Journal of Alzheimer's Disease - Volume 76, issue 4

Authors: Solis, Jr. , Ernesto | Hascup, Kevin N. | Hascup, Erin R.

Article Type: Review Article

Abstract: While prevailing evidence supports that the amyloid cascade hypothesis is a key component of Alzheimer’s disease (AD) pathology, many recent studies indicate that the vascular system is also a major contributor to disease progression. Vascular dysfunction and reduced cerebral blood flow (CBF) occur prior to the accumulation and aggregation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Although research has predominantly focused on the cellular processes involved with Aβ-mediated neurodegeneration, effects of Aβ on CBF and neurovascular coupling are becoming more evident. This review will describe AD vascular disturbances as they relate to Aβ, including chronic cerebral hypoperfusion, hypertension, altered …neurovascular coupling, and deterioration of the blood-brain barrier. In addition, we will describe recent findings about the relationship between these vascular defects and Aβ accumulation with emphasis on in vivo studies utilizing rodent AD models. Show more

Keywords: Amyloid-β peptide, amyloid cascade hypothesis, blood-brain barrier, cerebral amyloid angiopathy, chronic cerebral hypoperfusion, functional hyperemia, in vivo mouse model, in vivo rat model, neurovascular coupling, vascular hypothesis

DOI: 10.3233/JAD-200473

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1179-1198, 2020

Authors: Maccioni, Ricardo B. | Navarrete, Leonardo P. | González, Andrea | González-Canacer, Alejandra | Guzmán-Martínez, Leonardo | Cortés, Nicole

Article Type: Review Article

Abstract: Several hypotheses have been postulated to explain how Alzheimer’s disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid-β peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmuno modulation theory, based on …the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer’s disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multi targeting compounds appear to provide a new pathway for Alzheimer’s disease treatment. Show more

Keywords: Alzheimer’s disease, astrocytes, proinflammatory mediators, microglial cells, neuroinflammation, tau pathology

DOI: 10.3233/JAD-191014

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1199-1213, 2020

Authors: Bakulski, Kelly M. | Seo, Young Ah | Hickman, Ruby C. | Brandt, Daniel | Vadari, Harita S. | Hu, Howard | Park, Sung Kyun

Article Type: Review Article

Abstract: Alzheimer’s disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer’s disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, …lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer’s disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer’s disease specifically though two studies have reported a link between cadmium and Alzheimer’s disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer’s disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer’s disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer’s disease and related dementias and makes recommendations of critical areas of future investment. Show more

Keywords: Cadmium, epidemiology, heavy metal, lead, manganese, toxicant, window of susceptibility

DOI: 10.3233/JAD-200282

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1215-1242, 2020

Authors: Pekkala, Timo | Hall, Anette | Mangialasche, Francesca | Kemppainen, Nina | Mecocci, Patrizia | Ngandu, Tiia | Rinne, Juha O. | Soininen, Hilkka | Tuomilehto, Jaakko | Kivipelto, Miia | Solomon, Alina

Article Type: Short Communication

Abstract: We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE ɛ 4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.

Keywords: Amyloid-β, apolipoprotein E, plasminogen activator, positron emission tomography, type 2 diabetes

DOI: 10.3233/JAD-200145

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1243-1248, 2020

Authors: Waragai, Masaaki | Ho, Gilbert | Takamatsu, Yoshiki | Wada, Ryoko | Sugama, Shuei | Takenouchi, Takato | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Article Commentary

Abstract: Despite the apparent neurotoxicity of amyloid-β (Aβ), recent clinical trials of Aβ immunotherapy have not shown any clinical benefit in Alzheimer’s disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD. Accordingly, preventing the adiponectin paradox by suppressing adiponectin signaling might prove therapeutic in AD.

Keywords: Aβ immunotherapy, adiponectin, adiponectin paradox, Alzheimer’s disease, amyloid-β, amyloidogenic evolvability, antagonistic pleiotropy

DOI: 10.3233/JAD-200416

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1249-1253, 2020

Authors: Jin, Jing | Guo, Jia | Cai, Hongbin | Zhao, Chongchong | Wang, Huan | Liu, Zhiyan | Ge, Zhao-Ming

Article Type: Research Article

Abstract: Many Alzheimer’s disease (AD) patients suffer from persistent neuropathic pain (NP), which is mediated, at least partially, but microglia. Nevertheless, the exact underlying mechanism is unknown. Moreover, a clinically translatable approach through modulating microglia for treating AD-associated NP is not available. Here, in a doxycycline-induced mouse model (rTg4510) for AD, we showed development of NP. We found that the total number of microglia in the CA3 region was not increased, but polarized to pro-inflammatory M1-like phenotype, with concomitant increases in production and secretion of pro-inflammatory cytokines. To examine whether this microglia polarization plays an essential role in the AD-associated NP, …we generated an adeno-associated virus (AAV) serotype PHP.B (capable of crossing the blood-brain barrier) carrying shRNA for DNA methyltransferase 1 (DNMT1) under a microglia-specific TMEM119 promoter (AAV-pTMEM119-shDNMT1), which specifically targeted microglia and induced a M2-like polarization in vitro and in vivo in doxycycline-treated rTg4510 mice. Intravenous infusion of AAV-pTMEM119-shDNMT1 induced M2-polarization of microglia and attenuated both AD-associated behavior impairment but also NP in the doxycycline-treated rTg4510 mice. Thus, our data suggest that AD-associated NP may be treated through M2-polarization of microglia. Show more

Keywords: Alzheimer’s disease, microglia polarization, neuropathic pain, shDNMT1

DOI: 10.3233/JAD-200099

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1255-1265, 2020

Authors: Palacios, Natalia | Lee, Jong Soo | Scott, Tammy | Kelly, Rachel S. | Bhupathiraju, Shilpa N. | Bigornia, Sherman J. | Tucker, Katherine L.

Article Type: Research Article

Abstract: Background: Minorities, including mainland Puerto Ricans, are impacted disproportionally by Alzheimer’s disease (AD), dementia, and cognitive decline. Studying blood metabolomics in this population has the potential to probe the biological underpinnings of this health disparity. Objective: We performed a comprehensive analysis of circulating plasma metabolites in relation to cognitive function in 736 participants from the Boston Puerto Rican Health Study (BPRHS) who underwent untargeted mass-spectrometry based metabolomics analysis and had undergone a battery of in-person cognitive testing at baseline. Methods: After relevant exclusions, 621 metabolites were examined. We used multivariable regression, adjusted for age, sex, education, …apolipoprotein E genotype, smoking, and Mediterranean dietary pattern, to identify metabolites related to global cognitive function in our cohort. LASSO machine learning was used in a complementary analysis to identify metabolites that could discriminate good from poor extremes of cognition. We also conducted sensitivity analyses: restricted to participants without diabetes, and to participants with good adherence to Mediterranean diet. Results: Of 621 metabolites, FDR corrected (p  < 0.05) multivariable linear regression identified 3 metabolites positively, and 10 negatively, associated with cognitive function in the BPRHS. In a combination of FDR-corrected linear regression, logistic regression regularized via LASSO, and sensitivity analyses restricted to participants without diabetes, and with good adherence to the Mediterranean diet, β-cryptoxanthin plasma concentration was consistently associated with better cognitive function and N-acetylisoleucine and tyramine O-sulfate concentrations were consistently associated with worse cognitive function. Conclusion: This untargeted metabolomics study identified potential biomarkers for cognitive function in a cohort of Puerto Rican older adults. Show more

Keywords: Cognitive function, diabetes, Puerto Ricans, metabolomics

DOI: 10.3233/JAD-200040

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1267-1280, 2020

Authors: Kim, Dong Yeol | Choi, Sung Hyun | Lee, Jee Sun | Kim, Hyoung Jun | Kim, Ha Na | Lee, Ji Eun | Shin, Jin Young | Lee, Phil Hyu

Article Type: Research Article

Abstract: Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of the central nervous system and are currently being tested in clinical trials for neurological disorders. However, no studies have examined the various roles of embryonic stem cell derived (ES)-MSCs in eliciting therapeutic effects for Alzheimer’s disease (AD). In the present study, we investigated the neuroprotective effect of ES-MSCs in cellular and animal models of AD, as well as the safety of the intra-arterial administration of ES-MSCs in an AD animal model. ES-MSCs displayed higher cell viability than that of bone marrow (BM)-MSCs in amyloid-β (Aβ )-induced cellular …models. Moreover, the efficacy of autophagy induction in ES-MSCs was comparable to that of BM-MSCs; however, intracellular Aβ levels were more significantly reduced in ES-MSCs than in BM-MSCs. In a rat model of AD, ES-MSCs significantly inhibited Aβ -induced cell death in the hippocampus and promoted autophagolysosomal clearance of Aβ , which was concomitantly followed by decreased levels of Aβ in the hippocampus. Furthermore, ES-MSC treatment in Aβ -treated rats featured a higher memory performance than that of rats injected solely with Aβ . Finally, intra-arterial administration of an appropriate cell density of ES-MSCs was safe and free from in situ occlusion or cerebral ischemia. These data support the therapeutic potential of ES-MSCs and clinical applications of the intra-arterial route of ES-MSC administration in AD. Show more

Keywords: Alzheimer’s disease, autophagy, intra-arterial injection, mesenchymal stem cell, protection

DOI: 10.3233/JAD-200026

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1281-1296, 2020

Authors: Assogna, Martina | Casula, Elias Paolo | Borghi, Ilaria | Bonnì, Sonia | Samà, Domenico | Motta, Caterina | Di Lorenzo, Francesco | D’Acunto, Alessia | Porrazzini, Francesco | Minei, Marilena | Caltagirone, Carlo | Martorana, Alessandro | Koch, Giacomo

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD. Objective: Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients. Methods: Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mg×2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental …State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity. Results: Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range. Conclusion: PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission. Show more

Keywords: Brain inflammation, behavioral symptoms, EEG, executive functions, frontotemporal dementia, GABA activity, transcranial magnetic stimulation

DOI: 10.3233/JAD-200426

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1297-1308, 2020

Authors: Wing, Jeffrey J. | Levine, Deborah A. | Ramamurthy, Arun | Reider, Carson

Article Type: Research Article

Abstract: Background: Areas within the Appalachian region may have a greater burden of under diagnosed Alzheimer’s disease and related disorders (ADRD). Objective: To estimate the prevalence of ADRD in the Appalachian counties of Ohio, and to determine if differences exist by geographic location (Appalachian/non-Appalachian and rural/urban) and across time among Medicare beneficiaries. Methods: Centers for Medicare and Medicaid Services Public Use Files from 2007–2017 were used to estimate county-level ADRD prevalence among all fee-for-service beneficiaries in Ohio. Negative binomial regression was used to estimate prevalence overall, by Appalachian Regional Commission’s Appalachian/non-Appalachian designation, and by rural/urban (Rural-Urban Continuum …Codes) classification. Models were repeated, adjusting for county-level demographics and comorbidities. Results: The prevalence of ADRD varied by both Appalachian residence and rural status (p  = 0.008). Before adjustment by county-level demographics and comorbidities, the prevalence of ADRD in urban Appalachian counties was 1–3% lower than in urban non-Appalachian counties, while rural Appalachian counties had 2–3% higher prevalence compared to rural non-Appalachian counties. After adjustment, the differences between prevalence ratios were accentuated; the prevalence ratio was consistently higher for rural Appalachian counties, yet varied across the study period for urban counties (1.03 in 2007 to 0.97 in 2017). Conclusion: The results suggest a disparate burden of ADRD in Ohio with higher prevalence in rural Appalachian counties. This potential difference by Appalachian region is important to consider for availability of services and subsequent delivery of care. In order to better understand the disparity, further epidemiologic studies are necessary to better estimate the burden of ADRD. Show more

Keywords: Alzheimer’s disease, Appalachian region, epidemiology, health disparities, medicare

DOI: 10.3233/JAD-200491

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1309-1316, 2020