Journal of Alzheimer's Disease - Volume 67, issue 4

Authors: Zhang, Xiaohua | Lao, Kejing | Qiu, Zhongying | Rahman, Md Saidur | Zhang, Yuelin | Gou, Xingchun

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by the progressive loss of memory and cognition in the aging population. However, the etiology of and therapies for AD remain far from understood. Astrocytes, the most abundant neuroglia in the brain, have recently aroused substantial concern due to their involvement in synaptotoxicity, amyloidosis, neuroinflammation, and oxidative stress. In this review, we summarize the candidate molecules of astrocytes, especially receptors and transporters, that may be involved in AD pathogenesis. These molecules include excitatory amino acid transporters (EAATs), metabotropic glutamate receptor 5 (mGluR5), the adenosine 2A receptor (A2AR), …the α 7-nicotinic acetylcholine receptor (α 7-nAChR), the calcium-sensing receptor (CaSR), S100β, and cannabinoid receptors. We describe the characteristics of these molecules and the neurological and pharmacological underpinnings of these molecules in AD. Among these molecules, EAATs, A2AR, and mGluR5 are strongly related to glutamate-mediated synaptotoxicity and are involved in glutamate transmission or the clearance of extrasynaptic glutamate in the AD brain. The α 7-nAChR, CaSR, and mGluR5 are receptors of Aβ and can induce a plethora of toxic effects, such as the production of excess Aβ, synaptotoxicity, and NO production triggered by changes in intracellular calcium signaling. Antagonists or positive allosteric modulators of these receptors can repair cognitive ability and modify neurobiological changes. Moreover, blocking S100β or activating cannabinoid receptors reduces neuroinflammation, oxidative stress, and reactive astrogliosis. Thus, targeting these molecules might provide alternative approaches for treating AD. Show more

Keywords: A2AR, α7-nAChR, Alzheimer’s disease, astrocytes, cannabinoid receptor 2, CaSR, EAATs, mGluR5, S100β

DOI: 10.3233/JAD-181084

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1109-1122, 2019

Authors: Patel, Ankur A. | Ganepola, Ganepola A.P. | Rutledge, John R. | Chang, David H.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that affects the cognitive faculties of millions of people worldwide. There is still no known cure for AD, nor a clear understanding of AD etiology. Nevertheless, researchers have made significant strides in understanding various key aspects of AD neuropathology at the cellular and molecular levels. This review is intended to provide a general survey of what is known and unknown, based on the three hallmarks of AD, combined with our knowledge from microRNA research. Our goal is to reevaluate and reassess the current direction of AD research and therapeutic insights, charting a …new course and comprehensive plan to combat this imminent global health threat. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, circulating microRNA, cognition disorders, gene expression regulation, long-term memory, long-term potentiation, neurofibrillary tangles, synaptic potentials, tauopathy

DOI: 10.3233/JAD-181078

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1123-1145, 2019

Authors: Mansour, Yusra | Blackburn, Kaitlyn | González-González, Luis Oscar | Calderón-Garcidueñas, Lilian | Kulesza, Randy J.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a biological construct defined by abnormal deposits of hyperphosphorylated tau and amyloid-β. The 2050 projection for AD in the USA is 14 million. There is a strong association between AD, air pollution, and traffic. Early diagnosis is imperative for intervention in the initial disease stages. Hearing and, specifically, the ability to encode complex sounds are impaired in AD. Nuclei in the auditory brainstem appear to be sensitive to neurodevelopmental and neurodegenerative disorders. Specifically, sustained exposure to air pollution is harmful to the brainstem; young residents of Metropolitan Mexico City (MMC) exposed to fine particulate matter and …combustion-derived nanoparticles develop AD pathology in infancy. MMC clinically healthy children and teens have significant central delays in brainstem auditory evoked potentials (BAEPs). Herein, we review evidence that the auditory pathway is a key site of AD early pathology associated with air pollution and is significantly involved in AD patients. We strongly suggest electrophysiological screening, including BAEPs, be employed to screen individuals for early delays and to monitor progressive decline in patients diagnosed with mild cognitive impairment and AD. Understanding auditory dysfunction in early AD in pediatric and young adult populations may clarify mechanisms of disease progression. Air pollution is a risk factor for the development of AD and as the number of Americans with AD continues to grow without a cure, we need to focus on preventable, early causes of this fatal disease and intervene appropriately. Show more

Keywords: Air Pollution, alzheimer’s continuum, alzheimer’s disease, amyloid-β , brainstem evoked potential, cochlear, combustion-associated nanoparticles, fine particulate matter, hearing, hyperphosphorylated tau, neurofibrillary tangles, PM2.5 , vestibular nuclei

DOI: 10.3233/JAD-181186

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1147-1155, 2019

Authors: Grossberg, George T. | Tong, Gary | Burke, Anna D. | Tariot, Pierre N.

Article Type: Review Article

Abstract: An estimated 47 million people live with Alzheimer’s disease (AD) and other forms of dementia worldwide. Although no disease-modifying treatments are currently available for AD, earlier diagnosis and proper management of the disease could have considerable impact on patient and caregiver quality of life and functioning. Drugs currently approved for AD treat the cognitive, behavioral, and functional symptoms of the disease and consist of three cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. Treatment of patients with mild to moderate AD is generally initiated with a ChEI. Patients who show progression of symptoms while on ChEI monotherapy may be …switched to another ChEI and/or memantine can be added to the treatment regimen. In recent years, putative disease-modifying therapies have emerged that aim to slow the progression of AD instead of only addressing its symptoms. However, many therapies have failed in clinical trials in patients with established AD, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness. The goal of this narrative literature review is to discuss present treatment algorithms and potential future therapies in AD. Show more

Keywords: Keywords: Algorithm, Alzheimer’s disease, cholinesterase inhibitors, memantine, treatment

DOI: 10.3233/JAD-180903

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1157-1171, 2019

Authors: Fumagalli, Giorgio Giulio | Sacchi, Luca | Basilico, Paola | Arighi, Andrea | Carandini, Tiziana | Scarioni, Marta | Colombi, Annalisa | Pietroboni, Anna | Ghezzi, Laura | Fenoglio, Chiara | Serpente, Maria | D’anca, Marianna | Arcaro, Marina | Mercurio, Matteo | Triulzi, Fabio | Scola, Elisa | Marotta, Giorgio | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract: We report the case of two monozygotic twins with Thr272fs mutation in progranulin gene. Both patients developed frontotemporal dementia with 5 years difference in age at onset (Twin 1:73 years, Twin 2:68 years), with early behavioral, language, dysexecutive, and memory problems. They had the same formal education (5 years), but while Twin 1 dedicated more to social and leisure activity, Twin 2 worked all her life. At neuroimaging (MRI for Twin 1 and CT for Twin 2), they both showed asymmetric atrophy with left predominance. The two were discordant for total tau levels in cerebrospinal fluid, neuropsychological testing, and smoking …habits. The description of the twins can help identify environmental factors that influence the onset and phenotype of frontotemporal dementia. Show more

Keywords: Age at onset, atrophy, cerebrospinal fluid, frontotemporal dementia, progranulin (GRN), twins

DOI: 10.3233/JAD-180723

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1173-1179, 2019

Authors: Guzmán-Martínez, Leonardo | Tapia, José Pablo | Farías, Gonzalo A. | González, Andrea | Estrella, Matías | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: The establishment of a molecular biomarker for early detection of Alzheimer’s disease (AD) is critical for diagnosis and follow up of patients, and as a quantitative parameter in the evaluation of potential new drugs to control AD. A list of blood biomarkers has been reported but none has been validated for the Alzheimer’s clinic. The changes in hyperphosphorylated tau and amyloid peptide in the cerebrospinal fluid is currently used as a tool in the clinics and for research purposes, but this method is highly invasive. Recently, we reported a non-invasive and reliable blood biomarker that correlates the increase in the …ratio of heavy tau (HMWtau) and the low molecular weight tau (LMWtau) in human platelets and the decrease in the brain volume as measured by structural MRI. This molecular marker has been named Alz-tau®. Beyond the clinical trials developed with a Latin American population, the present study focuses on an evaluation of this biomarker in a Caucasian population. We examined 36 AD patients and 15 cognitively normal subjects recruited in Barcelona, Spain. Tau levels in platelets were determined by immunoreactivity and the cognitive status by using GDS and MMSE neuropsychological tests. The HMW/LMW tau ratio was statistically different between controls and AD patients. A high correlation was found between the increase in MMSE scores and HMW/LMW tau ratio. This study showed that this ratio is significantly higher in AD patients than controls. Moreover, this study on a peripheral marker of AD is valuable to understanding the AD pathogenesis. Show more

Keywords: Alzheimer’s disease, clinical study, early detection of the disease, HMWtau/ LMWtau ratio, molecular biomarkers, tau protein

DOI: 10.3233/JAD-180637

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1181-1186, 2019

Authors: Pražienková, Veronika | Schirmer, Claire | Holubová, Martina | Železná, Blanka | Kuneš, Jaroslav | Galas, Marie-Christine | Maletínská, Lenka

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. These tangles mainly consist of hyperphosphorylated tau protein. As it induces tau hyperphosphorylation in vitro and in vivo , hypothermia is a useful tool for screening potential neuroprotective compounds that ameliorate tau pathology. In this study, we examined the effect of prolactin-releasing peptide (PrRP), its lipidized analog palm11 -PrRP31 and glucagon-like-peptide-1 agonist liraglutide, substances with anorexigenic and antidiabetic properties, on tau phosphorylation and on the main kinases and phosphatases involved in AD development. Our study was …conducted in a neuroblastoma cell line SH-SY5Y and rat primary neuronal cultures under normothermic and hypothermic conditions. Hypothermia induced a significant increase in tau phosphorylation at the pThr212 and pSer396/pSer404 epitopes. The palmitoylated analogs liraglutide and palm11 -PrRP31 attenuated tau hyperphosphorylation, suggesting their potential use in the treatment of neurodegenerative diseases. Show more

Keywords: Hypothermia, lipidization, primary neuronal culture, prolactin-releasing peptide, SH-SY5Y, tau phosphorylation

DOI: 10.3233/JAD-180837

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1187-1200, 2019

Authors: Hirose, Daisuke | Shimizu, Soichiro | Hirao, Kentaro | Ogawa, Yusuke | Sato, Tomohiko | Kaneko, Yoshitsugu | Takenoshita, Naoto | Namioka, Nayuta | Fukasawa, Raita | Umahara, Takahiko | Sakurai, Hirofumi | Watanabe, Ryo | Hanyu, Haruo

Article Type: Research Article

Abstract: Background/Objective: Although frailty is closely linked to dementia, particularly Alzheimer’s disease (AD), underlying pathophysiology of frailty associated with AD remains uncertain. This study aimed to investigate differences in structural and functional brain imaging abnormalities between AD with and without frailty. Methods: A total of 191 outpatients with probable AD (men: 91; women: 100; age: 80.7±6.3 years) who underwent both magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) were enrolled in this study. Frailty was determined in accordance with the Obu study Health Promotion for the Elderly. We compared numbers of small infarctions in the subcortical gray …and white matter and severity of white matter abnormalities (periventricular hyperintensity [PVH] and deep white matter hyperintensity [DWMH]) on MRI, and regional cerebral blood flow (rCBF) changes on SPECT between AD with and without frailty. Results: The prevalence of frailty was 43.4% in patients with AD. PVH and DWMH scores were significantly higher in AD with frailty compared to those without frailty. AD with frailty had a trend of decreased rCBF in the bilateral anterior cingulate gyrus, whereas those without frailty tend to have decreased rCBF in the left dominant parietal lobe and precuneus. Conclusion: Our MRI and SPECT imaging studies suggest different underlying pathophysiology in the brain between AD with frailty and without frailty. Show more

Keywords: Alzheimer’s disease, frailty, magnetic resonance imaging, single-photon emission computed tomography

DOI: 10.3233/JAD-180701

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1201-1208, 2019

Authors: Gyanwali, Bibek | Shaik, Muhammad Amin | Tan, Boon Yeow | Venketasubramanian, Narayanaswamy | Chen, Christopher | Hilal, Saima

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (SVD) is one of the major contributors to cognitive impairment and dementia. However, data on the incidence and progression of SVD in an Asian population are lacking. Objective: The present study aims to investigate the incidence, progression, associated risk factors, and clinical relevance of SVD in a memory clinic setting. Methods: A prospective case-control study, where 346 patients underwent repeated brain MRI with a mean interval of 24.5 months, accessing white matter hyperintensities (WMH), lacunes and cerebral microbleeds (CMBs). Severity of cognitive impairment was assessed using Clinical Dementia Rating scale and …change in clinical diagnosis. Data on demographics, vascular risk factors, and clinical history were collected at baseline. Results: The prevalence of significant WMH (Fazekas ≥2) was 56.6% at baseline which progressed to 59.0% at follow-up. Overall prevalence of CMBs increased from 42.2% to 47.4% (9% new cases) and lacunes increased from 31.8% to 33.2% (2.1% new cases). Hypertension was associated with WMH progression (OR: 1.78, 95% CI: 1.01, 2.99) and increasing age was associated with incident CMBs (OR: 1.04, 95% CI: 1.01, 1.08). Moreover, the use of lipid-lowering medications decreased the incidence of lacunes (OR: 0.15, 95% CI: 0.04, 0.61). The major risk factor for incident SVD was baseline SVD lesion load. WMH progression was associated with increased severity of cognitive impairment (OR: 1.95, 95% CI: 1.16, 3.23). Conclusion: Vascular risk factors and baseline severity of SVD lesion load were associated with progression of SVD. Furthermore, WMH progression was linked with increased severity of cognitive impairment. Future studies should be aimed to slow cognitive deterioration by preventing SVD related brain damage by targeting vascular risk factors. Show more

Keywords: Cerebral small vessel disease, clinical dementia rating, cognitive impairment, magnetic resonance imaging, vascular risk factors

DOI: 10.3233/JAD-180911

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1209-1219, 2019

Authors: Chen, Yuanxin | Wang, Tianduo | Rogers, Kem A. | Rutt, Brian K. | Ronald, John A.

Article Type: Research Article

Abstract: Microglial activation and oxidative stress have been linked to the formation of amyloid plaques found in Alzheimer’s disease (AD). Epidemiologic and experimental evidence also suggests that cholesterol (CH) contributes to the pathogenesis of AD, particularly the formation of amyloid plaques. We have previously described the development of amyloid-β (Aβ) plaques in New Zealand white rabbits maintained on a 0.125%–0.25% w/w CH diet for extended periods of time (28 months). Here we further characterize this model with combined immunofluorescence and immunohistochemical staining to evaluate markers of immune cell activation. Five out of eight CH-fed rabbits, but not control rabbits, developed extracellular …Aβ plaques in both the hippocampus and cortex. Significantly (p  < 0.05) higher CD11b microglial staining was found in the hippocampus, temporal cortex, and frontal cortex of CH-fed versus control rabbits. In the temporal cortex and parietal cortex, active CD-11b- and ferritin-positive microglia were found in close proximity to Aβ plaques. Classification and quantification of activated microglia in the temporal cortex showed that 68±12.9%, 25±7.3%, and 7±2.7% of all microglia had a primed, reactive, and amoeboid phenotype, respectively. Activated microglia also expressed myeloperoxidase which was co-localized to amyloid deposits. Our findings in this dietary-based model lend further support of a role of activated microglia and oxidative stress during the development of AD and strengthens the links between hypercholesterolemia, inflammatory status, and AD. Show more

Keywords: Alzheimer’s disease, amyloid-β plaque, cholesterol, microglia, myeloperoxidase, rabbit model

DOI: 10.3233/JAD-180714

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1221-1234, 2019