bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Suspected Dementia in a Sample of Adults Living in Kinshasa‐Democratic Republic of the Congo
Authors: Ikanga Jean N
Published: December 2022

Background

The improved life expectancy in Sub‐Saharan Africa are leading to increased burden of dementia. This study investigates the prevalence and risk factors for suspected dementia in elderly adults in Kinshasa, Democratic Republic of the Congo (DRC).

Method

Participants included 356 individuals over 65 years old (mean = 73.6 years; SD = 6.7 years; range = 65‐98 years) recruited in Kinshasa. The sample was 51% male with an average 7.3 (SD = 4.7 years; range 0‐20 years) years of education. Participants were screened using Community Screening Instrument for Dementia, Alzheimer’s Questionnaire, Geriatric Depression Scale, Beck Anxiety Inventory and Individual Fragility Questionnaire followed by clinical interview and neurological screening. Suspected dementia diagnoses were made based on DSM‐5 criteria including significant cognitive and functional impairments. Prevalence and odd ratios with 95% confidence interval were calculated using logistic regression.

Result

The crude prevalence was 6.2% in Kinshasa. The prevalence of suspected dementia was 9.0% in women and 3.8% in men. Female sex was a significant predictor of suspected dementia [OR = 2.81, 95% CI (1.08‐7.41), p = 0.03]. The prevalence of dementia increased with age (14.0% after 75 years and 23.1% after 85 years), with age being a significant risk factor [OR = 5.42, 95% CI (2.86‐10.28), p <.0001. Greater education was associated with lower prevalence of suspected dementia [OR = 0.36, 95% CI (0.14‐0.94), p = 0.04, comparing those with ≥7.3 to <7.3 years of education]. Widow and being semi‐retired or retired were significant risk factors. Anxiety [OR = 2.56, 95% CI (1.05‐6.13), p = 0.04] and death of a spouse or a relative after age 65 [OR = 0.73, 95% CI (0.58‐0.92), p = 0.01] were significant risk factors for suspected dementia while depression [OR = 1.92, 95% CI (0.81‐4.57)], hypertension [OR = 1.16, 95% CI (0.79‐1.71)], BMI [OR = 1.06, 95% CI (0.40‐2.79)], and alcohol consumption [OR = 0.83, 95% CI (0.19‐3.58)] were not significant predictors of suspected dementia.

Conclusion

This study found a prevalence of suspected dementia in Kinshasa/DRC similar to other developing countries and Central African countries. Being elderly, female, less educated, widow, retired, having anxiety and experiencing death after age 65 were significant risk factors for suspected dementia.
Hyperorality in Frontotemporal dementia: Cognitive, Behavioral, and Neuroanatomic Profiles in Early‐Stage Disease
Authors: Morrow Christopher , Kamath Vidyulata , Onyike Chiadi U. ,   ALLFTD Consortium
Published: December 2022

Background

Hyperorality represents a key feature observed in the behavioral variant of frontotemporal dementia (bvFTD). While hyperorality is common in advanced cases of bvFTD, less is known about its frequency in early‐stage disease. The cognitive, behavioral, and neuroanatomic patterns of patients with early stage bvFTD and hyperorality have also not been well established. The primary aim of this study is to describe the frequency of hyperorality in a sample of patients with early stage bvFTD while also exploring patterns of cognitive, behavioral, and neuroanatomic change.

Method

Data are from subjects enrolled in the ALLFTD study, an established US consortium with an ongoing cohort study of FTD. Cognitive profiles were assessed using validated neuropsychological batteries, and social behavior was measured using validated scales. Psychiatric states were coded as binary variables. Differences in baseline characteristics and clinical outcomes were compared using t‐tests for continuous variables and Pearson χ2 tests for categorical variables. Statistical significance was based on p values <0.05.

Result

We enrolled 1,694 subjects, comprising 145 with a CDR® plus NACC FTLD global score less than or equal to 1 at the first visit who were used in our analysis. 50% of subjects exhibited hyperorality. There were no demographic differences between groups other than CDR global scores which were higher in the hyperorality group (0.8 versus 0.7, p = 0.003). Cognitive profiles encompassing domains of processing speed, language, executive functioning, memory, and attention did not differ between groups. Subjects with hyperorality had lower scores on scales of self‐monitoring, empathetic concern, and perspective taking. Subjects with hyperorality had higher rates of motor disturbance, and ritualistic/compulsive behaviors. There were no volumetric differences in neuroanatomic regions of interest.

Conclusion

Our findings indicate that hyperorality is common in early stage bvFTD, arising prior to cognitive and neuroanatomic changes. Hyperorality travels with motor disturbances and ritualistic/compulsive behaviors alongside eroding social behavioral functioning. Hyperorality may serve as an early signal of disease, providing an opportunity for intervention prior to significant neurodegeneration using novel therapeutics and non‐invasive brain stimulation.
Multi‐omics analyses reveal unexpected effects of PLCg2 deficiency in the brain
Authors: Palavicini Juan Pablo , Miller Henry E. , Smith Sabrina , Campos Gabriela , Hopp Sarah C.
Published: December 2022

Background

Plcg2 polymorphisms are associated with both reduced (P522R) and increased (M28L) risk of Alzheimer’s disease (AD). The normal function of phospholipase C‐gamma‐2 (PLCg2) protein is to catalyze the hydrolysis of the membrane phosphatidylinositol‐4,5‐bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), which subsequently feed into downstream signaling pathways involving protein kinase C (PKC) activation, lipid homeostasis, and calcium regulation. In the brain, Plcg2 is primarily expressed by microglia. The Plcg2 P522R protective variant is a functional hypermorph, while it is predicted that M28L is a loss‐of‐function variant. The specific consequences of PLCg2 loss of function in the brain are unknown. We predicted that reduction of PLCg2 would lead to disrupted PIP2 and DAG metabolism, and that these changes would be associated with decreased PKC and calcium signaling resulting in changes in microglia phenotype.

Methods

At 3 months of age, PLCg2 knockout (KO), PLCg2 heterozygous, and wild‐type (WT) littermate mice were euthanized. We analyzed their brains using, shotgun lipidomics, proteomics, gene expression analysis by a Nanostring Glia Profiling panel, and immunohistochemistry (IHC).

Results

Lipidomic analyses revealed expected but sex‐specific changes in total brain PIP2 and DAG content in KOs compared to WTs. Surprisingly, significant decreases in myelin‐specific lipids (e.g., cerebrosides) were identified in both sexes. Unexpectedly, Nanostring gene expression analysis revealed sex‐specific changes in myelin‐related genes, as well as subtle effects on microglia phenotype in KOs compared to WTs, suggestive of reduced microglia . Surprisingly, exploratory proteomics analyses revealed subtle changes in KO females compared to WTs, primarily related to amino acid metabolism. IHC for microglial markers confirmed subtle differences in microglia (Iba1 density and area) in KOs compared to WTs.

Conclusions

Our data demonstrate that loss of PLCg2 in the brain generally leads to subtle differences in microglia phenotype in the absence of inflammatory stimuli (suggestive of reduced microglial reactivity) and a surprising potential role for PLCg2 in myelin and amino acid homeostasis that requires further investigation. Overall, our data indicate that loss of PLCg2 function has subtle effects on brain homeostasis that may underlie enhanced vulnerability to AD pathology via microglia and myelin dysfunction.
Affective and ergogenic effects of beat‐accented synchronous music on acute exercise training in older adults with mild cognitive impairment or mild dementia
Authors: Park Kyoung Shin , Hong Jiyeong , Etnier Jennifer L
Published: December 2022

Background

Given the increasing dementia population and that no cure for dementia is available, exercise may be important for older adults in the early stages of cognitive decline (ESCD) to delay the progression of cognitive deterioration. However, functional limitations are prevalent in older adults, which often hinder their exercise participation. Exercising with music is a novel approach to facilitate exercise and maximize health benefits because humans like to move in synchrony with music and because both music and exercise can help improve cognitive health. As part of a proof‐of‐concept study, we tested the acute effects of beat‐accented synchronous music (BSM) on affective and psychophysiological responses to exercise in older adults with ESCD.

Method

We developed a chair‐based group exercise program consisting of 30 min of aerobic, strength, and balance training for older adults with functional limitations. A BSM playlist at 85 beats/min was created by imposing 4/4 drumbeats on top of instrumental country music that matched participants’ exercise pace and music preference. Nine older adults with ESCD (M
age = 80.9±15.1 years; 2 females; Montreal Cognitive Assessment scores ranged 11‐24) exercised with and without BSM (twice each, counterbalanced) and provided their ratings of feelings (FS) and perceived exertion (RPE) immediately before, midway through, and immediately after each exercise session. Data were analyzed by Friedman tests.

Result

We found significant effects of BSM on FS [χ
2(1) = 4, p<0.05] and RPE [χ
2(1) = 4.5, p<0.05] during exercise. Participants reported more positive feelings (9.78±0.22 > 8.56±0.56) and higher exertion (6±0.96 > 3.94±0.49) during BSM‐based exercise compared with no‐BSM exercise. No effects of BSM on FS and RPE were found before or after exercise (p’s>0.5).

Conclusion

Cognitive and functional decline restrains exercise participation in older adults, which exacerbates the cognitive and functional decline, creating a vicious cycle. Our findings suggest that BSM can make exercise more pleasurable while increasing perceived exercise intensity from ‘somewhat hard’ to above ‘hard’ in older adults with ESCD. These are important findings because positive affect during an acute bout of exercise is associated with future exercise participation. Future research needs to test the efficacy of a long‐term BSM‐based exercise intervention for older adults.
Cell type specific gene expression profiles of the candidate genes for Alzheimer’s disease
Authors: Sandhu Sumiti , Kong Sek Won
Published: December 2022

Background

Decades of genetic studies discovered candidate genes for Alzheimer’s disease (AD). Molecular mechanistic insights, however, are available for few candidate genes. This lack of understanding on gene function has been a challenge to translate the role of candidate genes to discovering treatment and diagnostic biomarkers. Recent advances in single cell profiling provide an opportunity to understand functional significance of candidate genes and their products for the cell types implicated in AD.

Method

We performed an integrative analysis of single cell gene expression profiling datasets (i.e., scRNA‐seq and snRNA‐seq) comprising 11 datasets generated from animal models (0.3 million cells) and 15 datasets prepared with human brain tissues (3.1 million cells) that were retrieved from AD Knowledge Portal and the other public repositories. All human and mouse datasets were merged using Harmony to discover cell subpopulations that were unique to conditions compared to controls and/or wild type. For AD candidate genes, cell types were ranked according to their relative expression levels and correlation structure.

Result

Clustering of brain cell types such as excitatory and inhibitory neurons, glial and vascular endothelial cells was similar across datasets and species; however, we found that transcriptional signature of microglia at different stage of human AD was distinct from disease‐associated microglia (DAM) observed in the mouse AD models. Of note, several homeostatic microglial genes known to be downregulated in mouse DAM were upregulated in human AD samples. Moreover, microglia were the only cell type that expressed all reported AD candidate genes. Nonetheless, the cell type specific expression pattern of AD candidate genes was different between species and across datasets suggesting biological and technical biases.

Conclusion

Using an unbiased approach, we highlight the (dis)similarity between human and mouse AD datasets and potential molecular pathways for AD risk genes within microglia and the other cell types implicated in AD.
A novel mouse model of SARS‐CoV‐2 induced neuroinflammation
Authors: Biose Ifechukwude Joachim , Narayanappa Amruta , Gressett Timothy E , Leist Sarah R , Srivastava Akhilesh , Ismael Saifudeen , Kolls Jay , Baric Ralph S , Bix Gregory J
Published: December 2022

Background

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection may impact neurological function acutely or chronically, even in the absence of severe respiratory illness. Developing clinically relevant laboratory models to understand the neuropathogenesis of SARS‐CoV‐2 infection is an important step towards unravelling this neurologic consequence. We hypothesize that mouse adapted SARS‐CoV‐2 viral infection will induce neuroinflammation in immuno‐competent C57BL/6J (10 weeks old male) as well as immunodeficient RAG2−/‐ (10 weeks old male) and BALB/c (1 year old female) mice.

Method

All three mouse strains were inoculated intranasally with a dose of 1×103 PFU/mouse (50 µL) of either mock or the mouse‐adapted (MA)10 strain of SARS‐CoV‐2 (BEI resource, NR‐55329). Mice were euthanized on day 2, 3, 7, 15 or 30 post infection and brain samples processed for qRT‐PCR, immunofluorescence, and H&E analysis.

Result

SARS‐CoV‐2 MA10 resulted in a significantly higher (p < 0.05) mRNA expression for chemokine ligand 2 (CCL2) and lower (p < 0.05) mRNA expression for the blood‐brain barrier component Claudin‐5 in RAG2−/‐ and WT mice when compared to mock infection. Also, SARS‐CoV‐2 MA10 infection increased microglial expression in 1 year old female BALB/c mice after 2 days of infection, compared to mock infected group. At 30 days post infection, MA10 infected BALB/c mice had a higher perivascular lymphocyte cuffing in the brain.

Conclusion

This study demonstrates that the mouse‐adapted MA10 strain of SARS‐CoV‐2 can induce a neuroinflammatory state in the brain and more so in immunodeficient and aging mouse models. These mouse models will enable the investigation of the long‐term neurological effects of SARS‐CoV‐2 infection.
Testing the Association Between Neighborhood Disadvantage and White Matter Hyperintensities
Authors: Merkel Emily X. , Ennis Gilda E. , Cadman Robert V. , Koscik Rebecca Langhough , Ma Yue , Asthana Sanjay , Johnson Sterling C. , Kind Amy J. , Bendlin Barbara B.
Published: December 2022

Background

Social determinants of health—the conditions in the places where people live, learn, work, and play—have been shown to affect a broad range of health outcomes, including risk for Alzheimer’s disease and related dementias (ADRD). However, the biological mechanisms by which socio‐contextual factors increase risk for ADRD are poorly known. Higher levels of neighborhood disadvantage have been linked with increased cardiovascular disease (CVD) risk. CVD risk has been associated with white matter lesions known as white matter hyperintensities (WMH) because they produce increased signal on fluid‐attenuated inversion recovery (FLAIR) MRI scans. WMH have been associated with increased risk for stroke, cognitive decline, and dementia. We investigated whether greater neighborhood‐level disadvantage was associated with greater WMH volume.

Method

Participants (n = 804) were enrolled in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center Clinical Core. MRI was performed at 3 T to acquire T2‐weighted FLAIR images which were then processed using the lesion prediction algorithm from the Lesion Segmentation Toolbox to measure WMH volume. Area Deprivation Index (ADI) distributions from the state of Wisconsin were used to create a dichotomous variable that compared the highest state‐ranked quintile (most disadvantaged neighborhoods) to the lowest 4 state‐ranked quintiles (least disadvantaged neighborhoods). Multiple linear regression tested ADI as a predictor of natural log‐transformed WMH volume. Age, sex, education, intracranial volume, MRI head coil, and study cohort were controlled.

Result

Four percent (n = 33) of participants were identified as living in the most disadvantaged neighborhoods (see Table 1). The association between neighborhood‐level disadvantage and log‐transformed WMH volume was not statistically significant (see Table 2 and Figure 1).

Conclusion

Neighborhood disadvantage was not related to WMH volume in this study. This finding contrasts with previous studies demonstrating associations between increased neighborhood disadvantage and reduced cerebral and hippocampal volume (Hunt et al., 2020) and increased odds for AD neuropathology (Powell et al., 2020). Statistical power to assess the primary effect was likely limited by the small number of participants from the most disadvantaged neighborhoods. This illustrates the need for additional research and increased population‐representative recruitment from disadvantaged contexts for ADRD research studies.
Mechanisms of Cognitive Decline due to White Matter Lesions in Cognitively Intact Older Adults
Authors: Taghvaei Mohammad , Cook Philip , Khandelwal Pulkit , Shakibajahromi Banafsheh , Sadaghiani Shokufeh , Das Sandhitsu R. , Brown Christopher , Tackett William , Dolui Sudipto , Shinohara Russell T. , Wolk David A. , Detre John A.
Published: December 2022

Background

White matter hyperintensities (WMH) on FLAIR MRI are highly prevalent in older adults and are linked to cognitive deficits as well as dementia. Likely mechanisms underlying associations between WMH and cognitive deficits include widespread partial disconnection due to the diffuse nature of progressive WMH and/or tract‐specific disconnection syndromes. We used a virtual lesion approach to evaluate cognitive deficits in domains associated with three tracts: left arcuate fasciculus (LAF; verbal working memory), inferior longitudinal fasciculus (ILF; visual processing), and fornix (memory).

Method

WMH were semi‐automatically segmented from FLAIR MRI data in 481 ADNI controls and applied as regions of avoidance for probabilistic fiber tracking on DTI data in 46 healthy older subjects from the Human Connectome Lifespan database. Correlations between overall WMH burden or individual tract disruption and global or tract‐domain‐specific cognitive tests were assessed. Tract disconnection was also compared in subgroups with enriched disruption of specific tracts with respect to global WMH burden, Amyloid beta deposition status, and best (>Mean+1SD) versus worst (<Mean‐1SD) test performance.

Result

All three tracts showed disconnections due to WMH and the mean tract disconnection increased significantly with overall WMH burden (ILF; p<0.001, LAF: p<0.001, Fornix; p=0.025) (Figure 1A). Also, both overall WMH burden and percent disconnection in ILF were associated with prolonged Trail A and Trail B times after correction for age and education (Table 1). In subgroup analyses, Amyloid beta positive status significantly moderated correlation of Trail B times with overall WMH burden (p=0.007) and ILF disconnection (p=0.020) (Figure 2). Subjects with enriched ILF disconnection (Figure 1B) also had prolonged Trail A times than the average group (34.3 vs 30.2, p=0.003). Based on cognitive tests performance, subjects with better scores on verbal category fluency or verbal logical memory tests had lower LAF (p=0.035) and fornix (Test I; p=0.003, Test II; 0.025) disconnection.

Conclusion

While overall WMH burden correlates with cognitive deficits in ADNI controls, significant correlations between specific tract disconnection and tract‐domain‐specific cognitive tests are also observed. Both mechanisms likely contribute to age‐associated cognitive decline. Furthermore, amyloid beta accumulation strengthens these relationships.
Combining quantitative and survival trait analyses identifies novel general and sex‐specific genes for age‐at‐onset of Alzheimer’s disease
Authors: Li Yi‐Ju , Nuytemans Karen , La Jong ok , Jiang Rong , Slifer Susan H. , Naj Adam C. , Gao Xiaoyi Raymond , Martin Eden R.
Published: December 2022

Background

Alzheimer’s disease (AD) has high genetic heritability for both disease risk and age‐at‐onset (AAO) of AD. However, our understanding of genetics of AAO of AD lags behind AD risk. Here, we utilized two statistical approaches to identify genes modifying AAO of AD globally or in a sex‐specific manner.

Method

Pooled data from 9,219 AD cases and 10,345 controls from 20 cohorts from the Alzheimer Disease Genetic Consortium were analyzed using a linear mixed model (LMM) for AAO from cases only, and a Cox proportional hazard frailty model (CoxFM) from all subjects with AAO observed in cases and censored at age‐at‐exam in controls. Both methods modeled outcome on SNP, sex, APOE‐e4, and 10 principal components (PCs), and incorporated random intercept by cohort. Fisher’s method was used to combine results of LMM and CoxFM. Genome‐wide significant variants were determined based on p < 5×10−8 in individual or combined tests. Multiple secondary analyses were performed including sex‐specific association tests for top SNPs (p< 10−6). Two gene‐expression datasets of prefrontal cortex tissues from NCBI/GEO were analyzed by sex to evaluate the sex‐specific AAO genes.

Result

We identified 34 genome‐wide significant loci. We confirmed 6 known AD risk genes (APOE, CR1, BIN1, TREM2, PICALM, and FERMT2) also regulating AAO as AD. Twenty‐eight potential novel loci were identified including ARFGEF2, MAPK9, and the MLX region harboring functional related genes for AD. Sex‐specific analyses showed the effects of PICALM, MLX, and CDH2 on AAO were solely from females, and ATP2C1 from males. Particularly, the MLX region harboring 10 genes in strong LD, including variants in COASY and HSD17B1 previously reported to associate with earlier AAO of AD in female AD patients with Down Syndrome. Gene expression further supported higher differential expression of AD over controls for HSD17B1, COASY, PLEKHH3, and MLX in females than males.

Conclusion

Using two statistical methods to model AAO of AD, we identified six known AD risk genes and 28 novel loci associated with AAO of AD, and further narrowed down four loci with sex‐specific effects. Notably, HSD17B1, involved in estrogen activation, has strong functional implications warrant for further investigation.
Alzheimer’s pathology disrupts cortical processing of repeated stimuli in cognitively intact older adults
Authors: Giorgio Joseph , Adams Jenna N. , Maass Anne , Jagust William J. , Breakspear Michael
Published: December 2022

Background

We used functional imaging (fMRI) and generative modelling to investigate effects of Alzheimer’s disease (AD) pathology (β‐amyloid/Aβ, pathological tau) on cortical mechanisms that support differentiation of novel and repeated stimuli.

Method

66 subjects (45 Older Adults (OA), 21 Younger Adults) underwent an fMRI task involving stimuli of novel and repeated scenes and objects (stimulus conditions; scenes and objects, context condition; repetition); 42 OA also had PIB‐PET measurement of Aβ and flortaucipir (FTP)‐PET of pathological tau. fMRI data were decomposed into functional networks using group spatial Independent Component Analysis (ICA). We used Dynamic Causal Modelling (DCM) to predict local cortical activity from the time‐course associated with stimulus‐related activity and stimulus repetition. AD pathology was defined as Entorhinal cortex FTP‐SUVR (EC‐tau) and continuous global Aβ. A hierarchical approach uncovered the optimal model that best described our data while considering subject variability due to Aβ and EC‐tau.

Result

Five ICA networks were selected for DCM analysis (Figure 1), two input; related to stimulus category (LOC Objects>Scenes: t(65) = 21.64 p<0.001; PPA Scenes>Objects: t(65) = 22.4 p<0.001) and three higher order showing significant effects of repetition (DMN (t(65) = 14.04 p<0.001, MTL t(65) = 11 p<0.001, SAL ‐13.14, p<0.001). Time‐courses modelled using DCM included all possible connections (except between LOC and PPA), allowing repetition to modulate any of these connections with stimuli modelled as inputs to LOC and PPA. From this analysis we observed very strong evidence that increased Aβ removes the inhibition of the DMN by MTL leading to over stimulation when stimuli are repeated (Commonality(repeated) ‐0.38 Pp = 1; Ab(repeated) 1.99, Pp = 1). Conversely, we observed very strong evidence that increased EC‐tau removes the inhibition of the MTL by DMN when stimuli are repeated leading to over stimulation when stimuli are repeated (Commonality(repeated) ‐0.29, Pp = 1, EC‐tau(repeated) 1.7, Pp = 1).

Conclusion

AD pathology disrupts the normal cortical processes that subserve the ability to recognise repeated stimuli in cognitively intact OA. Critically, global Aβ disinhibits the DMN and EC‐tau disinhibits the MTL, two previously described functional phenomena linked to AD pathology. These models provide a systems‐level account of how pathology affects interactions between functional brain networks that may underlie cognitive decline.
Potential Involvement of Varicella Zoster Virus in Alzheimer’s Disease/Dementia via Reactivation of Herpes Simplex Virus Type 1
Authors: Cairns Dana M , Itzhaki Ruth F , Kaplan David L
Published: December 2022

Background

Infections are associated with cognitive decline and development of AD/dementia. Epidemiological studies have revealed an increased AD/dementia risk after shingles, caused by varicella zoster virus (VZV), and/or a decreased risk after vaccination against shingles. This suggests that VZV might reside latently in brain, and on reactivation might cause direct damage in brain, as is thought to be the case with herpes simplex virus type 1 (HSV1), a virus strongly implicated in AD. Alternatively, shingles‐induced inflammation could lead to neuroinflammation and reactivation of HSV1 in brain, i.e., to an indirect consequence – a suggestion previously made to account for the risk of AD/dementia conferred by infections (Itzhaki and Dobson 2002), and for the reduction in risk after certain vaccinations ‐ by preventing occurrence of infection and consequent reactivation. Our aim was to investigate these possibilities by infecting cell cultures with VZV.

Method

Experiments were carried out infecting human‐induced neural stem cells (hiNSC) cultures, and cultures quiescently infected with HSV1 with VZV. Cultures were observed for the presence of AD‐related phenotypes such as beta amyloid and P‐tau accumulation, gliosis, and neuroinflammation.

Result

Cells infected with VZV do not show the main AD characteristics ‐ beta amyloid and P‐tau accumulation – which HSV1 does cause ‐ but do show gliosis and increased levels of several cytokines, suggesting that VZV’s action is indirect. However, very intriguingly, we found that VZV infection of cells quiescently infected with HSV1 leads to reactivation of HSV1 and consequent AD‐like changes, including beta amyloid and P‐tau accumulation, supporting the above infection‐reactivation concept.

Conclusion

Our results support a role for VZV in AD/dementia via reactivation of HSV1 in brain and in combination with some current preliminary results, indicate that the risk of cognitive decline and of dementia conferred by some infectious diseases might indeed result from their causing HSV1 reactivation in brain.
Regulation of Epigenetic BET Proteins on Alzheimer’s Disease in Preclinical Models
Authors: Zhang Can , Tanzi Rudolph E. , Wang Changning
Published: December 2022

Background

Epigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through targeting epigenetic pathways. Emerging evidence from both preclinical and clinical studies suggested the potential in developing therapeutics of Alzheimer’s disease (AD) by targeting epigenetic regulatory proteins. Recently there has been keen interest in the family of bromodomain (BD)‐containing BET (bromodomain and extra terminal domain) proteins, which consists of 4 protein members. All BET proteins have two BD domains, which confer significant and complex regulatory mechanisms for AD.

Method

Here, we developed domain‐specific small molecule probe targeting BD1 and evaluated expression of BET in AD transgenic animals compared to wild type animals using positron emission tomography‐based molecular imaging. We also investigated the effects of pharmacological inhibition of BET on AD cell models.

Result

We found that 5xFAD animals were characterized by increased signal in the brain in association with our BD1‐specific probe. Using BET inhibitors, AD‐related proteins were significantly changed.

Conclusion

Our study shows that BET protein may associate with AD by a gain of function mechanism and that inhibitors for specific domains may be utilized for AD in the presence of BET increase.
A transcriptomic signature of late‐life depression
Authors: Matan‐Lithwick Stuart A , Bennett David A , Wang Yanling , Tripathy Shreejoy , Felsky Daniel
Published: December 2022

Background

Late‐onset Alzheimer’s disease (AD) is commonly accompanied by symptoms of depression. While genes associated with pathological AD diagnosis and mid‐life depression have been identified, the transcriptomic signature of late‐life depression has not been described. We hypothesized that neocortical gene expression would be associated with symptoms of late‐life depression proximal to death, independent of pathologic AD diagnosis and medication status.

Method

Bulk tissue RNA sequencing data from frontal cortex of 1,001 elderly brain donors were analyzed (mean age at death: 89.7yrs [range: 67‐108]). All donors had genotype, demographic, and clinical assessments within one year prior to autopsy, as well as detailed postmortem neuropathological characterization. Differential expression analysis was performed with robust linear modeling including technical and demographic covariates, cell type proportions, educational attainment, APOE e4 genotype, and medication status for AD‐ and depression‐prescribed drugs. We then included main effects of depressive symptom burden proximal to death (CESD‐sum) and pathologic diagnosis of AD (NIA‐Reagan criteria).

Result

After false discovery rate correction (FDR q<0.05), only one gene, Prader Willi/Angelman region RNA1 (PWAR1), was associated with depressive symptoms (t=5.2, q=0.005); greater PWAR1 abundance was linked to higher symptom burden. At q<0.1, 14 genes showed association. Strikingly, a majority of these genes (e.g. CTDSPL2, ACR2B‐AS1, ADGRE2, MRM1, IRF8, COL19A1) have been previously implicated in unipolar depression or bipolar disorder. Gene Set Enrichment Analysis revealed upregulation of processes related to energy metabolism (top: “oxidative phosphorylation”, p=2.1x10‐8) and downregulation of DNA modifying processes (top: “DNA conformation change”, p=2.0x10‐7), among others. Results were not changed when controlling for smoking and alcohol consumption, and no significant associations were observed for depression medication status (top q>0.23).

Conclusion

Here we describe a cortical transcriptomic signature of late‐life depressive symptoms. Among our top signals are genes with known links to mid‐life depression, as well as biological processes relevant to energy metabolism, synaptic plasticity, DNA modification, antigen presentation, and response to pH. Our work provides a depression‐specific expression signature for elderly frontal cortex and lays the foundation for investigation of specific mechanisms toward precision therapeutics.
The association of 25(OH)D levels and hippocampal morphology in a clinically mixed sample
Authors: Dogan Melike Karacam , Karakaşlı Ahmet Alp , Özkan Esra , Türkoğlu Özge , Yalcinkaya Oguz Kaan , Oytun Merve Güner , Zengin Hatice Yağmur , Doğu Burcu Balam , Karaosmanoğlu Ayça , Karahan Sevilay , Topçuoğlu Esen Saka , Ayhan Yavuz
Published: December 2022

Background

25(OH)D may play role in differentiation and development of the hippocampus(1).25(OH)D deficiency was associated with reduced hippocampal volume in mild cognitive impairment(MCI)(2).We previously have shown that 25(OH)D levels were independently associated with reduced cognition independent from disease and AD‐related morphological changes(3),however the association with hippocampal subfields was not studied.We aimed to study the possible association between hippocampal subvolumes and 25(OH)D levels in our middle‐old age research participants.

Method

The participants were collected from a cognitive disorders research clinic at Hacettepe University.Those who use 25(OH)D supplements at the evaluation,have renal failure or diseases that could affect 25(OH)D metabolism were excluded.Concurrent serum 25(OH)D levels,Modified Mini Mental Test(3MS) scores and brain MRI data were retrospectively analyzed.FreeSurfer v.6.0 was used for automated structural neuroimaging analysis.Desikan‐Killiany atlas was utilized and in addition to the total volumes,the volumes of 12 distinct subfields of right and left hippocampi were analysed.Volumes were normalized to total intracranial volumes.Linear regression was used to determine the factors associated with the hippocampal volumes and the hippocampal subfields.Age, gender, education(years),3MS scores,syndromic diagnoses and 25(OH)D levels were used as the independent variables.Funded by TUBITAK 214S048,Hacettepe University THD2018‐17363 and Psychiatric Association of Turkey.

Result

208 patients(54 AD,83 subjective and mild CI,71 cognitively intact)were evaluated.Mean age was 70±9. 58.7% of the sample was female.19.7% had not finished primary school.Mean 25(OH) level was 20.5±12.16 ng/ml,57% of the sample had clinical vitamin D deficiency.25(OH)D levels were not different among diagnostic groups.Cognitive scores and age were the most consistent predictors of hippocampal subfields.In the multivariate analyses there was no association between hippocampal subunits and 25(OH)D levels regardless of the diagnoses(F=0.207, df=2, p=0.813).

Conclusion

Hippocampal volumes were not associated with 25(OH)D levels in line with our previous findings.This finding further support the hypothesis that vitamin D might be an independent factor for cognitive impairment.However our results differed from studies reporting positive correlation between hippocampal atrophy and 25(OH)D deficiency.This may be due to the heterogenous and limited nature of our sample,cross‐sectional nature of the study (those with previous vitamin D use were not eliminated) and the limited low range of 25(OH)D levels in our sample,consistent with the Turkish population.Further studies are needed to assess the role of 25(OH)D in neurodegeneration and cognitive decline.
The cross‐sectional association between APOE ε4 and cognition in midlife: Baseline data analysis of the Physical Activity and Alzheimer’s Disease study ‐ II
Authors: Park Kyoung Shin , Slutsky‐Ganesh Alexis B , Anderson Travis , Holder Hadassah , Vance Jarod C , DuBois Samantha L , Kibildis Samuel , Labban Jeffrey D , Wahlheim Christopher N , Wideman Laurie , Etnier Jennifer L
Published: December 2022

Background

Carrying at least one ε4 allele of Apolipoprotein E (APOE ε4) is a strong genetic risk factor for cognitive decline in late life. However, how APOE ε4 is associated with cognition in midlife (to what extent and in which domains) remains unspecified. We investigated the association between APOE ε4 carrier status and various domains of memory and executive function in healthy, sedentary adults in midlife.

Method

A subset of 91 participants (M
age = 57±6 years; 86.8% females; 33 carriers and 58 non‐carriers of APOE ε4) from a larger study (PAAD‐II, NCT03876314) were included for analyses. At baseline, participants provided a passive drool saliva sample to determine APOE ε4 carrier status and completed a comprehensive cognitive assessment. Composite scores for auditory verbal learning, visuospatial memory, associative memory, story memory, mnemonic discrimination, working memory, inhibitory control, and fluid intelligence were computed. Analyses of covariance tested the effects of APOE ε4 on the composite scores with demographic factors as covariates.

Result

Significant effects of APOE ε4 on auditory verbal learning [F(1, 82) = 4.8, p<0.05] and fluid intelligence [F(1, 73) = 5.155, p<0.05] were found after controlling for the effects of age, race, education, and gender. APOE ε4 carriers’ z‐scores for auditory verbal learning (‐0.202±0.208) were lower than non‐carriers (0.164±0.104), and the same was found for fluid intelligence (carriers: ‐0.218±0.183; non‐carriers: 0.145±0.139). APOE ε4 was unrelated to other composite scores of memory and executive function (p’s>0.5).

Conclusion

Evidence from longitudinal studies suggests that negative effects of APOE ε4 on cognition are evident at 65–75 years old. We conducted a comprehensive assessment of multiple cognitive domains and demonstrated that APOE ε4 is negatively associated with some cognitive domains in midlife. These findings imply that, although APOE ε4 is a strong risk factor for cognitive decline in late life, its effects on cognitive aging could gradually start in midlife. The small but notable effects of APOE ε4 on comparably intact cognitive function in midlife suggests the potential importance of early preventive interventions (e.g., physical activity, healthy diet) for cognitive preservation in late life, especially in people with higher genetic risk for cognitive decline.
L‐Type calcium channel antagonist isradipine decreases area of plaque associated dystrophic neurites in 5XFAD mouse model
Authors: Wickline Jessica L , Smith Sabrina , Odfalk Kristian F , Shin Riley , Sanchez Jesus J , Cundey Rachael , Javors Martin , Ginsburg Brett , Hopp Sarah C.
Published: December 2022

Background

Epidemiological studies suggest that L‐type calcium channel (LTCC) antagonists may reduce the incidence of neurodegenerative diseases including Alzheimer’s disease (AD). However, the neuroprotective mechanism of LTCC antagonists is unknown. Amyloid‐β (aβ) increases intracellular calcium signaling, which regulates lysosomal processing and microglial inflammatory responses, both of which are altered in AD. Neurons near aβ plaques develop dystrophic neurites, which are abnormal axonal swellings that accumulate lysosomes. Further, microglia accumulate around aβ plaques and secrete inflammatory cytokines. We hypothesized that antagonism of LTCCs with isradipine would reduce aβ plaque associated dystrophic neurites and inflammatory microglia in the 5XFAD mouse model of AD by restoring normal intracellular calcium regulation.

Method

We treated 6‐ and 9‐month‐old 5XFAD mice with isradipine (3 mg/kg/day) or vehicle via subcutaneous pellets for 30 days. Following three weeks of treatment we tested locomotion and cognitive behavior via open field, novel object recognition and Morris water maze. We measured gene expression of inflammatory mediators (IL1β, TNF, CD68) and LTCC subunits (Cav1.2, Cav1.3) using qPCR. Using immunohistochemistry (IHC), we examined aβ plaque number and area (D54D2 and ThioS), microglia area (Iba1), dystrophic neurites area and particle number (LAMP1) normalized to total brain area.

Result

IHC revealed that isradipine treatment in 9‐month‐old 5XFADs decreased the total area of LAMP1 positive dystrophic neurites (p = 0.0310) compared to vehicle‐treated 5XFADs; this change was not observed in the 6‐month‐old group. Isradipine treatment in the 9‐month‐old 5XFADs also led to a decreasing trend (p = 0.0552) in plaque load compared to vehicle‐treated 5xFADs as measured by IHC. Isradipine treatment did not modulate plaque associated microglia as measured by IHC or inflammatory gene expression as measured by qPCR, regardless of age. There was no treatment effect on behavior or expression of LTCC subunits.

Conclusion

Our data show that isradipine reduces aβ plaque associated dystrophic neurite pathology in 9‐month‐old 5XFAD mice, potentially showing LTCC play a role in mediating this specific phenotype. Our future studies will focus on understanding why antagonizing LTCCs leads to a decrease in LAMP1 and whether this is due to changes in lysosomal development and processing or other possible mechanisms.
Mild behavioral impairment is associated with sleep apnea, insomnia and brain white matter hyperintensity burden
Authors: Sanderlin Ashley H. , Lockhart Samuel N. , Hayden Kathleen M. , Craft Suzanne , Yang Mia , Sachs Bonnie C. , Cleveland Maryjo , Williams Benjamin J. , Williamson Jeff D. , Bateman James R.
Published: December 2022

Background

Mild behavioral impairment (MBI) is a neurobehavioral syndrome associated with increased risk for Alzheimer’s disease (AD) and other neurodegenerative disorders. White matter hyperintensities (WMH) are brain lesions associated with cerebrovascular insult and contribute to cognitive decline across the cognitive spectrum (normal cognition, mild cognitive impairment (MCI) and dementia). Sleep disturbance is common among older adults with cognitive impairment and like MBI, is a modifiable AD risk factor that can affect brain structure including WMH. We sought to examine the prevalence of MBI and its relationship with sleep and WMH in a community cohort of older adults.

Method

Participants enrolled in the Wake Forest AD Research Center (ADRC) Clinical Core cohort (N = 633, mean age = 70.4 years) provided history of sleep apnea and insomnia, underwent neuropsychological assessment and neuropsychiatric symptom assessment, as reported by an informant on the Neuropsychiatric Inventory Questionnaire (NPI‐Q). MBI scores were derived from the NPI‐Q severity and included 10 symptoms reflecting affective dysregulation, impulse control, decreased motivation, social inappropriateness and abnormal perception or thought content, and excluded NPI‐Q questions on sleep and appetite. T1 and T2 FLAIR MRI were obtained; T1 and FLAIR were segmented to quantify WMH volume, which was scaled by head size and log transformed. Global cognitive status was assessed using the clinical dementia rating (CDR) global score.

Result

In our sample, 24% of participants had MBI. Normal cognition (CDR = 0) participants had significantly lower rates of MBI compared to both MCI (CDR = 0.5) and dementia (CDR ≥ 1, Figure 1, p<.001). MBI scores were also significantly higher in participants with than without sleep apnea (Fig. 2, p = 0.003) and insomnia (Figure 3, p = 0.043). Further, WMH volume was higher in participants with MBI (Figure 4, p<.001).

Conclusion

MBI increased in prevalence with cognitive impairment. Sleep disturbances and greater WMH burden in our MBI participants may increase their risk of cognitive decline for normal cognition and MCI groups and relate to poor behavioral and health outcomes in participants with dementia. Future studies will assess interactions of sleep, MBI and WMH across cognitive groups and their association with risk of conversion to MCI or AD.
Distinct cerebrospinal fluid immune perturbations in healthy brain aging and cognitive impairment
Authors: Piehl Natalie , Ramakrishnan Abhirami , Wyss‐Coray Tony , Gate David
Published: December 2022

Background

Cerebrospinal fluid (CSF) contains a tightly regulated, specialized immune system. Yet, little is known about how aging influences CSF immunity in cognitively typical versus cognitively impaired individuals.

Method

Here, we performed single cell RNA sequencing (scRNAseq) on CSF collected from 45 cognitively typical subjects ranging from 54‐82 years old. We then assessed age‐related transcriptomic changes using bioinformatic approaches, including linear and local polynomial regression. We reveal pronounced changes to several CSF immune cell types, underscored by increased expression of lipid processing genes in activated monocytes with age. We then compared CSF immune systems from cognitively typical subjects to 14 subjects with mild cognitive impairment or Alzheimer’s disease.

Result

Our results indicate disparate age‐related CSF immune system perturbations, including the upregulation of C‐X‐C Motif Chemokine Receptor 6 in clonally expanded T cells of cognitively impaired subjects.

Conclusion

These results highlight the utility of CSF immune system changes to identify therapeutic targets of neurodegenerative disease‐associated neuroinflammation.
Pathological tau activates nuclear factor‐kappa B (NF‐κB) and drives neuroinflammation
Authors: Bhaskar Kiran , Jiang Shanya , Dadras Somayeh , Hulse Jonathan P , Tangavelou Karthikeyan , Chisholm Devon C , Mandell Michael
Published: December 2022

Background

Hyperphosphorylation and aggregation of tau is a pathological hallmark of Alzheimer’s disease and related tauopathies. Pathologically modified tau (pTau) displays varying degree of gain‐of‐toxic functions, in addition to loss of its normal homeostatic function in neurons. Several prior studies have suggested occurrence of innate immune activation in brain regions that spatio‐temporally overlap with pTau burden in brains of various tauopathies. Recent studies have suggested that once tau is hyperphosphorylated and misfolded, the neurons tend to expel pTau to the extracellular space, which is taken up by other neurons and results in trans‐neuronal propagation of pTau. We made a compelling discovery that en route to other neurons, pTau can also interact with and serve as an initial trigger to lead to microglial activation and neuroinflammation (Cell Reports 2021). However, it is not unclear if pTau driven innate immune activation involve canonical NF‐κB pathway.

Methods

First, we determined the levels of NF‐κB activation in autopsy brains of different tauopathies via Western blot analyses for markers of NF‐κB. Second, we performed bulk‐RNA sequence analyses of human primary microglia treated with paired‐helical filaments (PHFs) purified from human tauopathy brains. Third, we crossed PS19 mouse model of tauopathy to NF‐κB‐GFP‐Luciferase reporter mice (Luc) to generate PS19/Luc+ mice and performed IVIS® live image analyses at different time points. Finally, we treated Luc expressing BV2 cells, primary microglia, and bone marrow derived macrophages (BMDMs) with pTau and validated nuclear localization of NF‐κB via Cellomics® high‐content microscopy.

Results

Phosphorylated NF‐κB p65 (Ser536) levels were significantly high in the autopsy brains of Corticobasal degeneration (CBD), Progressive supranuclear Palsy (PSP) and Pick’s disease (PiD) compared to healthy controls. RNA‐seq and bioluminescence analyses suggested human brain‐derived pTau induced NF‐κB activation in microglial cells and BMDMs. PS19/Luc+ mice displayed increased NF‐κB activation with age.

Conclusions

Together, these results suggest NF‐κB activation in the brains of human tauopathy and that pTau can directly activate NF‐κB in various model systems. Neutralization of pTau via immunotherapy and determining if it has any effect on NF‐κB activation is in progress.