Journal of Alzheimer's Disease - Volume 41, issue 4

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Scientists working in the fields of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review “Cognitive enhancers (nootropics): drugs interacting with receptors” was accepted for publication in July 2012. Since then, new targets for the potential treatment of Alzheimer's disease were identified. This update describes drugs interacting with 42 receptors versus 32 receptors in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through March 2014.

Keywords: Alzheimer's disease, cognitive enhancers, memantine, memory, nootropics, receptors

DOI: 10.3233/JAD-140228

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 961-1019, 2014

Authors: Ethell, Douglas W.

Article Type: Research Article

Abstract: Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal …submucosa. Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas—among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis—all of which have been linked to AD risk. Problems with CSF-mediated clearance could also provide a link between these seemingly disparate factors and familial AD mutations that induce plaque and tangle formation. I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrospinal fluid, neurodegenerative disorder, olfactory bulb

DOI: 10.3233/JAD-130659

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1021-1030, 2014

Authors: Miyashita, Akinori | Wen, Yanan | Kitamura, Nobutaka | Matsubara, Etsuro | Kawarabayashi, Takeshi | Shoji, Mikio | Tomita, Naoki | Furukawa, Katsutoshi | Arai, Hiroyuki | Asada, Takashi | Harigaya, Yasuo | Ikeda, Masaki | Amari, Masakuni | Hanyu, Haruo | Higuchi, Susumu | Nishizawa, Masatoyo | Suga, Masaichi | Kawase, Yasuhiro | Akatsu, Hiroyasu | Imagawa, Masaki | Hamaguchi, Tsuyoshi | Yamada, Masahito | Morihara, Takashi | Takeda, Masatoshi | Takao, Takeo | Nakata, Kenji | Sasaki, Ken | Watanabe, Ken | Nakashima, Kenji | Urakami, Katsuya | Ooya, Terumi | Takahashi, Mitsuo | Yuzuriha, Takefumi | Serikawa, Kayoko | Yoshimoto, Seishi | Nakagawa, Ryuji | Saito, Yuko | Hatsuta, Hiroyuki | Murayama, Shigeo | Kakita, Akiyoshi | Takahashi, Hitoshi | Yamaguchi, Haruyasu | Akazawa, Kohei | Kanazawa, Ichiro | Ihara, Yasuo | Ikeuchi, Takeshi | Kuwano, Ryozo

Article Type: Short Communication

Abstract: Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002–0.0059); however, no significant association with LOAD was observed in these variants. Considering …low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese. Show more

Keywords: Alzheimer's disease, Japanese, rare variants, SNP, TREM2

DOI: 10.3233/JAD-140225

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1031-1038, 2014

Authors: Sun, Jiya | Song, Fuhai | Wang, Jiajia | Han, Guangchun | Bai, Zhouxian | Xie, Bin | Feng, Xuemei | Jia, Jianping | Duan, Yong | Lei, Hongxing

Article Type: Research Article

Abstract: Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency …of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD. Show more

Keywords: Alzheimer's disease, generalized multifactor dimensionality reduction, genetic risk, high-order, intragenic epistasis

DOI: 10.3233/JAD-140054

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1039-1056, 2014

Authors: Brandner, Sebastian | Thaler, Christian | Lelental, Natalia | Buchfelder, Michael | Kleindienst, Andrea | Maler, Juan Manuel | Kornhuber, Johannes | Lewczuk, Piotr

Article Type: Research Article

Abstract: Background: Little information is available on the rostro-caudal concentration gradient of Alzheimer’s disease (AD) biomarkers. Objective: We studied the concentrations of amyloid-β (Aβ) peptides 1-42 and 1-40 as well as the Tau and pTau proteins in simultaneously collected ventricular and lumbar cerebrospinal fluid (CSF) samples. Methods: The samples were simultaneously collected from the ventricle and the lumbar spinal canal in two groups of patients: 10 subjects being treated for normal pressure hydrocephalus (NPH) by the placement of a ventriculo-peritoneal shunt and 5 patients treated simultaneously with an external ventricular drain and a lumbar CSF drain due …to posttraumatic hydrocephalus (PTH). Results: The ventricular-lumbar (V/L) concentration ratio for Aβ1-40 was 0.81 in NPH patients and 0.71 in PTH patients. The V/L-ratio for Aβ1-42 was 0.84 in NPH, reflecting significantly higher concentrations in lumbar CSF than in ventricular CSF, and 1.02 in PTH patients. The V/L-ratios for Tau and pTau differed significantly depending on the diagnostic group: the median V/L-ratio for Tau was 6.83 in NPH patients but only 0.97 in PTH patients. The median V/L-ratio for pTau was 2.36 in NPH patients and 0.91 in PTH patients. Conclusions: We conclude that the rostro-caudal concentration gradient for brain-derived proteins (Tau and pTau in this study) depends on the diagnosis and clinical status of the patient, which were largely neglected in the previously postulated models. Show more

Keywords: Amyloid-β, biomarker, cerebrospinal fluid, rostro-caudal gradient, tau

DOI: 10.3233/JAD-132708

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1057-1062, 2014

Authors: Szigeti, Kinga | Kellermayer, Blanka | Lentini, Jenna M. | Trummer, Brian | Lal, Deepika | Doody, Rachelle S. | Yan, Li | Liu, Song | Ma, Changxing | The Texas Alzheimer Research and Care Consortium

Article Type: Research Article

Abstract: Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer's disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15 : 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor …that facilitates amyloid-β1-42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets. Show more

Keywords: Age at onset, Alzheimer's disease, copy number variation

DOI: 10.3233/JAD-132693

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1063-1071, 2014

Authors: Hernández-Rodríguez, Maricarmen | Correa-Basurto, José | Martínez-Ramos, Federico | Padilla-Martínez, Itzia Irene | Benítez-Cardoza, Claudia G. | Mera-Jiménez, Elvia | Rosales-Hernández, Martha Cecilia

Article Type: Research Article

Abstract: Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were …designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models. Show more

Keywords: Acetylcholinesterase, Alzheimer's disease, amyloid-β, β-site AβPP cleaving enzyme 1, inhibitor

DOI: 10.3233/JAD-140471

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1073-1085, 2014

Authors: Blanc, Frederic | Philippi, Nathalie | Cretin, Benjamin | Kleitz, Catherine | Berly, Laetitia | Jung, Barbara | Kremer, Stephane | Namer, Izzie Jacques | Sellal, François | Jaulhac, Benoit | de Seze, Jerome

Article Type: Research Article

Abstract: Introduction: Descriptions of Lyme disease and dementia are rare. Objective: To describe patients with dementia and a positive “intrathecal anti-Borrelia antibody index” (AI), specific for neuroborreliosis. Methods: Among 1,594 patients seen for dementia, we prospectively identified and studied 20 patients (1.25%) with dementia and a positive AI. Patients underwent a battery of neuropsychological tests brain, MRI, FDG-PET, and cerebrospinal fluid (CSF) analysis. An etiological diagnosis of the dementia was made at the end of the follow-up of 5.0 ± 2.9 years. Results: We found two groups of patients with dementia, the first (n = …7, 0.44%) with certain neuroborreliosis and stability or mild improvement of dementia after treatment by antibiotics and the second (n = 13, 0.81%) with progressive worsening of dementia, despite the antibiotics. In the second group, the final diagnoses were Alzheimer’s disease (AD) (n = 4), AD and Lewy body disease (LBD) (n = 3), LBD (n = 1), FTLD (n = 3), hippocampal sclerosis (n = 1), and vascular dementia (n = 1). We did not observe any differences in cognitive test between the two patient groups at baseline. Brain MRI showed more focal atrophy and FDG-PET showed more frontal hypometabolism in the second group. Tau, p-tau, and Aβ42 concentrations in the CSF were normal in the neuroborreliosis group, and coherent with diagnosis in the second. Conclusion: Pure Lyme dementia exists and has a good outcome after antibiotics. It is advisable to do Lyme serology in demented patients, and if serology is positive, to do CSF analysis with AI. Neurodegenerative dementia associated with positive AI also exists, which may have been revealed by the involvement of Borrelia in the CNS. Show more

Keywords: Alzheimer's disease, dementia, frontotemporal lobe dementia, hippocampal sclerosis, intrathecal anti-Borrelia antibody index, Lewy body dementia, Lewy body disease, Lyme disease, Lyme neuroborreliosis, vascular dementia

DOI: 10.3233/JAD-130446

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1087-1093, 2014

Authors: Mowszowski, Loren | Hermens, Daniel F. | Diamond, Keri | Norrie, Louisa | Cockayne, Nicole | Ward, Philip B. | Hickie, Ian B. | Lewis, Simon J.G. | Batchelor, Jennifer | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: With predicted increases in dementia incidence, interventions targeting neuroplasticity and neuroprotection are required. Cognitive Training (CT) is an intervention which has been shown to improve aspects of cognition, but the pathophysiological mechanisms contributing to its efficacy are unknown. Objective: We aimed to explore the neurobiological correlates of CT using Mismatch Negativity (MMN), a neurophysiological marker of pre-attentive information processing, which in turn, is postulated to underpin higher-order cognitive processes. Methods: As part of a larger randomized controlled trial, forty ‘at risk’ (i.e., mild cognitive impairment or late-life depression) participants aged 51–79 years underwent neurophysiological, neuropsychological, …and psychiatric assessments before and after a multi-faceted seven-week CT program or a ‘treatment-as-usual’ seven-week waitlist period. Results: The treatment group demonstrated significantly increased fronto-central MMN responses (p < 0.05), as well as improved phonemic verbal fluency (p < 0.05) and decreased self-rated memory difficulties (p < 0.05) following CT, in comparison to the waitlist control group. However, there were no significant correlations between enhanced MMN and cognitive/psychosocial outcomes. Conclusions: Results from this preliminary investigation indicate that CT is associated with enhanced neurophysiological mechanisms suggestive of improved pre-attentive processing, which may reflect alterations in underlying neurobiology. Further research is warranted to confirm these findings, to explicate whether CT is associated with restorative or compensatory neuroplastic processes and to determine whether MMN is a useful biomarker for treatment response. Show more

Keywords: Cognitive training, late-life depression, mild cognitive impairment, Mismatch Negativity, neurophysiological, neuropsychological

DOI: 10.3233/JAD-131985

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1095-1108, 2014

Authors: Xie, Jing | Gabelle, Audrey | Dorey, Aline | Garnier-Crussard, Antoine | Perret-Liaudet, Armand | Delphin-Combe, Floriane | Bathsavanis, Anthony | Dauphinot, Virginie | Lehmann, Sylvain | Mercier, Bernadette | Desestret, Virginie | Roullet-Solignac, Isabelle | Vighetto, Alain | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) clinical onset is usually characterized by a memory complaint and a progressive memory deficit. The proportion of typical medial-temporal amnesia revealing AD remains unknown. Objective: The present study explores the episodic memory impairment profiles by the Free and Cued Selective Recall Reminding Test (FCSRT) in patients with initial memory complaint and a cerebrospinal fluid (CSF) biomarker signature of AD. Methods: Seventy-three patients referred for memory complaint to the Centers for Memory, Resource and Research of Lyon and Montpellier (France) were included consecutively. All patients underwent an extensive neuropsychological examination and had a …Mini-Mental State Examination (MMSE) score ≥20 and a positive CSF AD signature. The patients were classified as having mild dementia or prodromal AD. Verbal episodic memory was assessed using the French version of the FCSRT exploring encoding, storage/consolidation, and cued delayed retrieval phases of memorization. Three different memory profiles were identified according to the results of FCSRT. Results: The median age was 72 year-old [interquartiles: 65–76]. The median MMSE score was 23 [interquartiles: 21–25]. 88% of the patients (n = 64) presented with a medial temporal amnesia profile. The dysexecutive amnesia and normal verbal episodic memory profiles represented respectively 5% (n = 4) and 7% (n = 5). There were no significant differences in term of age, gender, and MMSE score between the three profile groups. Conclusion: In a population initially presenting with memory complaints and depicting a CSF AD signature, a high proportion of medial temporal amnesia is disclosed as expected, but also a proportion of dysexecutive amnesia and normal FCSRT. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, memory

DOI: 10.3233/JAD-131916

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1109-1116, 2014

Authors: Yang, Meifeng | Lu, Jing | Miao, Junye | Rizak, Joshua | Yang, Jianzhen | Zhai, Rongwei | Zhou, Jun | Qu, Jiagui | Wang, Jianhong | Yang, Shangchuan | Ma, Yuanye | Hu, Xintian | He, Rongqiao

Article Type: Research Article

Abstract: Although methanol toxicity is well known for acute neurological sequelae leading to blindness or death, there is a new impetus to investigate the chronic effects of methanol exposure. These include a recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology. In the present study, mice were fed with methanol to revisit the chronic effects of methanol toxicity, especially as it pertains to AD progression. Three groups of mice (n = 9) were given either water as a control or a methanol solution (concentrations of 2% or 3.8%) over a 6-week period. The methanol-fed mice were found …to have impaired spatial recognition and olfactory memory in Y-maze and olfactory memory paradigms. Immunohistochemical analysis of the mouse brains found increased neuronal tau phosphorylation in the hippocampus and an increased cellular apoptotic marker in hippocampal CA1 neurons (~10% of neurons displayed chromatin condensation) in the methanol-fed groups. Two additional in vitro experiments in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells found that formaldehyde, but not methanol or the methanol end product formic acid, induced microtubule disintegration and tau protein hyperphosphorylation. The findings of the behavioral tests and immunohistochemical analysis suggested that the methanol-fed mice presented with partial AD-like symptoms. The in vitro experiments suggested that formaldehyde was most likely the detrimental component of methanol toxicity related to hippocampal tau phosphorylation and the subsequent impaired memory in the mice. These findings add to a growing body of evidence that links formaldehyde to AD pathology. Show more

Keywords: Alzheimer's disease, cognitive impairment, disease progression, formaldehyde, methanol, tau hyperphosphorylation

DOI: 10.3233/JAD-131529

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1117-1129, 2014

Authors: Yang, Meifeng | Miao, Junye | Rizak, Joshua | Zhai, Rongwei | Wang, Zhengbo | Huma, Tanzeel | Li, Ting | Zheng, Na | Wu, Shihao | Zheng, Yingwei | Fan, Xiaona | Yang, Jianzhen | Wang, Jianhong | Yang, Shangchuan | Ma, Yuanye | Lü, Longbao | He, Rongqiao | Hu, Xintian

Article Type: Research Article

Abstract: A recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology has provided a new impetus to investigate the chronic effects of methanol exposure. This paper expands this investigation to the non-human primate, rhesus macaque, through the chronic feeding of young male monkeys with 3% methanol ad libitum. Variable Spatial Delay Response Tasks of the monkeys found that the methanol feeding led to persistent memory decline in the monkeys that lasted 6 months beyond the feeding regimen. This change coincided with increases in tau protein phosphorylation at residues T181 and S396 in cerebrospinal fluid during feeding as …well as with increases in tau phosphorylated aggregates and amyloid plaques in four brain regions postmortem: the frontal lobe, parietal lobe, temporal lobe, and the hippocampus. Tau phosphorylation in cerebrospinal fluid was found to be dependent on methanol feeding status, but phosphorylation changes in the brain were found to be persistent 6 months after the methanol feeding stopped. This suggested the methanol feeding caused long-lasting and persistent pathological changes that were related to AD development in the monkey. Most notably, the presence of amyloid plaque formations in the monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defenses in mice against methanol toxicity may have limited previous investigations into AD pathology. Nonetheless, these findings support a growing body of evidence that links methanol and its metabolite formaldehyde to AD pathology. Show more

Keywords: Alzheimer's disease, amyloid plaque formation, cognitive impairment, disease progression, formaldehyde, methanol toxicity, tau hyperphosphorylation

DOI: 10.3233/JAD-131532

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1131-1147, 2014

Authors: Lin, Li | Yang, Shu-Sheng | Chu, Jiang | Wang, Lu | Ning, Lin-Na | Zhang, Teng | Jiang, Qian | Tian, Qing | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Region-specific neurodegeneration was reported in brains of Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we studied the expression of some AD-associated proteins in temporal cortex, frontal cortex, cerebellum, and hippocampus of 4-month-old male Sprague-Dawley rats. Levels of the phosphorylated tau at Thr231, Ser396, and Ser202/Thr205, phosphorylated amyloid-β protein precursor (AβPP) and amyloid-β, synapse-associated proteins glutamate receptors 2, N-methyl-D-aspartic receptors 1 (NR1), NR2A, NR2B, and postsynaptic density protein 95 were much lower in cerebellum, while the levels of total tau, phosphorylated tau at Thr205, Ser214, Ser262, and Ser198/199/202 epitopes, and total AβPP were similar in the four …brain regions. As endoplasmic reticulum (ER) stress was reported in the early stage of AD, we injected tunicamycin, an ER stress inducer, into the lateral ventricular of rats and 48 hours later found in the other three brain regions but not cerebellum, increasing of binding immunoglobulin protein with the increased phosphorylation of pancreatic ER kinase, inositol-requiring enzyme 1, and activating transcription factor 6. Simultaneously, levels of phosphorylated tau at all of the above sites were significantly increased with the activation of glycogen synthase kinase-3β in temporal cortex, frontal cortex, and/or hippocampus, but not cerebellum. The synapse-associated proteins, GluR2, PSD95, and synapsin1, were found decreased in the hippocampus after tunicamycin exposure. These data together may partially explain why the AD-like neuropathology, such as formation of neurofibrillary tangles, was rarely detected in cerebellum. Show more

Keywords: Cerebellum, endoplasmic reticulum stress, frontal cortex, hippocampus, synaptic protein, tau, temporal cortex

DOI: 10.3233/JAD-140207

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1149-1163, 2014

Authors: Qiao, Feng | Gao, Xiu-Ping | Yuan, Li | Cai, Hong-Yan | Qi, Jin-Shun

Article Type: Research Article

Abstract: Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the …CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+ /calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4. Show more

Keywords: Apolipoprotein E4, Ca2+/calmodulin-dependent protein kinase II (CaMKII), cAMP response element-binding protein (CREB), hippocampus, late-phase long-term potentiation, synaptic plasticity

DOI: 10.3233/JAD-140375

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1165-1176, 2014

Authors: Fu, YuHong | Rusznák, Zoltán | Kwok, John B.J. | Kim, Woojin Scott | Paxinos, George

Article Type: Research Article

Abstract: The J20 mouse expresses human mutant amyloid-β protein precursor (hAβPPSwInd) and is an established transgenic model of Alzheimer's disease (AD). From the age of 5 months, amyloid-β (Aβ) deposits appear in the hippocampus with concomitant increase of AD-associated features. Although changes occurring after the appearance of Aβ deposits have been extensively studied, very little is known about alterations that occur prior to 5 months. The present study aimed to identify changes in the cellular composition and proliferative potential of the J20 hippocampus using 1–18-month-old mice. Neuronal, non-neuronal, Ki-67+, and TUNEL+ cell numbers were counted with the isotropic fractionator method. Age-dependent …changes of the expression of microglia-, astrocyte-, and neurogenesis-specific markers were sought in the entire hippocampus. Several transgene-associated changes were revealed before the appearance of Aβ deposits. The number of proliferating cells decreased whereas the number of microglia clusters increased as early as 4 weeks of age. The neurogenesis was also impaired in the dentate gyrus of 7–11-week-old J20 mice. A statistically significant negative correlation was found between the number of proliferating cells and age in both populations, but the time course of the age-dependence was steeper in wild-type than in J20 mice. Negative age-dependence was noted when the number of cells committed to apoptosis was examined. Our results indicate that overexpression of mutant hAβPP initiates a cascade of pathologic events well before the appearance of visible Aβ plaques. Accordingly, early signs of AD include reduced cell proliferation, impaired neurogenesis, and increased activity of microglia in the hippocampus. Show more

Keywords: Alzheimer's disease, cellular constituents, hippocampus, J20, neurogenesis, microglia, proliferation

DOI: 10.3233/JAD-132717

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1177-1192, 2014

Authors: Zhang, Ling | Liu, Cui | Wu, Jie | Tao, Jing-jing | Sui, Xiao-long | Yao, Zhi-gang | Xu, Yan-feng | Huang, Lan | Zhu, Hua | Sheng, Shu-li | Qin, Chuan

Article Type: Research Article

Abstract: Histone deacetylase 6 (HDAC6) is currently being discussed as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Mounting evidence indicates that increased HDAC6 expression may contribute to AD-associated neurodegeneration, although beneficial effects have also been identified. In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 …not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. Further, the decreased hyperphosphorylated tau and increased tubulin acetylation may account for the improved microtubule stability in AD mice after tubastatin A/ACY-1215 treatment. These preclinical results support the detrimental role of HDAC6 in AD, and offer prospective approaches for using tubastatin A/ACY-1215 as potential therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid, autophagy, histone deacetylase (HDAC), tau

DOI: 10.3233/JAD-140066

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1193-1205, 2014

Authors: Waragai, Masaaki | Hata, Saori | Suzuki, Toshiharu | Ishii, Ryotaro | Fujii, Chihiro | Tokuda, Takahiko | Arai, Hiroyuki | Ohrui, Takashi | Higuchi, Susumu | Yoshida, Madoka | Igarashi, Kazuei | Moriya, Masaru | Iwai, Naomichi | Uemura, Kenichi

Article Type: Research Article

Abstract: We validated the utility of SPM8 plus DARTEL (VSRAD) combined with magnetic resonance spectroscopy (1 H MRS) as an adjunct screening technique for dementia due to Alzheimer's disease (AD). We examined the posterior cingulate gyri of 228 subjects using VSRAD and 1 H MRS in addition to conventional cerebrospinal fluid biomarkers at baseline. At the 3-year follow-up, the 228 subject were classified as follows: 93 healthy subjects, 42 MCI-non-converters (MCI-NC), 25 MCI-converters to AD (MCI-C), 44 AD, 8 dementia with Lewy bodies (DLB), 5 normal pressure hydrocephalus, and 11 patients with other neurological diseases. Our results demonstrated that subjects with …increased medial temporal atrophy (MTA) severity on VSRAD, increased Cho/Cr, MI/Cr ratio, and decreased NAA/Cr and NAA/MI ratio on 1 H MRS at baseline were at risk of dementia due to AD. Receiver operating characteristic analysis showed that severity of MTA and the NAA/MI ratio distinguished patients with AD and MCI-C from controls. Furthermore, the 118 subjects without dementia and MTA showing only a decreased NAA/MI ratio at baseline developed to MCI-C, AD, and DLB 3 years later. 1 H MRS detected biochemical abnormalities preceding brain atrophy and cognitive decline. VSRAD combined with 1 H MRS may be routinely applied to screen for MCI/AD and prodromal AD in clinical practice. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, magnetic resonance spectroscopy (1H MRS), screening, SPM8 plus DARTEL (VSRAD), surrogate marker

DOI: 10.3233/JAD-132786

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1207-1222, 2014

Authors: Taipale, Heidi | Koponen, Marjaana | Tanskanen, Antti | Tolppanen, Anna-Maija | Tiihonen, Jari | Hartikainen, Sirpa

Article Type: Research Article

Abstract: Background: Antipsychotic polypharmacy (APP) is not recommended in treatment of behavioral and psychological symptoms of dementia (BPSD). There is lack of studies concerning prevalence of APP among persons with dementia. Objectives: The objective of our study was to describe prevalence and risk factors associated with antipsychotic polypharmacy among antipsychotic users with Alzheimer’s disease (AD). Methods: Data from nationwide MEDALZ-2005 cohort including all community-dwelling persons diagnosed with AD in Finland was utilized. Register-based data included prescriptions, comorbidities, and hospital discharge diagnoses. Users of antipsychotics during 2006–2009 were included (n = 9,803). The risk of starting antipsychotic polypharmacy …was evaluated with Cox proportional hazards model. Results: Prevalence of antipsychotic polypharmacy was 8% (n = 750) among antipsychotic users (n = 9,803). Quetiapine and risperidone was the most common combination of two antipsychotics followed by combination of quetiapine and haloperidol. Antipsychotic polypharmacy was associated with younger age (HR 1.35 [Confidence Interval, CI, 1.16–1.56]), male gender (HR 1.18 [CI 1.02–1.38]), and history of psychiatric disorder (HR 1.50 [CI 1.26–1.78]) in the adjusted model. Conclusions: In conclusion, we found higher prevalence of APP than previously reported among older populations. This is concerning since effectiveness of APP has not been demonstrated and APP is not recommended in the treatment of BPSD. Clinicians should pay more attention to avoid APP and use of antipsychotics to other indications than BPSD among persons with AD. Show more

Keywords: Alzheimer's disease, antipsychotics, antipsychotic polypharmacy, prescription register

DOI: 10.3233/JAD-140282

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1223-1228, 2014

Authors: Krajcovicova, Lenka | Mikl, Michal | Marecek, Radek | Rektorova, Irena

Article Type: Research Article

Abstract: Changes in connectivity of the posterior node of the default mode network (DMN) were studied when switching from baseline to a cognitive task using functional magnetic resonance imaging. In all, 15 patients with mild to moderate Alzheimer's disease (AD) and 18 age-, gender-, and education-matched healthy controls (HC) participated in the study. Psychophysiological interactions analysis was used to assess the specific alterations in the DMN connectivity (deactivation-based) due to psychological effects from the complex visual scene encoding task. In HC, we observed task-induced connectivity decreases between the posterior cingulate and middle temporal and occipital visual cortices. These findings imply successful …involvement of the ventral visual pathway during the visual processing in our HC cohort. In AD, involvement of the areas engaged in the ventral visual pathway was observed only in a small volume of the right middle temporal gyrus. Additional connectivity changes (decreases) in AD were present between the posterior cingulate and superior temporal gyrus when switching from baseline to task condition. These changes are probably related to both disturbed visual processing and the DMN connectivity in AD and reflect deficits and compensatory mechanisms within the large scale brain networks in this patient population. Studying the DMN connectivity using psychophysiological interactions analysis may provide a sensitive tool for exploring early changes in AD and their dynamics during the disease progression. Show more

Keywords: Alzheimer's disease, default mode network, functional MRI, posterior cingulate, visual processing

DOI: 10.3233/JAD-131208

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1229-1238, 2014

Authors: Vecchio, Fabrizio | Miraglia, Francesca | Bramanti, Placido | Rossini, Paolo Maria

Article Type: Research Article

Abstract: Modern analysis of electroencephalographic (EEG) rhythms provides information on dynamic brain connectivity. To test the hypothesis that aging processes modulate the brain connectivity network, EEG recording was conducted on 113 healthy volunteers. They were divided into three groups in accordance with their ages: 36 Young (15–45 years), 46 Adult (50–70 years), and 31 Elderly (>70 years). To evaluate the stability of the investigated parameters, a subgroup of 10 subjects underwent a second EEG recording two weeks later. Graph theory functions were applied to the undirected and weighted networks obtained by the lagged linear coherence evaluated by eLORETA on cortical sources. …EEG frequency bands of interest were: delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10.5 Hz), alpha2 (10.5–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30–40 Hz). The spectral connectivity analysis of cortical sources showed that the normalized Characteristic Path Length (λ) presented the pattern Young > Adult>Elderly in the higher alpha band. Elderly also showed a greater increase in delta and theta bands than Young. The correlation between age and λ showed that higher ages corresponded to higher λ in delta and theta and lower in the alpha2 band; this pattern reflects the age-related modulation of higher (alpha) and decreased (delta) connectivity. The Normalized Clustering coefficient (γ) and small-world network modeling (σ) showed non-significant age-modulation. Evidence from the present study suggests that graph theory can aid in the analysis of connectivity patterns estimated from EEG and can facilitate the study of the physiological and pathological brain aging features of functional connectivity networks. Show more

Keywords: Delta and alpha bands, EEG, eLORETA, functional connectivity, graph theory, small-world networks

DOI: 10.3233/JAD-140090

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1239-1249, 2014

Authors: Mukaetova-Ladinska, Elizabeta B. | Krsteska, Roza | Vaskova, Olivija | Makazlieva, Tanja | Tsolaki, Magda

Article Type: Meeting Report

Abstract: We present a report on the recent symposium on dementia and depression in older adults, held in Ohrid, Macedonia and discuss the urgent need for development of psychogeriatric and affiliated services in the Southeast European region. The limited epidemiological data from nine countries in this region suggest high variability of prevalence rates for mental health problems in older adults (>65 years of age). At the moment, there are over 520,000 older adults in the region living with dementia alone. The prevalence rates for dementia (%) are either similar to those of the developed countries (9–9.6% in build-up northern Greece and …Albania, respectively) or substantially lower (3.6–4% in rural northern Greece and Montenegro, respectively). The latter may be due to either cultural diversity or lack of adequate medical health service provision and expertise to recognize and diagnose dementia. Indeed, there is a lack of organized specialized services for older adults with mental health problem in the region. The symposium raised the awareness of this problem in the region and called for networking between isolated individuals working in this field to improve the current situation and facilitate further development of adequate clinical services to meet the growing needs of the older adults in the countries of the Southeast Europe. Show more

Keywords: Dementia, depression, older adults, Southeast Europe

DOI: 10.3233/JAD-131640

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1251-1260, 2014

Article Type: Other

DOI: 10.3233/JAD-140091B

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1261-1262, 2014

Article Type: Other

DOI: 10.3233/JAD-2014-41423

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1263-1275, 2014