iron (Haacke, 2004, Liu, 2017). We explore CMB associations with demographic, disease, and imaging markers in a subset of participants with varying dementia subtypes and complaints in the UK Biobank (Miller, 2016).

Method

A total of 75 participants who had clinically diagnosed or self‐reported dementia and SWI imaging were selected; 4 participants were excluded due to extreme motion. We used MARS criteria (Gregoire, 2009) to identify CMBs on SWI and validated our findings using other sequences to exclude CMB ‘mimics’ (Figure 1A). The number, classification, and position of CMBs were recorded. Logistic regressions modeling the outcome of at least one ‘definite’ or ‘total’ (‘definite’ + ‘possible’) CMB were performed and effect sizes were calculated across hippocampal volume, white matter hyperintensity load (WMH), and global WM diffusion MRI (dMRI) microstructural measures.

Result

Participants were predominantly male (65%) with a mean age of 69.8 (± 7.1) years. 9 participants had at least one ‘definite’ CMB and 8 more had at least one ‘possible’ CMB for a ‘total’ of 17 individuals with CMBs. Individuals with CMB(s) were significantly older than those without. CMBs were mostly ‘strictly lobar’ for both definite (78%) and total (71%) classifications (Table 1). The presence of CMBs were found across a spectrum of dementia diagnoses (Figure 1B). Microstructural dMRI measures including global WM FA, MD, and ISOVF were significantly associated with presence of total CMBs (q<0.05) (Figure 2).

Conclusion

Measures reflecting WM organization were sensitive to the pathophysiology of CMBs in those with dementia. Future work should investigate whether WM microstructure can predict the development of CMBs in those with dementia, particularly in individuals undergoing amyloid clearing treatments.
[18F]MK6240 and [18F]PI2620 autoradiography on postmortem human brain tissue in AD
Authors: Aliaga Antonio , Therriault Joseph , Socualaya Kely Quispialaya , Aliaga Arturo Aliaga , Hopewell Robert , Tissot Cécile , Rahmouni Nesrine , Macedo Arthur C. , Massarweh Gassan , Pascoal Tharick A. , Soucy Jean‐Paul , Rosa‐Neto Pedro , Zimmer Eduardo R
Published: December 2023

Background

To compare the post mortem uptake of [18F]MK6240 and [18F]PI2620 in the brain hemisphere, of A‐T‐ (CN) and A+T+ tissue

Method

Autoradiography (ARG) imaging using [18F]MK6240 and [18F]PI2620 was used to assess uptake of CN and AD tissues. One study used sections of whole‐hemisphere of one CN tissue and one AD tissue. The uptake value of [18F]MK6240 was calculated from a regions of interest (ROI) drawn manually from the area of cortex gray matter (GM), cortex white matter (WM), and background (BG).

Other study was 24 tissues from the prefrontal cortex (Pfc) (12CN, 12AD), hippocampus (Hip) (12 CN, 12 AD) and cerebellum (Cer) (12 CN, 12 AD) were evaluated with [18F]MK6240, and [18F]PI2620. The uptake value of [18F]MK6240 and [18F]PI2620 was calculated from ROI drawn manually from the area of pfc GM, hip GM and cer GM.

Result

The ARG showed greater [18F]MK6240 uptake in AD than in CN tissue. There were significant differences between CN and AD tissue in terms of cortex gray GM distribution and cortex WM, but no significant differences in BG. These results also, there is no correlation between the specific activity of [18F]MK6240 and the uptake value in CN and AD tissues. In a second experiment, based on our findings there was a significant difference between CN and AD groups when assessed by [18F]MK6240 as well as [18F]PI2620 in the pfc_GM and hip_GM. Furthermore, we found no difference between AD and CN tissues when assessed by [18F]MK6240 and [18F]PI2620 in cerebellum GM. Ratio values Pfc/Cer and Hip/Cer assessed by [18F]MK6240 as well as there were significant differences between CN and AD. [18F]MK6240 and [18F]PI2620 were highly correlated in AD but not in CN brain tissues.

Conclusion

We also found that [18F]PI2620 and [18F]MK6240 have similar brain uptake in post‐mortem tissue.
Trajectory of depressive symptoms prior to dementia diagnosis
Authors: Werhane Madeleine L , Shofer Jane , Todd Kaitlin , Crane Paul K , Li Ge
Published: December 2023

Background

Depression has been repeatedly linked to increased risk for dementia. While there is some research to suggest that an individual’s trajectory of depression symptoms over time may inform dementia risk above and beyond depression symptoms at a single time point, this has yet to be demonstrated in a dataset specifically designed to capture longitudinal brain aging and dementia outcomes.

Method

A cohort study of 4,171 community‐dwelling older adults (65+ years) who were enrolled in the Adult Changes in Thought (ACT) study. Participants were initially non‐demented at baseline, and underwent biannual assessment of cognitive status (Cognitive Abilities Screening Instrument, diagnostic consensus) and self‐reported depression symptoms (via 20‐item Centers for Epidemiological Studies‐Depression [CESD]) for up to 24 years. We used Item Response Theory (CESD‐IRT) scores to address limited sensitivity to lower depressive symptom level in the general population and nonlinear measurement properties of the CESD. Diagnosis of dementia was made at consensus meeting based on history and clinical examination.

Result

Sample characteristics are summarized in Table 1. Linear mixed effects modeling, adjusted for covariates (age, sex, education, race), revealed that there was greater increase of depressive symptoms prior to diagnosis of dementia compared to those who did not receive diagnosis of dementia at end of study (p<.0001). This finding was consistent when depression symptom trajectories were estimated using CESD‐20 raw vs. CES‐IRT scores (Fig. 1 & 2, respectively). The difference in depression symptom trajectories by dementia outcome did not differ as a function of sex. Significant differences (p<0.001) in mean depression symptom total scores were observed by dementia outcome as early as 10 years prior to diagnosis/censoring for both the CESD‐20 raw score (1.0 ± 0.2) and the CESD‐IRT scores (0.16 ± 0.03).

Conclusion

The pattern of increasing depression symptoms many years prior to dementia diagnosis reinforces the notion that the association between depressive symptoms and dementia in older adults may be primarily due to a shared common cause, or that depressive symptoms represent an early sign of dementia in the preclinical phase. Changes in specific depressive symptoms prior to dementia diagnosis will also be examined.
Association of sarcopenia with cognitive impairment in older adults in the open population
Authors: Cervantes Maria Elena Alvarez
Published: December 2023

Background

Sarcopenia is a progressive and generalised skeletal muscle condition where there is a loss of muscle mass and function, while cognitive impairment is a clinical syndrome characterised by impairment in different cognitive and neuropsychological domains. Cognitive impairment has been studied as a risk factor for sarcopenia, however, it has not been established whether sarcopenia is a risk factor for cognitive impairment.

Method

This is a secondary analysis of 2,158 adults aged 65 and over assessed within the Dementia Research Group 10/66 protocols. In which grip strength, calf circumference and physical performance were measured to establish a diagnosis of sarcopenia. In addition, they were divided into groups depending on cognitive status.

Result

Of all the older adults assessed, those with cognitive impairment or dementia had worse indicators in anthropometric measurements and in sarcopenia‐related measurements.

Conclusion

In older Mexican adults, the presence of sarcopenia was not found to be associated with mild cognitive impairment, but was associated with the presence of dementia, even after controlling for other risk factors widely documented in the literature.
Spatial Transcriptomics Analysis of Vulnerable Cell Populations in Middle Temporal Gyrus
Authors: Long Brian
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by cognitive decline due to histopathological changes of neurodegeneration in a stereotypical neuroanatomical progression. Applying single‐nucleus ‘omics methods has extended our understanding of how AD impacts the brain and allowed the Seattle AD Brain Cell Atlas Center (SEA‐AD) to provide a detailed cellular‐molecular view of middle temporal gyrus (MTG) in AD. Previously, we identified transcriptomically‐defined cell types that are specifically affected by AD in MTG, however, cell types identified in ‘omics data lack spatial context. Identifying the location of these cell types in situ is necessary to pinpoint the location of affected cells and connect cellular‐molecular views of disease progression to histopathology. To accomplish this, spatial transcriptomics methods measure individual mRNA molecule locations with subcellular resolution and provide transcriptomic profiles of individual cells in situ.

Method

Using a panel of genes designed to identify transcriptomic cell types, we performed spatial transcriptomics experiments using the Vizgen MERSCOPE platform across MTG tissue from 25 donors spanning AD pathology, yielding transcriptional profiles of over 1M cells across the cortical depth and white matter of 68 sections. These cells were assigned to transcriptomically‐defined cell types by integrating the spatial transcriptomics data with our existing single nucleus dataset. From the resulting maps of cell type locations, we measured cortical layer thickness, cell proportions, densities and cell type‐dependent pairwise distance distributions for each donor.

Result

We have successfully applied the MERSCOPE platform to generate cellular‐resolution spatial transcriptomic data in MTG across a wide range of AD disease progression. We applied novel deep generative models to assign cell type identity. These measurements revealed cell type‐specific spatial distributions and changes in cell type proportions due to disease, validating observations from single‐nucleus studies. Enhanced loss of Layer 2/3 excitatory neuron types and somatostatin‐expressing inhibitory neurons is calculating cell density within layers. Additional analyses uniquely available to spatial transcriptomics studies will be useful for quantitative description of cytoarchitectural changes in AD.

Conclusion

Spatial transcriptomics experiments across disease progression in MTG confirm cell type abundance changes measured in single‐nucleus RNASeq. The cellular spatial distributions provide detailed knowledge of the location of vulnerable cells within cortex.
Length of stay is related to inpatient antipsychotic use in Alzheimer type dementia at a large US based tertiary care hospital.
Authors: Cahan Joshua Gabriel , Bonakdarpour Borna
Published: December 2023

Background

Antipsychotic(AP) medications carry a black box warning for increased risk of death in the elderly and should be used judiciously in a dementia population. Studies have shown that encounters with healthcare facilities increase the risk of AP exposure1. We wanted to know how admissions at our institution impacted antipsychotic use in patients with Alzheimer’s disease. Here we describe the results of a retrospective analysis of inpatient antipsychotic use in patients with Alzheimer’s disease at Northwestern Memorial Hospital(NMH), Chicago IL.

Method

Our cohort was generated using NMH’s Enterprise Data Warehouse, including patients over 65 with a chart diagnosis of AD admitted to the hospital for over 48hrs between May 2005 and March 2018. We excluded patients with schizophrenia, schizotypal disorder, bipolar disorder, or psychotic illness due to primary psychiatric disease, enrollment in hospice, presence of tracheostomy or PEG‐tube and pervasive developmental disorder.

Result

1712 patients were admitted for a total of 4603 admissions amounting to 25,721 hospital days during the period of analysis. Demographic information is provided in Table 1. A higher proportion of admissions were four days or longer in encounters with an antipsychotic(Figure 1). Though longer LOS becomes progressively less common, this trend continued through a LOS of 20 days. When comparing LOS for encounters with an AP in the home medication list to encounters without, there was no impact on LOS. However, when comparing encounters with an AP prescribed while inpatient to encounters without, inpatient AP administration was associated with a longer length of stay (Table 2).

Conclusion

These findings indicate that a longer LOS is associated with antipsychotic use. Because a longer length of stay was associated with new antipsychotic use but not the continuation of a home antipsychotic, our findings suggest that length of stay may contribute to behavioral and psychological symptoms of dementia requiring pharmacological treatment.

1. Koponen M, Lavikainen P, Taipale H, et al. Accumulation of Hospital Days Among Antipsychotic Initiators With Alzheimer’s Disease. J Am Med Dir Assoc. 2019;20(12):1488‐1494.e3. https://doi.org/10.1016/j.jamda.2019.07.009
AD8 revisited: what’s the optimal cutoff value?
Authors: Hwang Tzung‐Jeng , Yang Cho‐Hsiang
Published: December 2023

Background

The 8‐item Informant Interview to Differentiate Aging and Dementia (AD8) was developed as a screening tool for dementia with a cutoff of 2 suggested by the initial study. However, various studies found different cutoff values, and many suggested a cutoff of 2 might result in a high false positive rate (up to > 80%). A higher false positive rate in Taiwan was repeatedly shown when AD8 was self‐administered in local government screening programs. This study aimed to examine the performance of AD8, determine its best cutoff value, and discuss factors that may affect the performance of AD8.

Method

We recruited 119 participant‐informant dyads from a psychiatric outpatient clinic of a university medical center. For each dyad, the AD8 was administered first, and then Mini‐Mental Status Examination (MMSE) and the Clinical Dementia Rating (CDR) to minimize contamination effect. Two geriatric psychiatrists made a consensus clinical diagnosis for each subject based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) using all available clinical information, including MMSE, CDR, clinical history, other past neuropsychological tests, and neuroimaging examinations (if available).

Result

There were 37 subjects with normal cognition, 44 with mild neurocognitive disorder (mild NCD), and 28 with major neurocognitive disorder (major NCD). When the cutoff value was 2 for the differentiation between major NCD and no‐dementia subjects (including normal cognition and mild NCD), the AD8 had an AUC of 0.756, a sensitivity of 0.929, and a specificity of 0.582. But the optimal cutoff value was 4 according to the Youden index, with an AUC of 0.888, a sensitivity of 0.786, and a specificity of 0.835.

Conclusion

Although many studies recommended 2 as the best cutoff value for screening dementia, our findings and those of others suggest a cutoff of 2 may result in a high false positive rate. Many factors could affect the performance of AD8, including sample characteristics (e.g. education level), region, conduct of the test, flow of the administration (whether AD8 is administered first or contaminated by other tests), etc. Details will be discussed during the AAIC meeting.
Population attributable fraction of potentially modifiable risk factors for dementia among United States Veterans: A retrospective cohort study 2000‐2020.
Authors: Schliep Karen Cecilia , Redd Andrew , Zhang Yue , Shaaban C. Elizabeth , Sorweid Michelle , Rupper Randall , Christine Cliatt Brown J
Published: December 2023

Background

Prior international research has indicated that up to 40% of dementia risk may be amenable to prevention, before symptoms occur, by intervening on various factors. Whether modifiable factors vary between countries or within countries among different populations is beginning to be explored. Veterans are increasingly at elevated risk for dementia and cognitive decline due to health, lifestyle, and military‐related risk factors.

Methods

Data were collected from male and female United States (US) Veterans (≥45 years with no prevalent dementia by January 1, 2000) who had at least one inpatient or outpatient visit within Veterans Health Administration. 8,317,615 individuals were followed to January 1, 2020 to identify potential modifiable risk factors and subsequent dementia diagnoses. We calculated adjusted hazard ratios (aHR) and weighted population‐attributable fractions (PAF) for Alzheimer’s disease (AD) and Alzheimer’s disease related dementia (ADRD) for the following factors: hearing loss, smoking, obesity, depression, post‐traumatic stress disorder (PTSD), hypertension, diabetes, traumatic brain injury (TBI), and heavy alcohol use. Our models were adjusted for age at baseline, sex, race/ethnicity, and marital status and the PAFs accounted for communality among risk factors.

Results

Over the 20 year follow‐up period, 995,821 (12%) US Veterans developed AD/ADRD. The three highest risks for AD/ADRD were TBI (aHR: 3.11 [95% CI:3.08, 3.13]), depression (aHR: 3.06 [95% CI: 3.05, 3.07), and PTSD (aHR: 1.91 [95% CI: 1.90, 1.92]) (Table 1). A weighted estimate of 53.7% (95% CI, 53.2%, 54.1%) of Veteran dementia cases were attributable to the evaluated risk factors. The greatest attributable fraction of AD/ADRD cases was observed for depression (PAF, 19.3%; 95% CI 19.3%, 19.4%), hypertension (PAF, 14.4%; 95% CI: 14.3%, 14.5%), and diabetes (PAF, 6.4%; 95% CI: 6.3%, 6.4%).

Conclusion

The PAF for modifiable risk factors for AD/ADRD is higher than in previous world reports, due to not only greater prevalence of cardiovascular risk factors among Veterans, but also due to higher prevalence of military‐related risk factors including PTSD and TBI. Targeted interventions to reduce key risk factors may decrease the projected rise in dementia cases among Veterans over the next several decades.
Genetic diversity differentially regulates molecular mechanisms of brain aging under normal and pathological conditions
Authors: Uyar Asli , Onos Kristen D , Keezer Kelly J , Carter Gregory W , Sasner Michael , Howell Gareth R
Published: December 2023

Background

Genetically diverse mouse strains have varying life‐spans and varying brain‐aging hallmarks under normal conditions. Studies show that AD mouse models on diverse genomic backgrounds better recapitulate AD‐relevant neuropathological and molecular phenotypes. Mouse models carrying mutant APP and PS1 alleles (APPswe,PS1de9) were generated on eight diverse mouse strains, and significant strain‐specific differences were observed in amyloid deposition, vascular phenotypes, neurodegeneration and transcriptomic signatures. Among those, wild‐derived strains WSB/Eij‐(WSB) and PWK/Phj‐(PWK) gained further attention in AD research. Compared to the APP/PS1 model on standard C57BL/6J‐(B6) mice, WSB.APP/PS1 was associated with elevated neuronal and vascular impairments, whereas, PWK.APP/PS1 was shown to be resilient.

Method

Wild‐derived strains were originally generated via a backcross strategy, and all PWK.APP/PS1 and WSB.APP/PS1 used in this study were congenic. Cohorts of male and female PWK.APP/PS1 and WSB.APP/PS1 mice and wild‐type controls were aged to 4‐ and 14‐months, and brain hemispheres were processed for RNA‐Seq transcriptomics and neuropathological assessment. In both strains, 14‐months‐old wild‐type mice were compared to 4‐months‐old wild‐type controls to assess brain aging under normal conditions, and 14‐months‐old APP/PS1 mice were compared to 4‐months‐old wild‐type group to assess aging in presence of amyloid pathology (n = 12). Differentially expressed genes were identified and gene set enrichment analysis were performed to determine gene modules and biological pathways associated with brain aging in health and disease.

Result

Wild‐type aging signatures were mainly strain‐specific with a strong up‐regulation of immune response in WSB, and up‐regulation of metabolic and signaling pathways in PWK. Varying levels of amyloid plaques deposition was observed in the brain of both WSB.APP/PS1 and PWK.APP/PS1 mice. In presence of amyloid, consistent up‐regulation of microglia genes and an elevated immune response was observed. Down‐regulated genes were enriched in synaptic function in WSB, and in pathways of neurodegeneration in PWK.

Conclusion

This study suggests that molecular mechanisms of brain aging under normal conditions is modulated by genetic background, and is associated with the response to amyloid pathogenesis. Our findings suggest a potential link between aging‐associated inflammatory state in wild‐type WSB mice and elevated neuronal damage in amyloid pathogenesis, and between preservation of cellular communication in the brain of aged PWK mice and neuronal resilience.
Clinical and epidemiological baseline characterization of Dementia cases in a specialized center in Recife, Brazil
Authors: Santana Ana Rosa , Chagas Victor de Moraes , Costa Bruno Henrique Carneiro , Macedo Luísa Couceiro de Albuquerque , Shirahigue Livia , de Santana Joao Pedro Matos , da Silva Rodrigo Cavalcanti Machado , Brandao Simone Cristina Soares , Barbosa Breno José Alencar Pires
Published: December 2023

Background

Population aging has been considered the main risk factor for the development of dementia globally. In low‐ and middle‐income countries such as Brazil, the projections are for expressive numbers due to poor socio‐economic conditions. However, the epidemiological profile of dementias in Brazil is still little known due to the scarcity of studies, especially in the northeast of the country, where poverty and illiteracy are severe.

Method

Retrospective and descriptive study of data obtained from the comprehensive review of medical records after approval by the Ethics Committee. Records of cases treated between 2018 and 2021 were examined, cases that did not have information in the medical record were excluded from the study.

Result

128 medical records were analyzed, 109 of which met inclusion criteria. 57.8% of patients were male with a mean age of 65.3 years. 38.4% of the sample had less than 8 years of formal education and 15.1% were illiterate. Unskilled manual labor was the occupation type in 50% of the sample. The mean baseline Mini‐Mental State Examination (MMSE) score was 16.88. Alzheimer’s disease was the most frequent diagnosis (37%) mostly in a moderate (22%) to advanced stage (20%) of dementia. 32% of all cases met criteria for mixed forms of Dementia. Frontotemporal Dementia (14%), Lewy Body’s Disease (6%) and Pure Vascular Dementia (6%) were also reported. 69.7% of our sample underwent magnetic resonance imaging and 24% also had access to molecular imaging methods.

Conclusion

The low level of education possibly reflects socioeconomic inequalities in Brazil, since we had a lower level of education compared to epidemiological studies of Dementia in the south‐southeast region. The degree of dementia of the examined cases caught our attention, most of them in a moderate or advanced stage, probably related to the time patients wait for care at a specialized center. Such bias may also explain the high frequency of non‐AD pathologies in the sample, in contrast to data from the general population. With the limitation of its descriptive and retrospective design, the present study represents an important initiative in the sense of characterizing data on Dementia in northeastern Brazil.
Item‐based scoring and serial position of words generated during the Category Fluency Test: differences between controls and MCI subtypes
Authors: De Marco Matteo , Venneri Annalena
Published: December 2023

Background

The order in which words are recalled during the 1‐minute Category Fluency Test (CFT) can be informative about the integrity of the underlying semantic memory (SM) system. Typically, the first entries tend to be easier exemplars and, as the category is explored in more depth during the course of the minute, words generated tend to become more difficult. We hypothesised that an item‐based scoring method that quantifies this increase in difficulty will help identify the semantic feature(s) most sensitive to the loss of SM integrity observed in people with a form of mild cognitive impairment (MCI).

Method

Two‐hundred participants (age: 58.68 ± 12.08 years) were sub‐divided into four clinical diagnostic groups: 50 healthy controls, 50 individuals with amnestic MCI, 50 individuals with non‐amnestic MCI and 50 individuals with subjective cognitive complaints but no objective deficits. No differences in age, years of education or gender existed across the four groups. All participants were administered a 1‐minute CFT (two categories: animals and fruits). Individual performance was scored word‐by‐word according to nine semantic features: age of acquisition, frequency, prevalence, recognition time, valence, arousal, dominance, sensorimotor interaction and concreteness. Correlation coefficients (Spearman’s rho) were calculated between each feature and the serial position of each word within the list. Correlations were then converted to z‐scores and analysed across the four groups with Kruskal‐Wallis one‐way analyses of variance.

Result

The z‐converted correlation between serial position and dominance was the only one differing across groups (at a p = 0.009). Bonferroni‐corrected post‐hoc tests showed a difference between healthy controls and individuals with amnestic MCI (p = 0.008). The decline in word dominance was significantly steeper in the group of amnestic MCI (z = ‐0.322) than in controls (z = ‐0.199).

Conclusion

The study of SM is relevant to characterising the clinical mechanisms of normal and abnormal ageing. A procedure that focuses on CFT words difficulty and order of recall can complement classic methods that are typically used to detect loss of SM integrity. This pilot study indicates that ‘dominance’ is a semantic feature that might help characterise loss of SM integrity in individuals with amnestic MCI.
Continuous Picture Naming Performance in Older Adults
Authors: Chok Jas M. , Herron Timothy J , Lwi Sandy J. , Curran Brian , Schendel Krista , Geraci Kristin , Blank Michael , Williams Garrett , Hall Kathleen , Woods David L. , Baldo Juliana
Published: December 2023

Background

Tasks using speech and language have proven to be useful in assessing for neurodegenerative diseases and cognitive decline. Specifically, deficits in naming have been associated with various degrees of cognitive impairment in those with dementia.

Method

The Continuous Picture Naming (CPN) task was administered as part of a new computerized cognitive assessment tool, the California Cognitive Assessment Battery (CCAB), to 309 aging older adults (aged 56‐89, 40.6% female) with a six‐month and one‐year follow‐up to assess for cognitive changes due to aging. The CPN task measures how fast and accurately a subject can verbally produce the names of a series of items pictured onscreen. The battery scores tasks automatically and utilizes an online speech‐to‐text transcription, consensus automated speech recognition (CASR), to transcribe responses on verbal tasks.

Result

Response times and accuracy were on CPN collected and analyzed to observe for effects on age and education. The analysis showed that age and education were significantly associated with the task’s performance. Overall, CPN performance demonstrated good test‐retest reliability at the six‐month (r = .76, p<.001) and one‐year (r = .74, p<.001) follow‐ups. Moreover, a significant relationship was observed between the total time spent and the total errors on the task.

Conclusion

Overall, the CPN demonstrates good reliability in tracking changes in cognition. Ongoing evaluation of the CCAB will aid in assessing cognitive impairments in aging populations.
Utility of Cognitive Abilities Screening Instrument (CASI) subscores in detecting early impairment in autosomal dominant Alzheimer’s disease (ADAD)
Authors: Tureson Kayla N , Beam Christopher R. , Medina Luis Daniel , D'Orazio Lina M , Ringman John M
Published: December 2023

Background

Prior research among patients with autosomal dominant Alzheimer’s Disease (ADAD) has identified early cognitive changes 10‐20 years before formal dementia diagnosis. ADAD provides a model of Alzheimer’s disease (AD) with a relatively predictable onset and with fewer age‐related comorbidities, and as such, may aid in identifying presymptomatic stages of cognitive change for early AD detection. The CASI is a comprehensive screening tool for dementia with multilingual adaptations and may be useful in identifying early cognitive changes among those with or at risk of ADAD.

Method

We examined whether subscales of the Cognitive Abilities Screening Instrument (CASI) could identify early cognitive changes in ADAD as well as the effects of test language (English or Spanish), education, and acculturation on CASI subscales. 141 persons (96 mutation carriers [MC], 45 noncarriers [NC]) with or at risk for inheriting PSEN1/2 or APP mutations completed the CASI. Linear mixed‐effect models were used to examine the effects of adjusted age, mutation status, mutation type (APP or PSEN), test language, education, and acculturation on the 9 CASI subscales.

Result

MCs performed significantly worse on CASI subscales than NCs (ps<.001). Adjusted age (βs = ‐.29— ‐.09), mutation status (βs = ‐2.62—‐0.09), and adjusted age x mutation status (βs = ‐.29— ‐0.09) significantly predicted Attention (R2 = 0.36), Concentration (R2 = 0.40), Orientation (R2 = 0.53), Short‐Term Memory (R2 = 0.61), Long‐Term Memory (R2 = 0.27), Language (R2 = 0.39), Visuoconstruction (R2 = 0.53), Fluency (R2 = 0.34), and Abstraction/Judgment (R2 = 0.37), all ps <.001. Acculturation significantly predicted Long‐Term Memory (β = .34, p = .03). The effects of acculturation, test language, and education were not significant for any other CASI subscales.

Conclusion

Adjusted age, mutation status, and an interactive effect between adjusted age and mutation status appear to be important predictors in CASI performance, such that MCs closer to their familial age of dementia diagnosis are more likely to perform worse on the CASI. No subtest emerged as the best predictor of early cognitive changes in MCs. Attention to potential cultural influences on the Long‐Term Memory subtest warrants further research.
Fluid and imaging amyloid‐beta biomarkers discordant individuals present different blood transcriptomic phenotypes
Authors: Schlickmann Thomas Hugentobler , de Bastiani Marco Antônio , Bellaver Bruna , Zalzale Hussein , Souza Lara Angi , Machado Luiza Santos , da Rocha Andreia Silva , Da Ros Lucas Uglione , Ferrari‐Souza João Pedro , Carello‐Collar Giovanna , Lazzarotto Gabriela , Limberger Christian , de Carvalho Lavínia Perquim , Vidor Pedro , Borelli Wyllians Vendramini , Rohden Francieli , Pascoal Tharick A. , Zimmer Eduardo R. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

Background

Cerebrospinal fluid (CSF) and Positron emission tomography (PET) amyloid‐β biomarkers are commonly used interchangeably to measure amyloid‐β deposition, an early event in the development of Alzheimer’s disease (AD). However, it is not uncommon to find individuals with discordant measurements of amyloid‐β CSF and PET. It has been hypothesized that this discordance may be an intermediate step between the CSF and brain amyloid deposition, and that discordant individuals might be in different disease stages or have different disease phenotypes. Here, we applied blood transcriptomic analysis to evaluate differences in amyloid‐β CSF and PET discordant and concordant individuals.

Method

We analyzed the blood transcriptome of 200 individuals from the ADNI cohort who had measurements of both CSF amyloid‐β42 and [18F]Florbetapir PET at baseline and at 2‐year follow‐up. The demographic characteristics of the sample are presented in table 1. Our analysis yielded four groups: CSF+/PET‐ (n = 18), CSF‐/PET+ (n = 19), CSF+/PET+ (n = 76), and CSF‐/PET‐ (n = 87). The latter was the control group for all analyses. Differentially expressed genes (DEGs, uncorrected p‐value < 0.01) were used for gene set enrichment analysis (GSEA) to identify group‐specific altered biological pathways.

Result

CSF+/PET‐, CSF‐/PET+ and CSF+/PET+ individuals showed a great proportion of unshared DEGs (Figure 1). The CSF+/PET‐ group, which is thought to represent a very early stage in the disease, presented the highest number of unshared DEGs (273) with upregulated GO terms involved mainly in metabolic processes. The CSF‐/PET+ group possessed 113 unique DEGs, while the CSF+/PET+ possessed 47. Interestingly, these groups presented similar alterations in biological processes, representing mainly alterations in immune response and inflammation.

Conclusion

Our results highlight the differences in the blood transcriptomic phenotype between CSF and PET amyloid‐β concordant and discordant individuals. Importantly, individuals very early in the AD continuum (CSF+/PET‐) presented the most distinct phenotype. Our results suggest that blood transcriptomics are able to capture subtle changes in brain amyloid‐β and might help identify individuals in different stages of AD.
The effect of blood pressure on domain‐specific cognitive changes in older Black Americans: findings from the Baltimore Study of Aging – Patterns of Cognitive Aging
Authors: Byrd DeAnnah R. , Coon David W. , Thorpe Roland J. , Whitfield Keith E.
Published: December 2023

Background

Previous research suggests that hypertension shape cognitive health outcomes in older Blacks (Whitfield 2008). However, few studies have explored the relation between objective and subjective blood pressure (BP) measures and cognitive decline. This study examined whether systolic, diastolic, and self‐reported BP were associated with changes in cognition.

Method

Data are drawn from the Baltimore Study of Black Aging—Patterns of Cognitive Aging. At baseline, 602 Black participants (48‐95 years) were enrolled. At follow‐up, approximately 3 years later, 450 participants were re‐interviewed. Cognition included 5 domains: working memory, processing speed, verbal memory, vocabulary, and inductive reasoning. Using an oscillometer automated device (A&D model UA‐ 767), three readings of orthostatic BP were collected and mean systolic (SBP; range = 82‐230.3 mmHg) and diastolic BP (DBP; range = 51‐136.7 mmHg) values were calculated for each participant. BP was treated as a continuous variable. Participants were also asked “Have you ever been told by a doctor or nurse that you have high blood pressure? (yes/no response)” Data were analyzed using multiple linear regression, controlling for sociodemographic and health conditions.

Result

Majority of the sample was female (25.4% male) and had at least a high school education (57.1%). Systolic BP was inversely associated with inductive reasoning at follow‐up (b = ‐0.208, p = 0.023; see Table 1), but was not related to any other cognitive domains, after adjusting for age, sex, education, depressive symptoms, comorbidities, diastolic BP, and baseline cognition. Diastolic BP and self‐reported hypertensive status were both unrelated to changes in each of the five cognitive domains (all models, p> 0.05).

Conclusion

The present study adds to our understanding of cognitive aging among older Black Americans. Results support previous research, pointing to an independent effect of BP on domain‐specific cognitive changes (Buford 2016), but also extend the literature by highlighting a more pronounced negative effect of systolic BP. These findings suggest that the pathway to cognitive dysfunction is contributed to by BP. Several key mechanisms – including increased risk for stroke and “vascular dementia” (age‐ and hypertension‐related cerebral vasculature changes) – may explain the influence of hypertension on cognitive decline that warrant further study in Black Americans.
A Music Based Intervention: “Stay with Me” Results Reveal Challenges and Opportunities related to Burden in Family Caregivers of People with ADRD
Authors: Ray Kendra , Mittelman Mary S
Published: December 2023

Background

Family caregivers of home‐based people with ADRD took part in a 6‐week psychoeducational music‐based intervention, facilitated by a board‐certified music therapist. Caregivers identified care recipients’ strengths and needs related to symptoms of ADRD. In the following weeks, caregivers learned how to incorporate music‐based activities during their care. This included caregiver singing, adding background music to bath/shower routines, creating personalized playlists, the use of music for sundowning, etc. A concurrent, mixed methods approach was employed. The Short Zarit Burden Interview (12 item) was completed at baseline and follow‐up. During week 6, in small groups ranging from 2 – 6 persons, family caregivers (n = 20) rewrote the lyrics of Stand by Me, using a fill‐in‐the‐blank template.

Method

A content analysis of rewritten lyrics revealed a focus on themes. A paired samples t‐test was performed to determine changes in burden. To merge the lyrics and burden scores, a joint display analysis was performed. A box plot of mild to high burden was created to demonstrate how the post‐test scores were distributed across levels of burden accompanied by a descriptive display of the most dominant lyrics that reflected each level.

Result

Following the music‐based intervention, a paired samples t‐test found that caregiver burden reduced significantly from baseline (from M = 20.73 ± 6.72 to M = 16.1 ± 4.89; p = .000) indicating that caregiver participation in the 6‐week workshop contributed to perceived reduced burden. Post‐tests and box plot showed most caregivers (80%) scored with mild to moderate burden following the study. The results from content analysis of the lyrics described caregivers’ desire to persevere without fear, issues of falling or failing (a replica of the progression of ADRD) but indicate a desire to stay with the person for whom they are caring.

Conclusion

Burden decreased following participation in the psychoeducational, music‐based intervention. Nevertheless, caregivers cope with a range of emotions related to caring for a person with ADRD, revealing the facilitation of music‐based interventions at home is a useful tool for caregivers but also a need for continuous support. The study is ongoing.
Modulation of the p75 neurotrophin receptor in the PS19 tauopathy mouse model regulates transcription profiles and inter‐cellular communication across multiple populations of non‐neuronal cells
Authors: III Robert R. Butler , Yang Tao , Han Crystal , Guen Yann Le , Tran Kevin C , Lallani Shoeb , Liu Harry , Leng Song Albert , Massa Stephen M. , Longo Frank M.
Published: December 2023

Background

Tau pathologies contribute to neurodegeneration in Alzheimer’s Disease (AD) and other disorders via a variety of mechanisms. In tauopathy mouse models, administration of LM11A‐31 (C31), a small molecule modulator of the p75 neurotrophin receptor (p75NTR), reduced tau post‐translational modifications, accumulation of pathological tau species and microglial activation; restored synaptic plasticity, and reversed synaptic spine loss. We examined long‐term dosing with C31 at the single‐cell transcriptional level to further elucidate cell types and cellular mechanisms affected by treatment.

Method

Tauopathy model tauP301S mice (PS19) and age‐matched wildtype (Wt) mice were dosed by oral gavage with C31 or vehicle once daily for 3 months from 6 months of age, when tau pathology was well established. Whole cortex single‐nucleus RNA‐sequencing was analyzed using Seurat, with automated cell type annotation, followed by manual curation. Additional analyses compared AD‐associated biodomains and risk scored genes from TREAT‐AD with individual cell types. Finally, cell‐to‐cell communication was assessed via Liana ligand‐receptor (LR) interaction analysis.

Result

Several neuronal, glial, and vascular cell types showed inverse correlations between C31 differential expression and both PS19 differential expression and TREAT‐AD biodomains (Figure 1), suggesting shifts in expression profiles in the opposite direction from those in human AD cohorts and mouse tauopathy models. In LR interaction analysis, vascular and leptomeningeal cells (VLMCs) were highly active as a signaling source to most other cells—particularly neurons—in the PS19 vehicle mice compared to all other groups (Figure 2). VLMC LR signals that were stronger in PS19 vehicle mice versus Wt vehicle were enriched for Focal Adhesion/PI3K‐Akt signaling, TGF‐beta signaling, AD‐presenilin pathways and regulation of synapse organization (Figure 3). VLMC LR signals that were stronger in PS19 C31 versus PS19 vehicle showed similar pathway enrichments and included several neuropilin‐semaphorin‐plexin complexes which may direct neuronal wiring and development.

Conclusion

These findings demonstrate that broad patterns of expression and LR signaling in multiple cell types impacted by tauopathy show substantial reversion to wildtype‐like patterns when treated with C31. Further they indicate a possible role for VLMC signaling in the pathogenesis of tauopathies.
The human microglia response to amyloid plaques explains genetic risk of AD
Authors: De Strooper Bart
Published: December 2023

Background

Many GWAS genes associated with risk of AD are expressed in microglia

Method

microglia in vitro have poor resemblance to microglia in vivo. On the other hand mouse microglia are not really suitable to catch human polygenic risk. We have created chimeric human‐mouse models to study the human microglia response to amyloid plaques.

Result

We have improved the chimeric model dramatically and have routinely 60% chimerism. We have performed single cell analysis and functional analysis to characterize the multipronged response of microglia to amyloid plaques. We are investigating how drugs modulate this response. We are using spatial transcriptomic approaches to see how microglia and astroglia react in the amyloid plaque niche

Conclusion

The reaction of brain cells to amyloid pathology is complex and involves cell‐cell interactions that ultimately affect neuronal health. The simple linear interpretation of the amyloid hypothesis does not provide an explanation for this long cellular phase of the disease.