Journal of Alzheimer's Disease - Volume 72, issue 1

Authors: Fagiani, Francesca | Lanni, Cristina | Racchi, Marco | Pascale, Alessia | Govoni, Stefano

Article Type: Review Article

Abstract: It is now more than two decades since amyloid-β (Aβ), the proteolytic product of the amyloid-β protein precursor (AβPP), was first demonstrated to be a normal and soluble product of neuronal metabolism. To date, despite a growing body of evidence suggests its regulatory role on synaptic function, the exact cellular and molecular pathways involved in Aβ-driven synaptic effects remain elusive. This review provides an overview of the mounting evidence showing Aβ-mediated effects on presynaptic functions and neurotransmitter release from axon terminals, focusing on its interaction with synaptic vesicle cycle. Indeed, Aβ peptides have been found to interact with key presynaptic …scaffold proteins and kinases affecting the consequential steps of the synaptic vesicle dynamics (e.g., synaptic vesicles exocytosis, endocytosis, and trafficking). Defects in the fine-tuning of synaptic vesicle cycle by Aβ and deregulation of key molecules and kinases, which orchestrate synaptic vesicle availability, may alter synaptic homeostasis, possibly contributing to synaptic loss and cognitive decline. Elucidating the presynaptic mechanisms by which Aβ regulate synaptic transmission is fundamental for a deeper comprehension of the biology of presynaptic terminals as well as of Aβ-driven early synaptic defects occurring in prodromal stage of AD. Moreover, a better understating of Aβ involvement in cellular signal pathways may allow to set up more effective therapeutic interventions by detecting relevant molecular mechanisms, whose imbalance might ultimately lead to synaptic impairment in AD. Show more

Keywords: Amyloid-β, intracellular signaling, neurotransmitter release, presynaptic function, SNARE complex, synaptic vesicle cycle

DOI: 10.3233/JAD-190771

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 1-14, 2019

Authors: Rönkkö, Topi | Timonen, Hilkka

Article Type: Review Article

Abstract: Atmospheric nanoparticles can be formed either via nucleation in atmosphere or be directly emitted to the atmosphere. In urban areas, several combustion sources (engines, biomass burning, power generation plants) are directly emitting nanoparticles to the atmosphere and, in addition, the gaseous emissions from the same sources can participate to atmospheric nanoparticle formation. This article focuses on the sources and formation of nanoparticles in traffic-influenced environments and reviews current knowledge on composition and characteristics of these nanoparticles. In general, elevated number concentrations of nanoparticles are very typically observed in traffic-influenced environments. Traffic related nanoparticles can originate from combustion process or from …non-exhaust related sources such as brake wear. Particles originating from combustion process can be divided to three different sources; 1) primary nanoparticles formed in high temperature, 2) delayed primary particles formed as gaseous compounds nucleate during the cooling and dilution process and 3) secondary nanoparticles formed from gaseous precursors via the atmospheric photochemistry. The nanoparticles observed in roadside environment are a complex mixture of particles from several sources affected by atmospheric processing, local co-pollutants and meteorology. Show more

Keywords: Air quality, traffic, nanoparticles, particle emissions

DOI: 10.3233/JAD-190170

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 15-28, 2019

Authors: Thunell, Johanna | Ferido, Patricia | Zissimopoulos, Julie

Article Type: Short Communication

Abstract: We examined how methods used for identifying dementia in administrative claims affected dementia incidence across racial/ethnic populations using a 100% sample of Medicare beneficiaries (n  = 23,793,452). We found levels differed by method from 3.1% annual incidence to 3.6% in 2014. Dementia incidence declined from 2007 to 2014, but choice of method differentially impacted levels and trends by race/ethnicity. Methods using codes for dementia diagnosis and drugs to treat symptoms identified proportionally more Hispanics and Asians with dementia than other race/ethnicities, while codes for dementia diagnosis, drugs, and symptoms identified proportionally more whites and American Indians/Alaska Natives with dementia than other …race/ethnicities. Show more

Keywords: Alzheimer’s disease, dementia, diagnosis, incidence, measurement

DOI: 10.3233/JAD-190310

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 29-33, 2019

Authors: Snowden, Stuart G. | Ebshiana, Amera A. | Hye, Abdul | Pletnikova, Olga | O’Brien, Richard | Yang, An | Troncoso, Juan | Legido-Quigley, Cristina | Thambisetty, Madhav

Article Type: Research Article

Abstract: Background: Cholinesterase inhibitors represent three of the four treatments for Alzheimer’s disease (AD), and target the pathological reduction of acetylcholine levels. Here we aimed to study the role of other neurotransmitter pathways in AD pathology. Objective: This study aimed to determine associations between AD pathology at both symptomatic and asymptomatic stages of disease progression, and the metabolism of a range of non-cholinergic neurotransmitters. Methods: Tissue samples were obtained from three groups, controls, AD, and ‘asymptomatic AD’ (ASYMAD), i.e., cognitively normal individuals that had significant AD neuropathology. Three brain areas were studied, the middle frontal gyrus (MFG), …the inferior temporal gyrus (ITG), and the cerebellum. Results: 12 of 15 metabolites involved in neurotransmitter metabolism were shown to be associated with AD pathology. Decreases in dopamine were most pronounced in the MFG with lower levels seen in the ASYMAD group compared to control (FC = 0.78, p  = 2.9×10–2 ). In the ITG significant changes were seen in GABAergic and serotonin metabolism between control and AD patients; however, these changes were not seen between control and ASYMAD individuals. Conclusion: These results indicate that dopamine could be depleted in brains with AD pathology but intact cognition, while an imbalance of several neurotransmitters is evident in the brains of AD patients. Show more

Keywords: Asymptomatic Alzheimer’s disease, brain, metabolomics, neurotransmitters

DOI: 10.3233/JAD-190577

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 35-43, 2019

Authors: Rajan, Kumar B. | McAninch, Elizabeth A. | Wilson, Robert S. | Weuve, Jennifer | Barnes, Lisa L. | Evans, Denis A.

Article Type: Research Article

Abstract: Background: The association of the APOE ɛ 4 allele with incident Alzheimer’s dementia is higher among European Americans (EAs) than African Americans (AAs), but similar for the rate of cognitive decline. Objective: To examine the racial differences in the association of the APOE ɛ 4 allele with incident Alzheimer’s dementia and cognitive decline. Methods: Using a population-based sample of 5,117 older adults (66% AAs and 63% females), we identified cognitive trajectory groups from a latent class mixed model and examined the association of the APOE ɛ 4 allele with these groups. …Results: The frequency of the APOE ɛ 4 allele was higher among AAs than EAs (37% versus 26%). Four cognitive trajectories were identified: slow, mild, moderate, and rapid. Overall, AAs had a lower baseline global cognition than EAs, and a higher proportion had rapid (7% versus 5%) and moderate (20% versus 15%) decline, but similar mild (44% versus 46%), and lesser slow (29% versus 34%) decline compared to EAs. Additionally, 25% of AAs (13% of EAs) with mild and 5% (<1% of EAs) with slow decline were diagnosed with incident Alzheimer’s dementia. The APOE ɛ 4 allele was associated with higher odds of rapid and moderate decline compared to slow decline among AAs and EAs, but not with mild decline. Conclusions: AAs had lower cognitive levels and were more likely to meet the cognitive threshold for Alzheimer’s dementia among mild and slow decliners, explaining the attenuated association of the ɛ 4 allele with incident Alzheimer’s dementia among AAs. Show more

Keywords: Apolipoproteins E, Alzheimer’s disease, cognitive aging, race relations

DOI: 10.3233/JAD-190538

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 45-53, 2019

Authors: Tsentidou, Glykeria | Moraitou, Despina | Tsolaki, Magda

Article Type: Research Article

Abstract: Cardiovascular health declines with age, due to vascular risk factors, and this leads to an increasing risk of cognitive decline. Mild cognitive impairment (MCI) is defined as the negative cognitive changes beyond what is expected in normal aging. The purpose of the study was to compare older adults with vascular risk factors (VRF), MCI patients, and healthy controls (HC) in main dimensions of cognitive control. The sample comprised a total of 109 adults, aged 50 to 85 (M = 66.09, S.D. = 9.02). They were divided into three groups: 1) older adults with VRF, 2) MCI patients, and 3) healthy controls (HC). VRF and …MCI did not differ significantly in age, educational level, or gender as was the case with HC. The tests used mainly examine inhibition, cognitive flexibility, and working memory processing. Results showed that the VRF group had more Set Loss Errors in drawing designs indicating deficits in establishing cognitive set and in cognitive shifting. MCI patients displayed lower performance in processing. Hence, different types of specific impairments emerge in vascular aging and MCI, and this may imply that discrete underlying pathologies may play a role in the development of somewhat different profiles of cognitive decline. Show more

Keywords: Cardiovascular risk factors, cognitive impairment, inhibitory control, vascular hypothesis of cognitive aging, visuospatial ability, working memory

DOI: 10.3233/JAD-190638

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 55-70, 2019

Authors: Har-Paz, Ilona | Roisman, Nicole | Michaelson, Daniel M. | Moran, Anan

Article Type: Research Article

Abstract: The E4 allele of apolipoprotein (apoE4) is the primary genetic risk factor for late onset Alzheimer’s disease (AD), yet the exact manner in which apoE4 leads to the development of AD is undetermined. Human and animal studies report that apoE4-related memory deficits appear earlier than the AD clinical manifestation, thus suggesting the existence of early, pre-pathological, apoE4 impairments that may later lead to AD onset. While current research regards the hippocampus as the initial and primary effected locus by apoE4, we presently investigate the possibility that apoE4 innately impairs any brain area that requires synaptic plasticity. To test this hypothesis, …we trained young (3-4-month-old) target-replacement apoE3 and apoE4 mice in conditioned taste aversion (CTA) acquisition and extinction learnings— hippocampus-independent learnings that are easily performed at a young age. Synaptic vesicular markers analysis was conducted in the gustatory cortex (GC), basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and hippocampal CA3 to reveal underlying apoE4-related impairments. We have found that young apoE4 mice are severely impaired in CTA acquisition and extinction learning. CTA acquisition impairments were correlated with reduced vGat and vGlut levels in the BLA and GC, but not in the CA3. CTA extinction was correlated with lower synaptophysin and vGlut levels in the mPFC, a central region in CTA extinction. Our results support apoE4-related early-life plasticity impairments that precede the AD clinical manifestations and affect any brain area that depends on extensive plasticity; early impairments that may promote the development of AD pathologies later in life. Show more

Keywords: Apolipoprotein E, basolateral amygdala, conditioned taste aversion, extinction, gustatory cortex, hippocampus, learning, medial prefrontal cortex, synaptic plasticity, synaptophysin, taste, vesicular GABA transporter, vesicular glutamate transporter, young age

DOI: 10.3233/JAD-190564

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 71-82, 2019

Authors: Pang, Ruiqi | Wang, Xiaofan | Pei, Feifei | Zhang, Weizhe | Shen, Jiaming | Gao, Xiaoqun | Chang, Cheng

Article Type: Research Article

Abstract: Brain energy metabolic impairment is one of the main features of Alzheimer’s disease (AD) and is considered an underlying factor involved in cognitive impairment. Therefore, brain energy metabolism may represent a new therapeutic target for AD medical interventions. Among nutrients providing energy, glucose, the primary energy source, cannot cross the blood-brain barrier freely without specific glucose transporters (GLUTs), which are essential for the maintenance of cerebral energy metabolism homeostasis. Several converging lines of evidence suggest that GLUT1 deficiency in mice leads to synapse reduction and dysregulation coupled with mitochondrial morphological changes. In this study, the results revealed that regular exercise …(RE) decreased the expression of amyloid-β and phosphorylated tau by western blot, and enhanced the spatial learning and exploration ability of AD model mice as assessed by Morris water maze test. Mitochondrial cristae and edges were clear and intact, ATP production in the brain raised, the number of synapses increased, and GLUT1 and GLUT3 expression levels improved in the central nervous system (CNS) in AD model mice after RE. Changes in GLUT1 and GLUT3 expression at the protein level after RE are an important part of energy metabolic adaptation in AD model mice. Learning and memory improvement are highly associated with mitochondrial integrity and sufficient synapses in the CNS. This research suggests that increased brain energy metabolism attributed to RE exhibits promising therapeutic potential for AD. Show more

Keywords: Alzheimer’s disease, energy metabolism, glucose transporter, mitochondria, synapse

DOI: 10.3233/JAD-190328

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 83-96, 2019

Authors: Cao, Qin | Meng, Tian | Man, Jianhui | Peng, Dong | Chen, Hongxia | Xiang, Qi | Su, Zhijian | Zhang, Qihao | Huang, Yadong

Article Type: Research Article

Abstract: Glycogen synthase kinase 3β (GSK3β) is a key component of pathogenesis in Alzheimer’s disease, and its inhibitors can restore cognitive function as therapeutic interventions in neurodegenerative diseases. The previous studies showed that acidic fibroblast growth factor (aFGF) could increase the phosphorylation of GSK3β through the PI3K/Akt signaling pathway. We found that aFGF14–154 markedly increased the average length of neurites in neurons damaged by amyloid-β (Aβ), and this promoting effect was blocked by GSK3β inhibitor. It is still unknown which downstream substrates of GSK3β are related to the neurite growth facilitated by aFGF14-154 . The downstream substrates interacting with GSK3β …were screened by co-immunoprecipitation and LTQ-Orbitrap proteomics technology in our study. Collapsin response mediator protein 2 (CRMP2) has been identified as a protein interacting with GSK3β, which is involved in the axon formation and neuron regeneration by regulating microtubule reorganization. aFGF14-154 increased the phosphorylation of GSK3β (Ser9) to inhibit its activity, then was followed by a low phosphorylation level of CRMP2 (Thr514), which led to the neurite growth. The knockdown of CRMP2 blocked the rescue of aFGF14–154 with broken neurites and shrunken cell bodies in neurons with Aβ injury. These results highlight the important role of CRMP2 and its phosphorylation through GSK3β in the effect that aFGF14-154 promoted the growth of neurite damaged by Aβ. Show more

Keywords: Acidic fibroblast growth factor14-154, collapsin response mediator protein 2, glycogen synthase kinase 3β, neurons, CRMP2

DOI: 10.3233/JAD-190458

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 97-109, 2019

Authors: Serra, Laura | Petrosini, Laura | Salaris, Andrea | Pica, Lorenzo | Bruschini, Michela | Di Domenico, Carlotta | Caltagirone, Carlo | Marra, Camillo | Bozzali, Marco

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) explains the individual resilience to neurodegeneration. Years of formal education express the static measure of reserve (sCR). A dynamic aspect of CR (dCR) has been recently proposed. Objective: The aim of the study was to compare sCR and dCR indexes, respectively, to detect brain abnormalities in Alzheimer’s disease (AD) patients. Methods: 117 individuals [39 AD, 40 amnestic mild cognitive impairment (aMCI), 38 healthy subjects (HS)] underwent neuropsychological evaluation and a 3T-MRI. T1-weighted volumes were used for manual segmentation of the hippocampus and of the parahippocampal cortices. Years of formal education were used …as an index of sCR. Partial Least Square analysis was used to decompose the variance of individual MMSE scores, considered as a dCR index. In aMCI and AD patients, the brain abnormalities have been assessed comparing individuals with high and low levels of sCR and dCR in turn. Moreover, we investigated the effect of the different CR indexes in mediating the relationship between changes in brain volumes and memory performances. Results: sCR and dCR indexes classified differently individuals having high or low levels of CR. Smaller hippocampal and parahippocampal volumes in high dCR patients were found. The sCR and dCR indexes mediated significantly the relationship between brain abnormalities and memory in patients. Conclusions: CR mediated the relationship between brain and memory dysfunctions. We hypothesized that sCR and dCR indexes are a representation of different warehouses of reserve not operating in parallel but forming a complex system, in which crystalized cognitive abilities and actual cognitive efficiency interact with brain atrophy impacting on memory. Show more

Keywords: Alzheimer’s disease, dynamic and static cognitive reserve, hippocampus, mild cognitive impairment, parahippocampal gyrus

DOI: 10.3233/JAD-190716

Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 111-126, 2019