Journal of Alzheimer's Disease - Volume 79, issue 4

Authors: Wu, Ruozhen | Gu, Jianlan | Zhou, Dingwei | Tung, Yunn Chyn | Jin, Nana | Chu, Dandan | Hu, Wen | Wegiel, Jerzy | Gong, Cheng-Xin | Iqbal, Khalid | Liu, Fei

Article Type: Research Article

Abstract: Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer’s disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. Objective: To determine the seeding activity of tau in cerebral gray and white matters of AD. Methods: Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol–resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity …was quantitatively assessed by measuring RIPA buffer–insoluble tau in HEK-293FT/tau151-391 cells treated with brain extracts. Results: We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151–391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Conclusion: Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter. Show more

Keywords: Alzheimer’s disease, gray matter, propagation of tau pathology, seeding-competent tau, white matter

DOI: 10.3233/JAD-201290

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1647-1659, 2021

Authors: Costa, Ana Sofia | Pinho, João | Kučikienė, Domantė | Reich, Arno | Schulz, Jörg B. | Reetz, Kathrin

Article Type: Research Article

Abstract: Background: The overlap between cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) is frequent and relevant for patients with cognitive impairment. Objective: To assess the role of the diagnosis of CAA on the phenotype of amyloid-β (Aβ) positive patients from a university-hospital memory clinic. Methods: Consecutive patients referred for suspected cognitive impairment, screened for Aβ pathological changes in cerebrospinal fluid (CSF), with available MRI and neuropsychological results were included. We determined the association between probable CAA and clinical, neuropsychological (at presentation and after a mean follow-up of 17 months in a sub-sample) and MRI (atrophy, white …matter hyperintensities, perivascular spaces) characteristics. Results: Of 218 amyloid-positive patients, 8.3% fulfilled criteria for probable CAA. A multivariable logistic regression showed an independent association of probable CAA with lower Aβ1–42 (adjusted odds ratio [aOR] = 0.94, 95% confidence interval [95% CI] = 0.90–0.98, p  = 0.003), and Aβ1–40 (aOR = 0.98, 95% CI=0.97–0.99 p  = 0.017) levels in CSF, and presence of severe burden of enlarged perivascular spaces (EPVS) in the centrum semiovale (aOR = 3.67, 95% CI = 1.21–11.15, p  = 0.022). Linear mixed-model analysis showed that both groups significantly deteriorated in global clinical severity, executive function and memory. Nevertheless, the presence of probable CAA did not differently affect the rate of cognitive decline. Conclusion: The presence of probable CAA in Aβ positive patients was associated with lower Aβ1–42 and Aβ1–40 CSF levels and increased centrum semiovale EPVS burden, but did not independently influence clinical phenotype nor the rate of cognitive decline within our follow-up time window. Show more

Keywords: Alzheimer’s disease, brain perivascular spaces, cerebral amyloid angiopathy, cerebral small vessel disease, cognitive decline, longitudinal studies

DOI: 10.3233/JAD-201218

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1661-1672, 2021

Authors: Hassanin, Hany I. | Tawfik, Heba M. | Zygouris, Stelios | Tsatali, Marianna | Sweed, Hala S. | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: With greying of nations, dementia becomes a public health priority. The rising dementia prevalence escalates both health care expenses and burden, placing the entire healthcare system and caregivers under huge stress. Cognition-oriented interventions have been shown to enhance the overall cognitive performance among healthy and cognitively impaired older adults. Objective: This article is assumed to be a steppingstone for the introduction and establishment of cognition- oriented interventions in Egypt. In addition, it aims to offer provisional guidance for health care providers in Arab speaking countries in a stepwise approach in order to establish cognition-oriented intervention services and …help them to evaluate and monitor their efficacy. Methods: Aconsortium of Egyptian and Greek specialists developed a protocol for the operations of the Ain Shams Cognitive Training Lab and the provision of cognition-oriented interventions. This protocol is based on a previous successful protocol that has been implemented in Greece for more than 10 years and is co-designed to fit the needs of older adults in Arabic speaking countries. Results: The types of services offered, their objectives, recruitment of participants, delivery of interventions, measurement of outcomes and privacy policy are all outlined in the policy. Conclusion: Establishing the appropriate framework in which cognitive training strategies can be adapted and implemented in Arabic population, constitutes an inevitable achievement in healthy ageing and can be also assumed as a dementia prevention strategy. Moreover, setting up the first cognitive laboratory in Egypt older adults, can be a model of good practice across the Arabic countries. Show more

Keywords: Aging, Alzheimer’s disease, cognitive remediation, computers, dementia, memory disorders, mild cognitive impairment, psychosocial support systems, web-based intervention

DOI: 10.3233/JAD-201278

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1673-1682, 2021

Authors: Bohlken, Jens | Riedel-Heller, Steffi | Steininger, Gilles | Kostev, Karel | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: The number of patients with dementia is forecast to grow continuously. However, there are indications that the incidence and prevalence is falling in high-income countries. Objective: To examine whether any effects of declining incidence and prevalence rates of dementia and mild cognitive impairment (MCI) were evident in Germany between 2015 and 2019. Methods: The analysis was based on 797 general and 132 specialists (neurological/psychiatric) practices and included 10.1 million patients aged 18 years and older who visited between January 2014 and December 2019 one of the practitioners. The prevalence and incidence of dementia and MCI …were demonstrated descriptively. Results: Between 2015 and 2019, the prevalence (incidence) of dementia decreased from 2.18%(0.44%) in 2015 to 2.07%(0.35%) in 2019. A relatively large decrease in the prevalence (incidence) of dementia was observed in patients aged 80 and older, at –1.47%(–0.62%), compared to younger patients, at –0.40%(–0.18%). By contrast, the prevalence and incidence of MCI have remained constant over the years (0.19%to 0.22%and 0.06%, respectively). Overall, the number of patients diagnosed with dementia decreased slightly by 1%while the number of patients diagnosed with MCI increased by 17%. Conclusion: Our results confirmed the reduction in the prevalence and incidence of dementia and revealed a decrease in the number of patients with dementia despite continued demographic changes. Future studies are warranted to determine whether the results are caused by changing risk and lifestyle factors or changes in medical diagnosis and treatment behavior of the practitioners. Show more

Keywords: Alzheimer’s disease, dementia, diagnosis, incidence, mild cognitive impairment, prevalence

DOI: 10.3233/JAD-201385

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1683-1690, 2021

Authors: Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: There is a need for more reliable diagnostic tools for the early detection of Alzheimer’s disease (AD). This can be a challenge due to a number of factors and logistics making machine learning a viable option. Objective: In this paper, we present on a Support Vector Machine Leave-One-Out Recursive Feature Elimination and Cross Validation (SVM-RFE-LOO) algorithm for use in the early detection of AD and show how the SVM-RFE-LOO method can be used for both classification and prediction of AD. Methods: Data were analyzed on n  = 300 participants (n  = 150 AD; n  = 150 cognitively normal …controls). Serum samples were assayed via a multi-plex biomarker assay platform using electrochemiluminescence (ECL). Results: The SVM-RFE-LOO method reduced the number of features in the model from 21 to 16 biomarkers and achieved an area under the curve (AUC) of 0.980 with a sensitivity of 94.0% and a specificity of 93.3%. When the classification and prediction performance of SVM-RFE-LOO was compared to that of SVM and SVM-RFE, we found similar performance across the models; however, the SVM-RFE-LOO method utilized fewer markers. Conclusion: We found that 1) the SVM-RFE-LOO is suitable for analyzing noisy high-throughput proteomic data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance. Our recursive feature elimination model can serve as a general model for biomarker discovery in other diseases. Show more

Keywords: Alzheimer’s disease, blood biomarkers, machine learning, recursive feature elimination, support vector machine

DOI: 10.3233/JAD-201254

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1691-1700, 2021

Authors: Hayashi, Tetsuo | Shimonaka, Shotaro | Elahi, Montasir | Matsumoto, Shin-Ei | Ishiguro, Koichi | Takanashi, Masashi | Hattori, Nobutaka | Motoi, Yumiko

Article Type: Research Article

Abstract: Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of …the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions. Show more

Keywords: Microglia, neurodegeneration, propagation, tau protein, tauopathies

DOI: 10.3233/JAD-201002

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1701-1711, 2021

Authors: Borda, Miguel Germán | Ayala Copete, Ana María | Tovar-Rios, Diego Alejandro | Jaramillo-Jimenez, Alberto | Giil, Lasse Melvær | Soennesyn, Hogne | Gómez-Arteaga, Camilo | Venegas-Sanabria, Luis Carlos | Kristiansen, Ida | Chavarro-Carvajal, Diego Andrés | Caicedo, Sandra | Cano-Gutierrez, Carlos Alberto | Vik-Mo, Audun | Aarsland, Dag

Article Type: Research Article

Abstract: Background: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. Objective: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. Methods: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer’s disease (AD) (n  = 103), Lewy body dementia (LBD) (n … = 74), and other dementias (OD) (n  = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. Results: At baseline, the prevalence of general malnutrition was 28.7%; 17.3% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. Conclusion: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis. Show more

Keywords: Activities of daily living, Alzheimer’s disease, dementia, Lewy body dementia, malnutrition

DOI: 10.3233/JAD-200961

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1713-1722, 2021

Authors: Sragovich, Shlomo | Gershovits, Michael | Lam, Jacqueline C.K. | Li, Victor O.K. | Gozes, Illana

Article Type: Research Article

Abstract: Background: We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer’s disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targeted repair mechanisms. Objective: The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics. Methods: Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, …PTSD) was performed. Results: High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts. Conclusion: With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design. Show more

Keywords: Alzheimer’s disease, autism, blood biomarkers, cognition, post-traumatic stress disorder

DOI: 10.3233/JAD-201158

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1723-1734, 2021

Authors: Lehingue, Elsa | Gueniat, Julien | Jourdaa, Sandra | Hardouin, Jean BenoÎt | Pallardy, Amandine | Courtemanche, Hélène | Rocher, Laëtitia | Etcharry-Bouyx, Frédérique | Auriacombe, Sophie | Mollion, Hélène | Formaglio, Maité | Rouaud, Olivier | Bretonnière, Cédric | Thomas-Antérion, Catherine | Boutoleau-Bretonnière, Claire

Article Type: Research Article

Abstract: Background: The frontal variant of Alzheimer’s disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. Objective: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. …Methods: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. Results: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18 FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. Conclusion: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD. Show more

Keywords: Alzheimer’s disease, behavioral disorders, frontotemporal dementia, scale

DOI: 10.3233/JAD-201088

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1735-1745, 2021

Authors: Iliadou, Paraskevi | Paliokas, Ioannis | Zygouris, Stelios | Lazarou, Eftychia | Votis, Konstantinos | Tzovaras, Dimitrios | Tsolaki, Magdalini

Article Type: Research Article

Abstract: Background: Electroencephalography (EEG) has been used to assess brain activity while users are playing an immersive serious game. Objective: To assess differences in brain activation as measured with a non-intrusive wearable EEG device, differences in game performance and correlations between EEG power, game performance and global cognition, between cognitively impaired and non-impaired older adults, during the administration of a novel self-administered serious game-based test, the Virtual Supermarket Test (VST). Methods: 43 older adults with subjective cognitive decline (SCD) and 33 older adults with mild cognitive impairment (MCI) were recruited from day centers for cognitive disorders. Global …cognition was assessed with the Montreal Cognitive Assessment (MoCA). Brain activity was measured with a non-intrusive wearable EEG device in a resting state condition and while they were administered the VST. Results: During resting state condition, the MCI group showed increased alpha, beta, delta, and theta band power compared to the SCD group. During the administration of the VST, the MCI group showed increased beta and theta band power compared to the SCD group. Regarding game performance, alpha, beta, delta, and theta rhythms were positively correlated with average duration, while delta rhythm was positively correlated with mean errors. MoCA correlated with alpha, beta, delta, and theta rhythms and with average game duration and mean game errors indicating that elevated EEG rhythms in MCI may be associated with an overall cognitive decline. Conclusion: VST performance can be used as a digital biomarker. Cheap commercially available wearable EEG devices can be used for obtaining brain activity biomarkers. Show more

Keywords: Age-related memory disorders, cognitive assessment screening instrument, computer games, dementia, EEG, mild cognitive impairment, neurocognitive tests, screening, self-evaluation

DOI: 10.3233/JAD-201300

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1747-1759, 2021

Authors: Shaffer, Rachel M. | Li, Ge | Adar, Sara D. | Dirk Keene, C. | Latimer, Caitlin S. | Crane, Paul K. | Larson, Eric B. | Kaufman, Joel D. | Carone, Marco | Sheppard, Lianne

Article Type: Research Article

Abstract: Background: Evidence links fine particulate matter (PM2.5 ) to Alzheimer’s disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy. Objective: Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score). Methods: We used autopsy specimens (N = 832) from the Adult Changes in Thought (ACT) study, with …enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score. Results: 10-year average (SD) PM2.5 from death across the autopsy cohort was 8.2 (1.9) μg/m3 . Average age (SD) at death was 89 (7) years. Each 1μg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19)). There was no association with Braak stage (OR: 0.99 (0.64, 1.47)). Conclusion: We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding. Show more

Keywords: Air pollution, Alzheimer’s disease, autopsy, dementia, neuropathology, particulate matter

DOI: 10.3233/JAD-201005

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1761-1773, 2021

Authors: Lu, Yifei | Pike, James R. | Selvin, Elizabeth | Mosley, Thomas | Palta, Priya | Sharrett, A. Richey | Thomas, Alvin | Loehr, Laura | Sidney Barritt, A. | Hoogeveen, Ron C. | Heiss, Gerardo

Article Type: Research Article

Abstract: Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. …Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08–1.65). The corresponding HR was 1.22 (0.99–1.51) for AST. Conclusion: Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia. Show more

Keywords: ALT, Alzheimer’s disease, AST, dementia, liver hypometabolism

DOI: 10.3233/JAD-201241

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1775-1784, 2021

Authors: Qian, Xueshen | Zhang, Shuang | Duan, Lian | Yang, Fengchun | Zhang, Kun | Yan, Fuhua | Ge, Song

Article Type: Research Article

Abstract: Background: Although periodontitis is reportedly associated with increased cognitive decline in Alzheimer’s disease, the mechanisms underlying this process remain unknown. Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) is an endotoxin associated with periodontal disease. Objective: We investigated the effect of periodontitis on learning capacity and memory of amyloid-β protein precursor (AβPP)/presenilin (PS1) transgenic mice along with the mechanisms underlying these effects. Methods: Mice were randomly assigned to three groups, namely AβPP/PS1 (control), P.g-LPS Injection, and P.g-LPS Injection + Ligation. Mice from the P.g-LPS Injection group were injected with P.g-LPS in the periodontal tissue three times per week for …8 weeks, while mice from the P.g-LPS Injection + Ligation group were injected with P.g-LPS and subjected to ligation of the gingival sulcus of the maxillary second molar. Results: Expression of gingival proinflammatory cytokines as well as alveolar bone resorption in P.g-LPS-injected and ligatured mice was increased compared to that in control mice. Mice in the P.g-LPS Injection + Ligation group exhibited cognitive impairment and a significant reduction in the number of neurons. Glial cell activation in the experimental groups with significantly increased amyloid-β (Aβ) levels was more pronounced relative to the control group. Induction of periodontitis was concurrent with an increase in cyclooxygenase-2, inducible nitric oxide synthase, AβPP, and beta-secretase 1 expression and a decrease in A disintegrin and metalloproteinase domain-containing protein 10 expression. Conclusion: These findings indicated that periodontitis exacerbated learning and memory impairment in AβPP/PS1 mice and augmented Aβ and neuroinflammatory responses. Our study provides a theoretical basis for risk prediction and early intervention of Alzheimer’s disease and periodontitis. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, lipopolysaccharide, periodontitis, Porphyromonas gingivalis

DOI: 10.3233/JAD-201007

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1785-1800, 2021

Authors: Ly, Maria | Raji, Cyrus A. | Yu, Gary Z. | Wang, Qing | Wang, Yong | Schindler, Suzanne E. | An, Hongyu | Samara, Amjad | Eisenstein, Sarah A. | Hershey, Tamara | Smith, Gordon | Klein, Samuel | Liu, Jingxia | Xiong, Chengjie | Ances, Beau M. | Morris, John C. | Benzinger, Tammie L.S.

Article Type: Research Article

Abstract: Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer’s disease (AD) dementia. Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N = 62) or …overweight and obese (BMI ≥25, N = 42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. Results: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha = 0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly. Show more

Keywords: Alzheimer’s disease, neuroinflammation imaging, obesity

DOI: 10.3233/JAD-201242

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1801-1811, 2021

Authors: Gnanaprakash, Madhumathi | Staniszewski, Agnieszka | Zhang, Hong | Pitstick, Rose | Kavanaugh, Michael P. | Arancio, Ottavio | Nicholls, Russell E.

Article Type: Research Article

Abstract: Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in …vivo . Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive impairment, leucine carboxyl methyltransferase, long-term potentiation, MAPT protein, protein phosphatase 2A, protein phosphatase methylesterase

DOI: 10.3233/JAD-200462

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1813-1829, 2021