Journal of Alzheimer's Disease - Volume 62, issue 4

Authors: Balmik, Abhishek Ankur | Chinnathambi, Subashchandrabose

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz. , amyloid-β plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. …In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin’s pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-β needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection. Show more

Keywords: Alzheimer’s disease, hyperphosphorylation, melatonin, mitochondria, protein aggregation, tau protein

DOI: 10.3233/JAD-170900

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1481-1493, 2018

Authors: Gosztyla, Maya L. | Brothers, Holly M. | Robinson, Stephen R.

Article Type: Review Article

Abstract: The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer’s disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense …molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide. Show more

Keywords: bacteria, bioflocculant, infection, plaque, innate immune system, virus

DOI: 10.3233/JAD-171133

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1495-1506, 2018

Authors: Ghidoni, Roberta | Squitti, Rosanna | Siotto, Mariacristina | Benussi, Luisa

Article Type: Review Article

Abstract: The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42 ), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs …have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics. Show more

Keywords: Alzheimer’s disease, biomarkers, extracellular vesicles/exosomes, trace elements

DOI: 10.3233/JAD-170953

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1507-1518, 2018

Authors: Courtemanche, Hélène | Bigot, Edith | Pichelin, Matthieu | Guyomarch, Béatrice | Boutoleau-Bretonnière, Claire | Le May, Cédric | Derkinderen, Pascal | Cariou, Bertrand

Article Type: Short Communication

Abstract: The role of PCSK9 in Alzheimer’s disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n  = 20) compared to patients without neurodegenerative disorders (non-ND, n  = 11): 2.80 versus 2.30 (p  < 0.005) and 2.83 versus 2.30 ng/mL (p  = NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42 , T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders …rather than specifically in AD. Show more

Keywords: Aβ1-42, cerebrospinal fluid, frontotemporal lobar degeneration, LDL-cholesterol, P-tau, PCSK9, T-tau

DOI: 10.3233/JAD-170993

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1519-1525, 2018

Authors: Stipho, Faissal | Jackson, Robert | Sabbagh, Marwan N.

Article Type: Short Communication

Abstract: Background: Homozygous APOE ɛ 4 status is a well-known risk factor in the development of Alzheimer’s disease (AD). However, other genotypes of APOE have not yet been found to have equal clinical significance. There is a paucity of reports regarding clinically or pathologically described AD in APOE ɛ 2 homozygotes compared to the other alleles. Objective: To notify clinicians that patients with homozygous APOE ɛ 2 are also at risk of developing AD based on results from the largest prospectively gathered registry of brain samples to date. Methods: We …queried the National Alzheimer’s Coordinating Center (NACC) database for autopsy-confirmed AD cases. Of the Uniform Data Set (UDS) participants who are deceased, 5,779 were diagnosed with dementia at their last UDS visit prior to death, and autopsy data is available for 3,518. Results: Of the brains in the NACC database with pathologically confirmed dementia, seven were found to be homozygous for APOE ɛ 2 , which represents only 0.2% of the autopsy-confirmed sample. Furthermore, pathology-confirmed AD represents 29% (2/7) of the APOE ɛ 2/ ɛ 2 patients diagnosed with dementia. Conclusions: Although rare, autopsy-confirmed AD can be present in APOE ɛ 2/ ɛ 2 carriers. Show more

Keywords: Alzheimer’s disease, apolipoprotein, brain-derived neurotrophic factor, corticobasal degeneration, dementia, frontotemporal dementia

DOI: 10.3233/JAD-171060

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1527-1530, 2018

Authors: Jiménez-Altayó, Francesc | Sánchez-Ventura, Judith | Vila, Elisabet | Giménez-Llort, Lydia

Article Type: Short Communication

Abstract: Cardiovascular disease resulting from oxidative stress and inflammation can exacerbate Alzheimer’s disease. This brief report provides the first evidence of compromised small peripheral mesenteric resistance artery (MRA) properties in 15-month-old 3xTg-AD mice. Females showed worse physiologically relevant MRA structural (increased passive external and internal diameters, cross sectional area) and functional (increased active internal diameters) alterations suggesting sex-dependent dysfunctions. At both physiological and high intraluminal pressures, vascular alterations correlated with the anxious-like behavioral profile, in a sex-dependent manner. Finally, the results unveil a crosstalk between peripheral small vessel properties and behavior in both 3xTg-AD mice and age-matched counterparts with normal aging.

Keywords: 3×Tg-AD mice, aging, Alzheimer’s disease, cardiovascular disease, emerging concepts, gender medicine, oxidative stress, peripheral inflammation, small mesenteric resistance arteries, vascular remodeling

DOI: 10.3233/JAD-171019

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1531-1538, 2018

Authors: Hirano, Shigeki | Shinotoh, Hitoshi | Shimada, Hitoshi | Ota, Tsuneyoshi | Sato, Koichi | Tanaka, Noriko | Zhang, Ming-Rong | Higuchi, Makoto | Fukushi, Kiyoshi | Irie, Toshiaki | Kuwabara, Satoshi | Suhara, Tetsuya

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. Objective: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N -[11 C]methylpiperidinyl-4-acetate ([11 C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. Methods: 22 early onset AD (EOAD) with age at onset under 65, …the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11 C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p -value <0.05 on cluster-level and cluster extent over 30 voxels. Results: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann’s area 22, Zmax  = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. Conclusion: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD. Show more

Keywords: Acetylcholinesterase, age, Alzheimer’s disease, parametric analysis, positron emission tomography

DOI: 10.3233/JAD-170749

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1539-1548, 2018

Authors: Reddy, P. Hemachandra | Manczak, Maria | Yin, XiangLing | Reddy, Arubala P.

Article Type: Research Article

Abstract: The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer’s disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant AβPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-β (Aβ) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells. We …found significantly reduced levels of Aβ40 and Aβ42 in mutant AβPP cells treated with SS31, Mdivi1, and SS31+Mdivi1, and the reduction of Aβ42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunction is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treated cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons. Show more

Keywords: Amyloid-β, mitochondrial biogenesis, mitochondrial division inhibitor 1, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial fission, mitochondria-targeted antioxidant SS31, synergistic protective effects

DOI: 10.3233/JAD-170988

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1549-1565, 2018

Authors: Werhane, Madeleine L. | Thomas, Kelsey R. | Edmonds, Emily C. | Bangen, Katherine J. | Tran, My | Clark, Alexandra L. | Nation, Daniel A. | Gilbert, Paul E. | Bondi, Mark W. | Delano-Wood, Lisa | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background/Objective: The APOE ɛ 4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ɛ 4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methods: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants’ informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. …Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE ɛ 4 genotype on cross-sectional and longitudinal FAQ scores, respectively. Results: Adjusting for demographic and clinical covariates, results showed that both APOE ɛ 4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in ɛ 4 non-carriers versus carriers. Conclusion: Results show that, although APOE ɛ 4 status is the prominent predictor of functional difficulty for ɛ 4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging. Show more

Keywords: Activities of daily living, aging, apolipoprotein E4, arterial stiffness, genetic susceptibility

DOI: 10.3233/JAD-170918

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1567-1578, 2018

Authors: Giannouli, Vaitsa | Stamovlasis, Dimitrios | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: The influence of cognitive factors on financial capacity across the dementia spectrum of cognitive aging, Alzheimer’s disease (AD), and mild cognitive impairment (MCI) has been little investigated, while it has not been investigated at all in other types of dementia as well as in extended samples of elders in Greece. Objective: The aim of this study is to investigate financial capacity, to develop a tool, test its psychometric properties, validate, and then test the tool in groups of healthy controls compared to elders with dementia, while examining other facets of their cognitive performance. Methods: 719 …elders from Greece including healthy participants and patients with different types of dementia were examined with Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) and a battery of neuropsychological tests concerning various cognitive functions. Results: Significantly different profiles in the scores and subscores of LCPLTAS for all the groups of dementia patients were found, with a general incapacity finding for all the dementia groups including the MCI patients. Logistic regression showed that Mini-Mental State Examination (MMSE), Geriatric Depression Scale, and Trail Making Part B predicted competence on LCPLTAS for the dementia patients. Persons with MCI and dementia had lower financial knowledge scores than those without cognitive impairment, with MMSE scores below 27 suggestive as an indication of financial incapacity. Conclusion: The LCPLTAS provides information for a strong positive correlation with MMSE, while the use both of MMSE and LCPLTAS as adequate measures of financial (in)capacity is discussed for the Greek legal procedures regarding elder guardianship cases. Show more

Keywords: Alzheimer’s disease, cognition, financial capacity, frontotemporal dementia, healthy elders, mild cognitive impairment, mixed dementia, Parkinson’s disease dementia, vascular dementia

DOI: 10.3233/JAD-170812

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1579-1594, 2018