Journal of Alzheimer's Disease - Volume 95, issue 2

Authors: Che, Xiang-Qian | Lin, Guo-Zhen | Liu, Xiao-Hong | Wang, Gang | Zhao, Qian-Hua | Ren, Ru-Jing

Article Type: Research Article

Abstract: Background: Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1 ) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. Objective: The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. Methods: We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients …(female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. Results: Gene sequencing of SIGMAR1 revealed a rare 3′ UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. Conclusion: We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, genetic analysis, magnetic resonance imaging, SIGMAR1

DOI: 10.3233/JAD-221195

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 469-475, 2023

Authors: Rosales-Lagarde, Alejandra | Cubero-Rego, Lourdes | Menéndez-Conde, Federico | Rodríguez-Torres, Erika E. | Itzá-Ortiz, Benjamín | Martínez-Alcalá, Claudia | Vázquez-Tagle, Génesis | Vázquez-Mendoza, Enrique | Eraña Díaz, Marta L.

Article Type: Research Article

Abstract: Background: Sleep disruption in elderly has been associated with an increased risk of cognitive impairment and its transition into Alzheimer’s disease (AD). High arousal indices (AIs) during sleep may serve as an early-stage biomarker of cognitive impairment non-dementia (CIND). Objective: Using full-night polysomnography (PSG), we investigated whether CIND is related to different AIs between NREM and REM sleep stages. Methods: Fourteen older adults voluntarily participated in this population-based study that included Mini-Mental State Examination, Neuropsi battery, Katz Index of Independence in Activities of Daily Living, and single-night PSG. Subjects were divided into two groups (n  = 7 …each) according to their results in Neuropsi memory and attention subtests: cognitively unimpaired (CU), with normal results; and CIND, with –2.5 standard deviations in memory and/or attention subtests. AIs per hour of sleep during N1, N2, N3, and REM stages were obtained and correlated with Neuropsi total score (NTS). Results: AI (REM)  was significantly higher in CU group than in CIND group. For the total sample, a positive correlation between AI (REM)  and NTS was found (r  = 0.68, p  = 0.006), which remained significant when controlling for the effect of age and education. In CIND group, the AI (N2)  was significantly higher than the AI (REM)  . Conclusion: In CIND older adults, this attenuation of normal arousal mechanisms in REM sleep are dissociated from the relative excess of arousals observed in stage N2. We propose as probable etiology an early hypoactivity at the locus coeruleus noradrenergic system, associated to its early pathological damage, present in the AD continuum. Show more

Keywords: Alzheimer’s disease, arousals, locus coeruleus, mild cognitive impairment, neuropsychological testing, polysomnography, REM sleep

DOI: 10.3233/JAD-230101

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 477-491, 2023

Authors: Ng, Pei Y. | Zhang, Cheng | Li, Hu | Baker, Darren J.

Article Type: Research Article

Abstract: Background: The existence and contribution of microglia with senescent-like alterations in the pathogenesis of age-related neurodegenerative diseases like Alzheimer’s disease (AD) have been suggested in recent years. However, the identification of this distinct microglial population in vivo has proven challenging, largely due to overlaps in the inflammatory phenotype of activated and senescent microglia. Furthermore, attempts at recapitulating senescence in microglia in vitro are limited. Objective: To identify and characterize senescent microglia that occur in vivo in an animal model of neurodegeneration driven by pathologic tau. Methods: We analyzed the RNA expression patterns of …individual microglia from normal mice and the pathogenic tau P301 S PS19 mouse model. We have previously demonstrated that p16-expressing senescent microglia occur in these mice when neurodegeneration has occurred. Results: Here we identify a subset of disease-associated microglia with senescent features, notably characterized by the expression of Ccl4 . This signature overlaps with established markers of senescence from other cell types. Conclusion: Our characterization of senescent microglia can be used to better understand the role of senescent microglia in various age-related contexts, including whether clearance of senescent microglia represents a viable therapeutic option. Show more

Keywords: Alzheimer’s disease, cellular senescence, microglia, tauopathy

DOI: 10.3233/JAD-230109

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 493-507, 2023

Authors: Guevara, Jasmin E. | Kurniadi, Natalie E. | Duff, Kevin

Article Type: Research Article

Abstract: Background: Cognitive change in mild cognitive impairment (MCI), a likely prodrome to Alzheimer’s disease, can be tracked with repeated neuropsychological assessments, but there has been little work quantifying these changes over time. Cognitive change can be statistically examined using standardized regression-based (SRB) formulas, which yield a z-score indicating amount of change compared to a normative group. Objective: To use SRB z-scores to quantify cognitive change in a sample of patients classified as MCI at baseline, and to compare cognitive change in those who remained MCI on follow-up (MCI-Stable) and those who progressed to dementia (MCI-Decline). Methods: …Using 283 MCI patients from a cognitive disorders clinic who were re-assessed after approximately one- and one-half years, SRB z-scores were calculated for each test in a comprehensive neuropsychological battery for each participant. Results: There was a significant decline between timepoints across all cognitive tests, with the greatest amount of decline on tests of learning and memory. Group differences were seen on nearly all cognitive tests, with the MCI-Decline group showing more decline (i.e., significantly larger and negative z-scores) than the MCI-Stable participants. Notable cognitive decline was also observed in the MCI-Stable group, with z-scores ranging from –0.01 – –2.24 compared to normative data. Conclusion: This study highlights the amount of cognitive decline that occurs in MCI, including for those who remain “stable” and those who progress to dementia. It also demonstrates the value of the SRB method in more clearly quantifying cognitive decline, which may help identify individuals most vulnerable to MCI progression. Show more

Keywords: Alzheimer’s disease, cognitive decline, cognitive testing, dementia, mild cognitive impairment

DOI: 10.3233/JAD-230160

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 509-521, 2023

Authors: Zhuo, Bingting | Zheng, Dashan | Cai, Miao | Wang, Chongjian | Zhang, Shiyu | Zhang, Zilong | Tian, Fei | Wang, Xiaojie | Lin, Hualiang

Article Type: Research Article

Abstract: Background: Studies have reported the associations between inflammation, brain volume, and cognition separately. It is reasonable to assume peripheral inflammation may contribute to cognitive decline through brain volume atrophy. Objective: To examine the associations between peripheral inflammation, brain volume, and cognition among adults, and to investigate whether brain volume atrophy mediates the inflammation-cognition relationship Methods: We retrieved 20,381 participants with available data on peripheral inflammation, brain volume, and cognition from the UK Biobank cohort. Cognitive function was assessed by performance on cognitive tasks probing various cognitive domains. Brain volumes were measured by magnetic resonance imaging (MRI). …Multivariable linear models were used to investigate the associations between three peripheral inflammatory indexes (C-reactive protein, systemic immune-inflammatory index, neutrophil-to-lymphocyte ratio), brain volume, and cognition. Mediation analyses were conducted to assess the potential mediating effect of brain volume atrophy. All results were corrected for multiple comparisons using the false-discovery rate (FDR). Results: Peripheral inflammation was inversely associated with grey matter volume (GMV), white matter volume (WMV), and cognition after adjusting for potential covariates. For instance, CRP was associated with the GMV of left parahippocampal gyrus (β= –0.05, 95% confidence interval [CI]: –0.06 to –0.04, p FDR =1.07×10-16 ) and general cognitive factor (β= –0.03, 95% CI: –0. –0.04 to –0.01, p FDR  = 0.001). Brain volume atrophy mediated the inflammation-cognitive decline relationship, accounting for 15–29% of the overall impact. Conclusion: In this cohort study, peripheral inflammation was associated with brain volume atrophy and cognitive decline. Brain atrophy may mediate the inflammation-cognitive decline relationship. Show more

Keywords: Alzheimer’s disease, brain volume, cognitive function, inflammation, mediation effect

DOI: 10.3233/JAD-230253

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 523-533, 2023

Authors: Song, Shangchen | Asken, Breton | Armstrong, Melissa J. | Yang, Yang | Li, Zhigang

Article Type: Research Article

Abstract: Background: Assessing the risk of developing clinical Alzheimer’s disease (AD) dementia, by machine learning survival analysis approaches, among participants registered in Alzheimer’s Disease Centers is important for AD dementia management. Objective: To construct a prediction model for the onset time of clinical AD dementia using the National Alzheimer Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) registered cohorts. Methods: A model was constructed using the Random Survival Forest (RSF) approach and internally and externally validated on the NACC cohort and the ADNI cohort. An R package and a Shiny app were provided for accessing …the model. Results: We built a predictive model having the six predictors: delayed logical memory score (story recall), CDR® Dementia Staging Instrument - Sum of Boxes, general orientation in CDR®, ability to remember dates and ability to pay bills in the Functional Activities Questionnaire, and patient age. The C indices of the model were 90.82% (SE = 0.71%) and 86.51% (SE = 0.75%) in NACC and ADNI respectively. The time-dependent AUC and accuracy at 48 months were 92.48% (SE = 1.12%) and 88.66% (SE = 1.00%) respectively in NACC, and 90.16% (SE = 1.12%) and 85.00% (SE = 1.14%) respectively in ADNI. Conclusion: The model showed good prediction performance and the six predictors were easy to obtain, cost-effective, and non-invasive. The model could be used to inform clinicians and patients on the probability of developing clinical AD dementia in 4 years with high accuracy. Show more

Keywords: Alzheimer’s disease, dementia, machine learning, survival analysis

DOI: 10.3233/JAD-230208

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 535-548, 2023

Authors: Conti, Elisa | Grana, Denise | Angiulli, Federica | Karantzoulis, Aristotelis | Villa, Chiara | Combi, Romina | Appollonio, Ildebrando | Ferrarese, Carlo | Tremolizzo, Lucio

Article Type: Research Article

Abstract: Background: Neuroinflammation is one of the cardinal mechanisms of Alzheimer’s disease (AD). with amyloid-β (Aβ) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aβ species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. Objective: We aimed to evaluate the role of the oligomeric Aβ1-42 isoform at inducing peripheral monocyte chemotaxis, and the …possible involvement of TSPO in this process. Methods: In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n  = 60), and comparable cognitively intact controls (n  = 30) were used. Chemotaxis analyses were carried out through both μ -slide chambers and Boyden assays, using 125 pM oligomeric Aβ1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). Results: Oligomeric Aβ directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aβ-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. Conclusion: Oligomeric Aβ1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS. Show more

Keywords: Alzheimer’s disease, amyloid-β, chemotaxis, monocytes, neuroinflammation, PK11195, TSPO

DOI: 10.3233/JAD-230239

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 549-559, 2023

Authors: Spartano, Nicole L. | Wang, Ruiqi | Yang, Qiong | Chernofsky, Ariel | Murabito, Joanne M. | Levy, Daniel | Vasan, Ramachandran S. | DeCarli, Charles | Maillard, Pauline | Seshadri, Sudha | Beiser, Alexa S.

Article Type: Research Article

Abstract: Introduction: Cardiometabolic risk factors and epigenetic patterns, increased in physically inactive individuals, are associated with an accelerated brain aging process. Objective: To determine whether cardiometabolic risk factors and epigenetic patterns mediate the association of physical inactivity with unfavorable brain morphology. Methods: We included dementia and stroke free participants from the Framingham Heart Study Third Generation and Offspring cohorts who had accelerometery and brain MRI data (n  = 2,507, 53.9% women, mean age 53.9 years). We examined mediation by the 2017-revised Framingham Stroke Risk Profile (FSRP, using weights for age, cardiovascular disease, atrial fibrillation, diabetes and smoking status, …antihypertension medications, and systolic blood pressure) and the homeostatic model of insulin resistance (HOMA-IR) in models of the association of physical inactivity with brain aging, adjusting for age, age-squared, sex, accelerometer wear time, cohort, time from exam-to-MRI, and season. We similarly assessed mediation by an epigenetic age-prediction algorithm, GrimAge, in a smaller sample of participants who had DNA methylation data (n  = 1,418). Results: FSRP and HOMA-IR explained 8.3–20.5% of associations of higher moderate-to-vigorous physical activity (MVPA), higher steps, and lower sedentary time with higher brain volume. Additionally, FSRP and GrimAge explained 10.3–22.0% of associations of physical inactivity with lower white matter diffusivity and FSRP explained 19.7% of the association of MVPA with lower free water accumulation. Conclusion: Our results suggest that cardiometabolic risk factors and epigenetic patterns partially mediate the associations of physical inactivity with lower brain volume, higher white matter diffusivity, and aggregation of free water in the extracellular compartments of the brain. Show more

Keywords: Alzheimer’s disease, dementia, exercise, physical activity, sedentary time

DOI: 10.3233/JAD-230289

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 561-572, 2023

Authors: Miyawaki, Christina E. | McClellan, Angela | Bouldin, Erin D. | Brohard, Cheryl | Spencer, Helen | Tahija, Nina | Kunik, Mark E.

Article Type: Research Article

Abstract: Background: Due to the high prevalence of depressive symptoms and Alzheimer’s disease and related dementias in older Americans (≥65 years), we developed a six-week depression intervention, Caregiver-Provided Life Review (C-PLR) for care recipients (CRs) with early-stage dementia and mild depression. Objective: The objective of the study was to examine the feasibility and efficacy of C-PLR delivered by virtually-trained caregivers (CGs) on CRs who live with dementia and depression in community and long-term care settings (N = 25 CG-CR dyads). Methods: We used fidelity scores as a measure of CG’s feasibility to provide C-PLR. We collected the pre- …and post-measures on CRs’ depression (primary outcome), life satisfaction, CGs’ burden, positive aspects of caregiving, and CG-CR relationship quality (secondary outcomes) and compared them using paired t-tests. We evaluated if the effect differed by race/ethnicity, residential setting, or living alone. Results: The average fidelity check-in score was 14.8±0.78 indicating high feasibility. CGs were 52 years old (mean), 88% female, 64% working, 72% college-educated, and 72% in good-excellent health. CRs were 81 years old (mean), 84% female, and 56% in poor-fair health. CRs’ depression significantly improved (p  < 0.001), and this effect was found in CRs who were Asian (p  = 0.017), White (p  = 0.040), community-dwelling (p  < 0.001), lived alone (p  = 0.045), or with others (p  = 0.002). Conclusion: This study demonstrated that the C-PLR can be successfully taught to CGs virtually and is effective in reducing CR’s depressive symptoms. C-PLR could be implemented more broadly to improve symptoms among CRs in community and residential settings, as well as among a diverse population of CRs. Show more

Keywords: Alzheimer’s disease, caregiver education, dementia, depressive symptoms, internet-based intervention, program evaluation

DOI: 10.3233/JAD-230371

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 573-583, 2023

Authors: Silva, Jacqueline D. | Taglialatela, Giulio | Jupiter, Daniel C.

Article Type: Research Article

Abstract: Background: Evidence suggests patients prescribed calcineurin inhibitors (CNIs) have a reduced prevalence of dementia, including Alzheimer’s disease (AD); however, this result has never been replicated in a large cohort and the involved mechanism(s) and site of action (central versus periphery) remain unclear. Objective: We aim to determine if prescription of CNIs is associated with reduced prevalence of dementia, including AD, in a large, diverse patient population. Furthermore, we aim to gain insight into the mechanism(s) and site of action for CNIs to reduce dementia prevalence. Methods: Electronic health records (EHRs) from patients prescribed tacrolimus, cyclosporine, or …sirolimus were analyzed to compare prevalence, odds, and hazard ratios related to dementia diagnoses among cohorts. EHRs from a random, heterogeneous population from the same network were obtained to generate a general population-like control. Results: All drugs examined reduced dementia prevalence compared to the general population-like control. There were no differences in dementia diagnoses upon comparing tacrolimus and sirolimus; however, patients prescribed tacrolimus had a reduced dementia prevalence relative to cyclosporine. Conclusion: Converging mechanisms of action between tacrolimus and sirolimus likely explain the similar dementia prevalence between the cohorts. Calcineurin inhibition within the brain has a greater probability of reducing dementia relative to peripherally-restricted calcineurin inhibition. Overall, immunosuppressants provide a promising therapeutic avenue for dementia, with emphasis on the brain-penetrant CNI tacrolimus. Show more

Keywords: Alzheimer’s disease, calcineurin, cyclosporine, dementia prevalence, drug repurposing, electronic health records, sirolimus, tacrolimus, TriNetX

DOI: 10.3233/JAD-230526

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 585-597, 2023