Journal of Alzheimer's Disease - Volume 53, issue 1

Authors: Amen, Daniel G. | Willeumier, Kristen | Omalu, Bennet | Newberg, Andrew | Raghavendra, Cauligi | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: National Football League (NFL) players are exposed to multiple head collisions during their careers. Increasing awareness of the adverse long-term effects of repetitive head trauma has raised substantial concern among players, medical professionals, and the general public. Objective: To determine whether low perfusion in specific brain regions on neuroimaging can accurately separate professional football players from healthy controls. Method: A cohort of retired and current NFL players (n  = 161) were recruited in a longitudinal study starting in 2009 with ongoing interval follow up. A healthy control group (n  = 124) was separately recruited for comparison. …Assessments included medical examinations, neuropsychological tests, and perfusion neuroimaging with single photon emission computed tomography (SPECT). Perfusion estimates of each scan were quantified using a standard atlas. We hypothesized that hypoperfusion particularly in the orbital frontal, anterior cingulate, anterior temporal, hippocampal, amygdala, insular, caudate, superior/mid occipital, and cerebellar sub-regions alone would reliably separate controls from NFL players. Cerebral perfusion differences were calculated using a one-way ANOVA and diagnostic separation was determined with discriminant and automatic linear regression predictive models. Results: NFL players showed lower cerebral perfusion on average (p  < 0.01) in 36 brain regions. The discriminant analysis subsequently distinguished NFL players from controls with 90% sensitivity, 86% specificity, and 94% accuracy (95% CI 95-99). Automatic linear modeling achieved similar results. Inclusion of age and clinical co-morbidities did not improve diagnostic classification. Conclusion: Specific brain regions commonly damaged in traumatic brain injury show abnormally low perfusion on SPECT in professional NFL players. These same regions alone can distinguish this group from healthy subjects with high diagnostic accuracy. This study carries implications for the neurological safety of NFL players. Show more

Keywords: Brain imaging, cognition, concussion, football, NFL, SPECT, traumatic brain injury

DOI: 10.3233/JAD-160207

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 237-241, 2016

Authors: Maliszewska-Cyna, Ewelina | Xhima, Kristiana | Aubert, Isabelle

Article Type: Research Article

Abstract: Evidence suggests that physical exercise can serve as a preventive strategy against Alzheimer’s disease (AD). In contrast, much less is known about the impact of exercise when it is introduced after cognitive deficits are established. Using the TgCRND8 mouse model of amyloidosis, we compared the effects of exercise as an intervention strategy aimed at altering disease progression. Voluntary running for 1 month or 2 months was introduced in 3-month-old TgCRND8 mice, which exhibit amyloid-beta (Aβ) plaque pathology and cognitive deficits at this age. Specifically, we examined Aβ plaque load, spatial memory, and neurogenesis in the dentate gyrus in the hippocampus. …After 1 month of running, TgCRND8 mice spent more time in the novel arm of the Y-maze compared to the familiar arms, indicating improved memory. The levels of doublecortin (a marker of immature neurons) were increased in TgCRND8 mice running for 1 month, but with no significant difference in the number of new mature neurons or plaque burden. As the disease progressed, running prevented further deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology in TgCRND8 mice running for 2 months, compared to non-running transgenics. Therefore, the impact of running on memory, neurogenesis, and amyloid pathology was of greater significance when sustained through later stages of the disease. Show more

Keywords: Alzheimer’s disease, amyloid pathology, neurogenesis, physical exercise, spatial memory

DOI: 10.3233/JAD-150660

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 243-257, 2016

Authors: Verma, Nirmal | Ly, Han | Liu, Miao | Chen, Jing | Zhu, Haining | Chow, Martin | Hersh, Louis B. | Despa, Florin

Article Type: Research Article

Abstract: Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated amylin also accumulates in brains of Alzheimer’s disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. …Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD. Show more

Keywords: Alzheimer’s disease, amylin, 4-hydroxynonenal, malondialdehyde, neuroinflammation, type-2 diabetes

DOI: 10.3233/JAD-160047

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 259-272, 2016

Authors: Lovell, Mark A. | Lynn, Bert C. | Fister, Shuling | Bradley-Whitman, Melissa | Murphy, M. Paul | Beckett, Tina L. | Norris, Christopher M.

Article Type: Research Article

Abstract: Because traditional approaches to drug development for Alzheimer’s disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment …leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer’s disease. Show more

Keywords: Amyloid-β protein precursor, Elk-1, presenilin-1, presenilin-2

DOI: 10.3233/JAD-151160

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 273-287, 2016

Authors: Bobkova, Natalia | Vorobyov, Vasily | Medvinskaya, Natalia | Nesterova, Inna | Tatarnikova, Olga | Nekrasov, Pavel | Samokhin, Alexander | Deev, Alexander | Sengpiel, Frank | Koroev, Dmitry | Volpina, Olga

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n  = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the …loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155–164 and 167–176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients. Show more

Keywords: Acetyltransferase, amyloid-beta, cholinergic mediation, Morris water maze, olfactory bulbectomy, spatial memory

DOI: 10.3233/JAD-160146

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 289-301, 2016

Authors: Luis, Elkin | Ortiz, Alexandra | Eudave, Luis | Ortega-Cubero, Sara | Borroni, Barbara | van der Zee, Julie | Gazzina, Stefano | Caroppo, Paola | Rubino, Elisa | D’Agata, Federico | Le Ber, Isabelle | Santana, Isabel | Cunha, Gil | Almeida, Maria R. | Boutoleau-Bretonnière, Claire | Hannequin, Didier | Wallon, David | Rainero, Innocenzo | Galimberti, Daniela | Van Broeckhoven, Christine | Pastor, Maria A. | Pastor, Pau

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1 ), among other genes. Rare SQSTM1 gene mutations have been associated with Paget’s disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 …pathogenic variants (FTD/SQSTM1 mutation carriers; n  = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD ; n  = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n  = 20). The groups were matched according to current age, disease duration, and gender. Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern. Show more

Keywords: Dementia, frontotemporal dementia, SQSTM1 protein, voxel-based morphometry

DOI: 10.3233/JAD-160006

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 303-313, 2016

Authors: Ueda, Yukito | Satoh, Masayuki | Tabei, Ken-ichi | Kida, Hirotaka | Ii, Yuichiro | Asahi, Masaru | Maeda, Masayuki | Sakuma, Hajime | Tomimoto, Hidekazu

Article Type: Research Article

Abstract: Background: Lobar microbleeds (MBs) and cortical microinfarct (CMI) are caused by cerebral amyloid angiopathy in the elderly and increase in number in Alzheimer’s disease. Objective: The aim of this study is to elucidate the effects of lobar MBs and CMIs on cognitive function. Methods: The subjects were outpatients who visited the memory clinic of Mie University Hospital. Among 120 subjects, 109 patients fulfilled the inclusion criteria. We quantitatively estimated MBs and CMIs using double inversion recovery and 3D FLAIR images of 3T MRI. Neuropsychological assessments included intellectual, memory, constructional, and frontal lobe function. Results: …Of the 109 patients, MBs and CMIs were observed in 68 (62%) and 17 (16%) subjects, respectively. Of the 68 patients with MBs, lobar MBs were found in 28, deep MBs in 8 and mixed MBs in 31. In each age group, the number of MBs increased in patients with CMI (CMI+ group) than those without CMI (CMI– group), and MBs and CMIs additively decreased MMSE scores. In psychological screens, the MBs+ group with more than 10 MBs showed significantly lower scores of category- and letter-WF than MB- group. The CMI+ group showed significantly worse scores than CMI– group in Japanese Raven’s coloured progressive matrices, Trail Making Test-A, category- and letter-word fluency and copy and drawing of figures. Conclusion: Lobar MBs and CMIs in the elderly frequently coexisted with each other and additively contributed to cognitive impairment, which is mainly predisposed to frontal lobe function. Show more

Keywords: Bleeding, cerebral amyloid angiopathy, dementia, infarct, magnetic resonance imaging, neuropsychological test

DOI: 10.3233/JAD-151008

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 315-325, 2016

Authors: Paholpak, Pongsatorn | Li-Jung, Liang | Carr, Drew R. | Jimenez, Elvira | Barrows, Robin J. | Sabodash, Valeiry | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: Gaze and eye contact is a critical aspect of social interaction. Patients with behavioral variant frontotemporal dementia (bvFTD) may exhibit abnormally prolonged stare toward human faces. Objective: To study characteristics of social gaze in patients with bvFTD compared to age and education matched-patients with early-onset Alzheimer’s disease (eAD) and healthy controls (HC). Method: Fifty picture stimuli were presented to each participant (bvFTD = 12, eAD = 18, HC = 13). Each stimuli contained two properties: face (facial versus non-facial) and valence (positive, negative, and neutral). The “facial” stimuli contained human faces. The participants Visual Fixation Time (VFT) was measured for …each picture stimuli of interest (per facial expressions on the Facial Action Coding System). A linear mixed-effects regression model with participant-level of random effects was used to compare VFTs between groups. Results: The patients with bvFTD showed significantly prolonged VFTs to faces than the patients with eAD and the HC, regardless of valence (all p  < 0.01). There were no differences in VFTs for non-facial stimuli between patients with bvFTD and eAD. However, patients with bvFTD and eAD had significantly prolonged VFTs to negative non-facial stimuli than the HC (p  = 0.006 and 0.019, respectively). Conclusion: Patients with bvFTD exhibited a prolonged stare toward human faces. This prolonged visual facial grasp may contribute to the disturbed social interactions of patients with bvFTD and can help distinguish them from those with Alzheimer’s disease and other conditions. Additionally, both dementia groups tended to stare at negative stimuli whether faces or non-faces. Show more

Keywords: Alzheimer’s disease, eye movements, frontotemporal dementia, social behavior

DOI: 10.3233/JAD-150864

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 327-335, 2016

Authors: Hascup, Kevin N. | Hascup, Erin R.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-β (Aβ)42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), Aβ42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because Aβ42 binds the α 7 nicotinic acetylcholine receptors (α7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of Aβ42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6–9 month old male C57BL/6J …mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50×100μm) and minimal damage to the surrounding parenchyma (50–100μm). Local application of Aβ42 (0.01, 0.1, 1.0, and 10.0μM; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0μM Aβ42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0μM Aβ42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0μM α -Bungarotoxin, the potent α 7nAChR antagonist. Coapplication of 10.0μM tetrodotoxin, indicates Aβ42 -  induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric Aβ42 isoform evokes glutamate release through the α 7nAChR and varies across hippocampal subfields. Show more

Keywords: Alpha bungarotoxin, Alzheimer’s disease, amyloid-beta, biosensor, cognition, hippocampus, neurotransmission, nicotinic acetylcholine receptor, presynaptic, tetrodotoxin

DOI: 10.3233/JAD-160041

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 337-347, 2016

Authors: Tajeddinn, Walid | Persson, Torbjörn | Calvo-Garrido, Javier | Seed Ahmed, Mohammed | Maioli, Silvia | Vijayaraghavan, Swetha | Kazokoglu, Mehmet Selim | Parrado-Fernández, Cristina | Yoshitake, Takashi | Kehr, Jan | Francis, Paul | Winblad, Bengt | Höglund, Kina | Cedazo-Minguez, Angel | Aarsland, Dag

Article Type: Research Article

Abstract: Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer’s disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), …SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p  < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p  > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression. Show more

Keywords: 5-HT1B receptor, Alzheimer’s disease, APPswe, MAOA, p11, serotonin, SERT

DOI: 10.3233/JAD-160046

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 349-361, 2016

Article Type: Other

DOI: 10.3233/JAD-160381

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 363-366, 2016