Journal of Alzheimer's Disease - Volume 42, issue 3

Authors: Villarreal, Alcibiades E. | Barron, Rachel | Rao, K.S. | Britton, Gabrielle B.

Article Type: Review Article

Abstract: Persistent systemic hypoxia, a direct consequence of alterations in vascular function, can compromise the brain by increasing the risk of developing dementias such as Alzheimer's disease (AD). Vascular contributions to cognitive impairment and AD in aged individuals are common, and several vascular risk factors for AD are linked to hypoxia. Clinical evidence confirms that structural and functional changes characteristic of AD pathology also occur following hypoxic-ischemic events such as stroke and traumatic brain injury. Studies with transgenic and non-transgenic mouse models reliably show that hypoxia increases the levels of amyloid-β peptides that form the characteristic plaques in AD brains. Moreover, …some studies suggest that vascular lesions also promote tau phosphorylation, modulate apolipoprotein E expression, and have more profound effects in aged animals, but additional evidence is needed to establish these findings. Although the mechanisms underlying hypoxia-related effects remain unclear, controlled animal studies continue to reveal mechanistic aspects of the relationship between hypoxia and AD pathology that are necessary for therapeutic developments. The present review summarizes evidence from rodent studies regarding the effects of hypoxia on AD-related pathology and evaluates its impact on understanding human disease. Show more

Keywords: Amyloid-β, apolipoprotein E, cerebral amyloid angiopathy, cerebral hypoxia, ischemia, tau protein

DOI: 10.3233/JAD-140144

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 707-722, 2014

Authors: Singhrao, Sim K. | Harding, Alice | Simmons, Tal | Robinson, Sarita | Kesavalu, Lakshmyya | Crean, StJohn

Article Type: Review Article

Abstract: Periodontitis is a polymicrobial chronic inflammatory disease of tooth-supporting tissues with bacterial etiology affecting all age groups, becoming chronic in a subgroup of older individuals. Periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola are implicated in the development of a number of inflammatory pathologies at remote organ sites, including Alzheimer's disease (AD). The initial inflammatory hypothesis proposed that AD hallmark proteins were the main contributors of central nervous system (CNS) inflammation. This hypothesis is expanding to include the role of infections, lifestyle, and genetic and environmental factors in the pathogenesis of AD. Periodontal disease (PD) typifies a condition that …encompasses all of the above factors including pathogenic bacteria. These bacteria not only are the source of low-grade, chronic infection and inflammation that follow daily episodes of bacteremia arising from everyday tasks such as brushing, flossing teeth, chewing food, and during dental procedures, but they also disseminate into the brain from closely related anatomical pathways. The long-term effect of inflammatory mediators, pathogens, and/or their virulence factors, reaching the brain systemically or otherwise would, over time, prime the brain's own microglia in individuals who have inherent susceptibility traits. Such susceptibilities contribute to inadequate neutralization of invading agents, upon reaching the brain. This has the capacity to create a vicious cycle of sustained local inflammatory milieu resulting in the loss of cytoarchitectural integrity and vital neurons with subsequent loss of function (deterioration in memory). The possible pathways between PD and AD development are considered here, as well as environmental factors that may modulate/exacerbate AD symptoms. Show more

Keywords: Alzheimer's disease, inflammation, oral health, periodontal disease

DOI: 10.3233/JAD-140387

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 723-737, 2014

Authors: Chi, Song | Yu, Jin-Tai | Tan, Meng-Shan | Tan, Lan

Article Type: Review Article

Abstract: Depression occurs with a high prevalence of up to 50% in patients with Alzheimer's disease (AD) and increases the caregivers' burden. Depression symptoms can precede clinical diagnosis of AD for years or occurs around the onset of AD, although the etiology and pathologic mechanism of depression in AD pathogenesis remain unclear. Here, we provide an overview on recent studies, indicating that genetic factors, neuroanatomic changes, vascular risk factors, and the imbalance of neurotransmitters might contribute to depressive symptoms in AD. Tau pathology and amyloid-β accumulation also correlate with depression in AD. In addition, the alteration of hypothalamic-pituitary-adrenal axis, inflammatory pathway, …and neurotrophin deficiency are the possible biological mechanisms linking depression and AD, and might become the potential targets for AD treatment. Current data support that antidepressants are promising to alleviate the symptom, though the efficacy is controversial. Moreover, antidementia medication and non-pharmacological interventions can be potential choices. In this review, we describe the prevalence and clinical course of depression in AD, analyze the underlying mechanisms, and discuss the possible management strategies for depression in patients with AD. Show more

Keywords: Alzheimer's disease, depression, epidemiology, mechanism, therapy

DOI: 10.3233/JAD-140324

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 739-755, 2014

Authors: Delabio, Roger | Rasmussen, Lucas | Mizumoto, Igor | Viani, Gustavo-Arruda | Chen, Elizabeth | Villares, João | Costa, Isabela-Bazzo | Turecki, Gustavo | Linde, Sandra Aparecido | Smith, Marilia Cardoso | Payão, Spencer-Luiz

Article Type: Short Communication

Abstract: Presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes encode the major component of y–secretase, which is responsible for sequential proteolytic cleavages of amyloid precursor proteins and the subsequent formation of amyloid-β peptides. 150 RNA samples from the entorhinal cortex, auditory cortex and hippocampal regions of individuals with Alzheimer's disease (AD) and controls elderly subjects were analyzed with using real-time rtPCR. There were no differences between groups for PSEN1 expression. PSEN2 was significantly downregulated in the auditory cortex of AD patients when compared to controls and when compared to other brain regions of the patients. Alteration in PSEN2 expression may be …a risk factor for AD. Show more

Keywords: Alzheimer's disease, brain, gene expression, presenilin-1, presenilin-2, γ-secretase

DOI: 10.3233/JAD-140033

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 757-760, 2014

Authors: Manuel, Iván | de San Román, Estíbaliz González | Giralt, M. Teresa | Ferrer, Isidro | Rodríguez-Puertas, Rafael

Article Type: Short Communication

Abstract: The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation …might have therapeutic relevance. Show more

Keywords: Alzheimer's disease, cannabinoid receptors, functional autoradiography, G-protein, ligand binding

DOI: 10.3233/JAD-140492

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 761-766, 2014

Authors: Martin, Sarah B. | Dowling, Amy L.S. | Lianekhammy, Joann | Lott, Ira T. | Doran, Eric | Murphy, M. Paul | Beckett, Tina L. | Schmitt, Frederick A. | Head, Elizabeth

Article Type: Research Article

Abstract: Adults with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by 40 years of age. Synaptophysin (SYN) consistently declines with age and is further reduced with sporadic AD. Thus, we hypothesized that SYN would be reduced in DS with AD. The gene for synaptojanin-1 (SYNJ1), involved in synaptic vesicle recycling, is on chromosome 21. We measured SYN and SYNJ1 in an autopsy series of 39 cases with DS and 28 without DS, along with 7 sporadic AD cases. SYN was significantly lower in DSAD compared with DS alone and similar to sporadic AD. Reduced SYN is associated with AD neuropathology …and with Aβ levels in DS, as is seen in sporadic AD. SYNJ1 was significantly higher in DS and correlated with several measures of Aβ. SYNJ1 was higher in DSAD and significantly higher than SYNJ1 in sporadic AD. Although significantly higher in DS, SYNJ1 is further increased with AD neuropathology suggesting interesting differences in a synapse-associated protein that is overexpressed in trisomy 21. Show more

Keywords: Amyloid-β, neuroinflammation, oligomers, synapses, synaptojanin, synaptophysin, trisomy 21

DOI: 10.3233/JAD-140795

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 767-775, 2014

Authors: Valcárcel-Nazco, Cristina | Perestelo-Pérez, Lilisbeth | Molinuevo, José Luis | Mar, Javier | Castilla, Iván | Serrano-Aguilar, Pedro

Article Type: Research Article

Abstract: Background: The use of cerebrospinal fluid (CSF) biomarkers could facilitate early detection of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI) and the differential diagnosis between AD and non-AD dementias. Objective: To determine the cost-effectiveness of the use of amyloid-β peptide (Aβ42 ), total tau and phosphorylated tau proteins in CSF to diagnose AD in MCI and dementia patients. Methods: An economic evaluation was performed by means of cost-effectiveness analysis comparing two AD diagnostic alternatives: the combined determination of Aβ42 proteins, total tau and phosphorylated tau in CSF as biomarkers of AD, and …the standard clinical diagnosis based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINDS-ADRDA) criteria. A decision analytic model was developed to synthesize the identified evidence and to compare the costs and effectiveness associated with each diagnostic strategy. A probabilistic sensitivity analysis using 2nd order Monte Carlo simulations was performed. Subsequently, acceptability curves were calculated and ANCOVA models were applied to the results of the Monte Carlo simulations in order to identify the parameters that led greater variability in the model outcomes. Results: The use of CSF biomarkers as an early diagnostic strategy of AD in MCI patients is a dominant alternative (less costly and more effective strategy than standard clinical diagnostic criteria). In dementia patients, although there is a higher uncertainty, biomarkers in CSF seem a more cost-effective alternative than standard clinical diagnostic criteria. Conclusions: Detecting AD in MCI patients by determining Aβ42 , total tau and phosphorylated tau proteins biomarkers in CSF is a cost-effective diagnostic alternative. No conclusive results were obtained on dementia patients. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, cost-effectiveness, diagnosis, phosphorylated tau, total tau

DOI: 10.3233/JAD-132216

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 777-788, 2014

Authors: Nissou, Marie-France | Guttin, Audrey | Zenga, Cyril | Berger, François | Issartel, Jean-Paul | Wion, Didier

Article Type: Research Article

Abstract: Epidemiological and experimental studies suggest that 1,25-dihydroxyvitamin D3 (1,25D) plays a neuroprotective role in neurodegenerative diseases including Alzheimer's disease. Most of the experimental data regarding the genes regulated by this hormone in brain cells have been obtained with neuron and glial cells. Pericytes play a critical role in brain function that encompasses their classical function in blood-brain barrier control and maintenance. However, the gene response of brain pericyte to 1,25D remains to be investigated. Analyses of the transcriptomic response of human brain pericytes to 1,25D demonstrate that human brain pericytes in culture respond to 1,25D by regulating genes involved in …the control of neuroinflammation. In addition, pericytes respond to the pro-inflammatory cytokines tumor necrosis factor-α and Interferon-γ by inducing the expression of the CYP27B1 gene which is involved in 1,25D synthesis. Taken together, these results suggest that neuroinflammation could trigger the synthesis of 1,25D by brain pericytes, which in turn respond to the hormone by a global anti-inflammatory response. These findings identify brain pericytes as a novel 1,25D-responsive cell type and provide additional evidence for the potential value of vitamin D in the prevention or therapy of Alzheimer's disease and other neurodegenerative/neuropsychiatric diseases associated with an inflammatory component. Show more

Keywords: Alzheimer's disease, dementia, inflammation, intracrine, neurodegenerative diseases, pericyte, vitamin D

DOI: 10.3233/JAD-140411

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 789-799, 2014

Authors: Mato Abad, Virginia | Quirós, Alicia | García-Álvarez, Roberto | Loureiro, Javier Pereira | Álvarez-Linera, Juan | Frank, Ana | Hernández-Tamames, Juan Antonio

Article Type: Research Article

Abstract: 1 H-MRS variability increases due to normal aging and also as a result of atrophy in grey and white matter caused by neurodegeneration. In this work, an automatic process was developed to integrate data from spectra and high-resolution anatomical images to quantify metabolites, taking into account tissue partial volumes within the voxel of interest avoiding additional spectra acquisitions required for partial volume correction. To evaluate this method, we use a cohort of 135 subjects (47 male and 88 female, aged between 57 and 99 years) classified into 4 groups: 38 healthy participants, 20 amnesic mild cognitive impairment patients, 22 …multi-domain mild cognitive impairment patients, and 55 Alzheimer's disease patients. Our findings suggest that knowing the voxel composition of white and grey matter and cerebrospinal fluid is necessary to avoid partial volume variations in a single-voxel study and to decrease part of the variability found in metabolites quantification, particularly in those studies involving elder patients and neurodegenerative diseases. The proposed method facilitates the use of 1 H-MRS techniques in statistical studies in Alzheimer's disease, because it provides more accurate quantitative measurements, reduces the inter-subject variability, and improves statistical results when performing group comparisons. Show more

Keywords: Alzheimer's disease, dementia, magnetic resonance imaging, magnetic resonance spectroscopy, mild cognitive impairment, myoinositol, N-acetylaspartate

DOI: 10.3233/JAD-140582

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 801-811, 2014

Authors: Serrano, Geidy E. | Sabbagh, Marwan N. | Sue, Lucia I. | Hidalgo, Jose A. | Schneider, Julie A. | Bedell, Barry J. | Van Deerlin, Vivianna M. | Suh, Eunran | Akiyama, Haruhiko | Joshi, Abhinay D. | Pontecorvo, Michael J. | Mintun, Mark A. | Beach, Thomas G.

Article Type: Research Article

Abstract: Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia and amyotrophic lateral sclerosis, and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation, and dysphasia. Positron emission tomography imaging using the amyloid ligand 18 F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the …cerebral cortex, thalamus, and striatum, Braak stage II neurofibrillary degeneration, and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that Alzheimer's disease is the sole cause. Show more

Keywords: Alzheimer's disease, frontotemporal dementia, neuritic amyloid plaques, neurofibrillary degeneration

DOI: 10.3233/JAD-140162

Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 813-821, 2014