Journal of Alzheimer's Disease - Volume 69, issue 3

Authors: Thomson, Errol M.

Article Type: Review Article

Abstract:  Air pollution is a risk factor for cardiovascular and respiratory morbidity and mortality. A growing literature also links exposure to diverse air pollutants (e.g., nanoparticles, particulate matter, ozone, traffic-related air pollution) with brain health, including increased incidence of neurological and psychiatric disorders such as cognitive decline, dementia (including Alzheimer’s disease), anxiety, depression, and suicide. A critical gap in our understanding of adverse impacts of pollutants on the central nervous system (CNS) is the early initiating events triggered by pollutant inhalation that contribute to disease progression. Recent experimental evidence has shown that particulate matter and ozone, two common pollutants with differing …characteristics and reactivity, can activate the hypothalamic-pituitary-adrenal (HPA) axis and release glucocorticoid stress hormones (cortisol in humans, corticosterone in rodents) as part of a neuroendocrine stress response. The brain is highly sensitive to stress: stress hormones affect cognition and mental health, and chronic stress can produce profound biochemical and structural changes in the brain. Chronic activation and/or dysfunction of the HPA axis also increases the burden on physiological stress response systems, conceptualized as allostatic load, and is a common pathway implicated in many diseases. The present paper provides an overview of how systemic stress-dependent biological responses common to particulate matter and ozone may provide insight into early CNS effects of pollutants, including links with oxidative, inflammatory, and metabolic processes. Evidence of pollutant effect modification by non-chemical stressors (e.g., socioeconomic position, psychosocial, noise), age (prenatal to elderly), and sex will also be reviewed in the context of susceptibility across the lifespan. Show more

Keywords: Air pollution, brain, cognition, dementia, depression, hypothalamic-pituitary-adrenal (HPA) axis, mental health, ozone, particulate matter

DOI: 10.3233/JAD-190015

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 597-614, 2019

Authors: Hampel, Harald | Lista, Simone | Mango, Dalila | Nisticò, Robert | Perry, George | Avila, Jesus | Hernandez, Felix | Geerts, Hugo | Vergallo, Andrea | Alzheimer Precision Medicine Initiative (APMI)

Collaborators: AFSHAR, Mohammad | AGUILAR, Lisi Flores | AKMAN-ANDERSON, Leyla | ARENAS, Joaquín | AVILA, Jesus | BABILONI, Claudio | BALDACCI, Filippo | BATRLA, Richard | BENDA, Norbert | BLACK, Keith L. | BOKDE, Arun L.W. | BONUCCELLI, Ubaldo | BROICH, Karl | CACCIOLA, Francesco | CARACI, Filippo | CASTRILLO†, Juan | CAVEDO, Enrica | CERAVOLO, Roberto | CHIESA, Patrizia A. | CORVOL, Jean-Christophe | CUELLO, Augusto Claudio | CUMMINGS, Jeffrey L. | DEPYPERE, Herman | DUBOIS, Bruno | DUGGENTO, Andrea | EMANUELE, Enzo | ESCOTT-PRICE, Valentina | FEDEROFF, Howard | FERRETTI, Maria Teresa | FIANDACA, Massimo | FRANK, Richard A. | GARACI, Francesco | GEERTS, Hugo | GIORGI, Filippo S. | GOETZL, Edward J. | GRAZIANI, Manuela | HABERKAMP, Marion | HABERT, Marie-Odile | HAMPEL, Harald | HERHOLZ, Karl | HERNANDEZ, Felix | KAPOGIANNIS, Dimitrios | KARRAN, Eric | KIDDLE, Steven J. | KIM, Seung H. | KORONYO, Yosef | KORONYO-HAMAOUI, Maya | LANGEVIN, Todd | LEHÉRICY, Stéphane | LUCÍA, Alejandro | LISTA, Simone | LORENCEAU, Jean | MANGO, Dalila | MAPSTONE, Mark | NERI, Christian | NISTICÓ, Robert | O’BRYANT, Sid E. | PALERMO, Giovanni | PERRY, George | RITCHIE, Craig | ROSSI, Simone | SAIDI, Amira | SANTARNECCHI, Emiliano | SCHNEIDER, Lon S. | SPORNS, Olaf | TOSCHI, Nicola | VERDOONER, Steven R. | VERGALLO, Andrea | VILLAIN, Nicolas | WELIKOVITCH, Lindsay A. | WOODCOCK, Janet | YOUNESI, Erfan

Article Type: Review Article

Abstract:  Systems pharmacology is a novel framework for drug research that models traditional and innovative pharmacological parameters and provides the overall efficacy and safety profile of a drug across body systems and complex, non-linear, molecular interactions. Lithium chloride, a pharmacological compound approved for the therapy of psychiatric disorders, represents a poorly explored compound for the treatment of Alzheimer’s disease (AD). Lithium has been shown to reduce downstream effects associated with the aberrant overactivation of certain molecular pathways, such as glycogen synthase kinase 3 subunit β (GSK3-β)-related pathways, involved in AD-related pathophysiology. It seems that overactivation and overexpression of GSK3-β lead to …an impairment of long-term potentiation and amyloid-β induced neurotoxicity that can be normalized using lithium. Moreover, a growing body of evidence has demonstrated that lithium’s GSK3-β inhibitory effect prevents tau phosphorylation in mouse models of tauopathies. Clinical data have been inconclusive, partly due to methodological limitations. The lack of studies exploring the dynamics of protein misfolding in AD and investigating the specific tau-isoforms appearing prior to the accumulation of neurofibrillary tangles calls for new and optimized clinical trials. Advanced computer modeling based on a formal implementation of quantitative parameters and basic enzymatic insights into a mechanism-based model would present a good start to tackle these non-linear interactions. This innovative approach will pave the way for developing “molecularly” biomarker-guided targeted therapies, i.e., treatments specifically adapted (“tailored”) to the individual, consistently with the primary objectives and key conceptual points of precision medicine and precision pharmacology. Show more

Keywords: Alzheimer’s disease, GSK3, lithium, neurotoxicity, precision medicine, post-translational modification, systems pharmacology, tau

DOI: 10.3233/JAD-190197

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 615-629, 2019

Authors: Vegh, Caleb | Stokes, Kyle | Ma, Dennis | Wear, Darcy | Cohen, Jerome | Ray, Sidhartha D. | Pandey, Siyaram

Article Type: Review Article

Abstract: Neurons consume the highest amount of oxygen, depend on oxidative metabolism for energy, and survive for the lifetime of an individual. Therefore, neurons are vulnerable to death caused by oxidative-stress, accumulation of damaged and dysfunctional proteins and organelles. There is an exponential increase in the number of patients diagnosed with neurodegenerative diseases such as Alzheimer’s (AD) as the number of elderly increases exponentially. Development of AD pathology is a complex phenomenon characterized by neuronal death, accumulation of extracellular amyloid-β plaques and neurofibrillary tangles, and most importantly loss of memory and cognition. These pathologies are most likely caused by mechanisms including …oxidative stress, mitochondrial dysfunction/stress, accumulation of misfolded proteins, and defective organelles due to impaired proteasome and autophagy mechanisms. Currently, there are no effective treatments to halt the progression of this disease. In order to treat this complex disease with multiple biochemical pathways involved, a complex treatment regimen targeting different mechanisms should be investigated. Furthermore, as AD is a progressive disease-causing morbidity over many years, any chemo-modulator for treatment must be used over long period of time. Therefore, treatments must be safe and non-interfering with other processes. Ideally, a treatment like medicinal food or a supplement that can be taken regularly without any side effect capable of reducing oxidative stress, stabilizing mitochondria, activating autophagy or proteasome, and increasing energy levels of neurons would be the best solution. This review summarizes progress in research on different mechanisms of AD development and some of the potential therapeutic development strategies targeting the aforementioned pathologies. Show more

Keywords: Alzheimer’s disease, amyloid-β plaques, ashwagandha, autophagy, mitochondrial dysfunction, oxidative stress, presenilin-1, water-soluble coenzyme-Q10

DOI: 10.3233/JAD-181230

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 631-649, 2019

Authors: Elsworthy, Richard J. | Aldred, Sarah

Article Type: Review Article

Abstract:  Depression is a common co-morbidity seen in people with Alzheimer’s disease (AD). However, the successful treatment of depressive symptoms in people with AD is rarely seen. In fact, multiple randomized controlled trials have shown selective serotonin reuptake inhibitors (SSRIs), the current best recommended treatment for depression, to be ineffective in treating depressive symptoms in people with AD. One explanation for this lack of treatment effect may be that depressive symptoms can reflect the progression of AD, rather than clinical depression and are a consequence of more severe neurodegeneration. This raises several questions regarding not only the efficacy of SSRIs in …the treatment of depression in people with AD but also regarding the accuracy of diagnosis of depression in AD. However, there may be a rationale for the prescription of SSRIs in early AD. Even in the absence of depression, SSRIs have been shown to slow the conversion from mild cognitive impairment to AD. This may be attributed to the effect of SSRIs on the processing of amyloid-β precursor protein, which may cause a reduction in the accumulation of amyloid-β. Thus, although SSRIs may lack efficacy in treating depression in people with AD, they may hold therapeutic potential for treating and delaying the progression of AD especially if treatment begins in the early stages of AD. This article reviews the current consensus for SSRI treatment of depression in people with AD and highlights the possibility of SSRIs being a treatment option for delaying the progression of AD. Show more

Keywords: Aging, Alzheimer’s disease, amyloidosis, depression, second generation antidepressive agents

DOI: 10.3233/JAD-180780

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 651-661, 2019

Authors: Arighi, Andrea | Di Cristofori, Andrea | Fenoglio, Chiara | Borsa, Stefano | D’Anca, Marianna | Fumagalli, Giorgio Giulio | Locatelli, Marco | Carrabba, Giorgio | Pietroboni, Anna Margherita | Ghezzi, Laura | Carandini, Tiziana | Colombi, Annalisa | Scarioni, Marta | De Riz, Milena Alessandra | Serpente, Maria | Rampini, Paolo Maria | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract:  Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer’s disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.

Keywords: Alzheimer’s disease, Aquaporin 4, glymphatic system, normal pressure hydrocephalus

DOI: 10.3233/JAD-190119

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 663-669, 2019

Authors: Sadegh Malvajerd, Soroor | Izadi, Zhila | Azadi, Amir | Kurd, Masoumeh | Derakhshankhah, Hossein | Sharifzadeh, Mohammad | Akbari Javar, Hamid | Hamidi, Mehrdad

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and is caused by accumulation of amyloid-β (Aβ) peptide and is associated with neurological abnormalities in learning and memory. The protective role of curcumin on nerve cells, along with a potent antioxidant and free radical scavenging activity, has been widely studied. However, its low bioavailability and limited transport ability across the blood-brain barrier are two major drawbacks of its application in the treatment of different neurodegenerative diseases. The present study was designed to improve the effectiveness of curcumin in the treatment of Aβ-induced cognitive deficiencies in a rat model …of AD by loading it into nanostructured lipid carriers (NLCs). The accumulation rate of curcumin (505.76±38.4 ng/g–1  h) in rat brain, as well as its serum levels, were significantly increased by using curcumin-loaded NLCs. The effective role of NLCs for brain delivery of curcumin was confirmed by reduced oxidative stress parameters (ROS formation, lipid peroxidation, and ADP/ATP ratio) in the hippocampal tissue and improvement of spatial memory. Also, histopathological studies revealed the potential of Cur–NLCs in decreasing the hallmarks of Aβ in AD in the animal model. The result of studying the neuroprotective potential of Cur-NLC in both pre-treatment and treatment modes showed that loading curcumin in NLCs is an effective strategy for increasing curcumin delivery to the brain and reducing Aβ-induced neurological abnormalities and memory defects and that it can be the basis for further studies in the area of AD prevention and treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, blood-brain barrier, curcumin, nanostructured lipid carriers, neurodegeneration

DOI: 10.3233/JAD-190083

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 671-686, 2019

Authors: Kitaguchi, Nobuya | Tatebe, Harutsugu | Sakai, Kazuyoshi | Kawaguchi, Kazunori | Matsunaga, Shinji | Kitajima, Tomoko | Tomizawa, Hiroshi | Kato, Masao | Sugiyama, Satoshi | Suzuki, Nobuo | Mizuno, Masao | Takechi, Hajime | Nakai, Shigeru | Hiki, Yoshiyuki | Kushimoto, Hiroko | Hasegawa, Midori | Yuzawa, Yukio | Tokuda, Takahiko

Article Type: Research Article

Abstract: The accumulation of amyloid-β protein (Aβ) and tau in the brain is a major pathological change related to Alzheimer’s disease. We have continued to develop Extracorporeal Blood Aβ Removal Systems (E-BARS) as a method for enhancing Aβ clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aβ and evoke large Aβ influxes into the blood, resulting in a decrease in brain Aβ accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aβ accumulation than those who did not. Here, plasma total tau concentrations from 30 patients undergoing hemodialysis were measured using an …ultrasensitive immunoassay and compared to those from 11 age-matched controls. Plasma total tau concentrations were higher in patients with renal failure regardless of whether they underwent hemodialysis, suggesting the involvement of the kidneys in tau degradation and excretion. Hemodialyzers effectively removed blood Aβ but not extracorporeal blood tau. The influx of tau into the blood was observed at around the 1 h period during hemodialysis sessions. However, the influx amount of tau was far smaller than that of Aβ. Furthermore, histopathological analysis revealed similar, not significantly less, cerebral cortex phosphorylated tau accumulation between the 17 patients who underwent hemodialysis and the 16 age-matched subjects who did not, although both groups showed sparse accumulation. These findings suggest that hemodialysis may induce both tau and Aβ migration into the blood. However, as a therapeutic strategy for Alzheimer’s disease, it may only be effective for removing Aβ from the brain. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, blood component removal, hemodialysis, tau protein

DOI: 10.3233/JAD-190087

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 687-707, 2019

Authors: Mei, Xinchun | Chen, Yupeng | Zheng, Hailin | Shi, Zhongyong | Marcantonio, Edward R. | Xie, Zhongcong | Shen, Yuan

Article Type: Research Article

Abstract:  Previous studies showed that the Confusion Assessment Method based delirium severity evaluation tool (CAM-S) had good reliability and validity. However, there is no Chinese version of the CAM-S. Therefore, we set out to perform a prospective investigation in older Chinese patients who had total joint replacement surgery under general anesthesia in Tenth People’s Hospital in Shanghai, P.R. China. A total of 576 participants, aged 60 years or older, were screened, 179 participants were enrolled, and 125 of them were included for the final analysis. Pre-operative evaluations were conducted one day before the surgery. Postoperative evaluations were conducted twice daily from …postoperative day 1 to day 3. The incidence of postoperative delirium was 24.8%. The Chinese version of CAM-S [including a Short Form (CAM-S Short Form) and a Long Form (CAM-S Long Form)] had an optimal reliability reflected by internal consistency (Cronbach’s α = 0.748 and 0.839 for CAM-S Short Form and CAM-S Long Form respectively), split-halves reliability (Pearson correlation coefficient = 0.372 and 0.384 for CAM-S Short Form and CAM-S Long Form respectively), and inter-rater reliability (intra-class correlation coefficients = 0.629 and 0.945 for CAM-S Short Form and CAM-S Long Form respectively). Additionally, the Chinese version of CAM-S also showed a good discriminate validity. The domain scores of CAM-S were inversely correlated with corresponding domain scores of the MMSE. Finally, a receiver operating characteristic (ROC) analysis obtained an optimal cutoff point of 2.5 for CAM-S Short Form and 3.5 for CAM-S Long Form in recognizing delirium diagnosed by CAM. The areas under the ROC were 0.989 (95% CI 0.972 – 1.000, p  < 0.001) and 0.964 (95% CI 0.946 – 0.982, p  < 0.001), respectively. These data suggest that the Chinese version of CAM-S has good reliability and validity in evaluating postoperative delirium in geriatric Chinese patients and may be a useful tool to assess the severity of delirium. Show more

Keywords: Confusion assessment method, postoperative delirium severity, reliability, validity

DOI: 10.3233/JAD-181288

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 709-716, 2019

Authors: Eakin, Kelsey A. | Saleem, Mahwesh | Herrmann, Nathan | Cogo-Moreira, Hugo | Mielke, Michelle M. | Oh, Paul I. | Haughey, Norman J. | Venkata, Swarajya L.V. | Lanctôt, Krista L. | Swardfager, Walter

Article Type: Research Article

Abstract: Background: Exercise prevents recurrent cardiovascular events and it may combat cognitive decline in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome. Objective: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD. Methods: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization …tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test. Results: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p  = 0.01). At baseline, T2DM-associated sphingolipids (ceramide C22 : 0, monohexylceramide C16 : 1, and lactosylceramide C24 : 0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16 : 1 (0.86 fewer words recalled, 95% bootstrap confidence interval [–2.32, –0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22 : 0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [–1.17, –0.05]). Conclusions: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD. Show more

Keywords: Cognition, coronary artery disease, exercise, memory, sphingolipids, type 2 diabetes

DOI: 10.3233/JAD-181203

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 717-727, 2019

Authors: Bignoux, Monique J. | Cuttler, Katelyn | Otgaar, Tyrone C. | Ferreira, Eloise | Letsolo, Boitelo T. | Weiss, Stefan F.T.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) represents the most common form of neurodegenerative disorders with only palliative treatments currently available. Amyloid plaque formation caused by amyloid-β (Aβ) aggregation and neurofibrillary tangle formation caused by hyperphosphorylated tau are hallmarks for the development of AD. The 37 kDa/67 kDa laminin receptor (LRP/LR) has been implicated in AD and tools blocking or downregulating LRP/LR impede amyloid plaque formation in vitro and in vivo . We have recently shown that LRP::FLAG enhances telomerase activity with a concomitant reduction of senescent markers. Here, we overexpressed LRP::FLAG in HEK293 and SH-SY5Y cells, which resulted in an increase in hTERT levels …as well as increased telomerase activity and increased cell viability in the presence of cytotoxic levels of exogenous Aβ. LRP::FLAG overexpression decreased Aβ shedding and intracellular Aβ levels in HEK293 cells. This suggests that LRP::FLAG rescues cells from Aβ-induced cytotoxicity through increased telomerase activity. This study recommends LRP::FLAG as a novel alternative therapeutic for AD treatment through activation of telomerase activity. Show more

Keywords: Alzheimer’s disease, amyloid-β, 37 kDa/67 kDa laminin receptor (LRP/LR), telomerase, TERT

DOI: 10.3233/JAD-190075

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 729-741, 2019