Journal of Alzheimer's Disease - Volume 57, issue 4

Authors: Gonzales, Eric B. | Sumien, Nathalie

Article Type: Research Article

Abstract: Alzheimer’s disease prevalence has reached epidemic proportion with very few treatment options, which are associated with a multitude of side effects. A potential avenue of research for new therapies are protons, and their associated receptor: acid-sensing ion channels (ASIC). Protons are often overlooked neurotransmitters, and proton-gated currents have been identified in the brain. Furthermore, ASICs have been determined to be crucial for proper brain function. While there is more work to be done, this review is intended to highlight protons as neurotransmitters and their role along with the role of ASICs within physiological functioning of the brain. We will also …cover the pathophysiological associations between ASICs and modulators of ASICs. Finally, this review will sum up how the studies of protons, ASICs and their modulators may generate new therapeutic molecules for Alzheimer’s disease and other neurodegenerative diseases. Show more

Keywords: Acid-sensing ion channels, acidity, Alzheimer’s disease, ASIC, cognitive function, pH, protons

DOI: 10.3233/JAD-161131

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1137-1144, 2017

Authors: Huang, Chia-Chi | Isidoro, Ciro

Article Type: Review Article

Abstract: The continuous increasing rate of patients suffering of Alzheimer’s disease (AD) worldwide requires the adoption of novel techniques for non-invasive early diagnosis and monitoring of the disease. Here we review the various Raman spectroscopic techniques, including Fourier Transform-Raman spectroscopy, surface-enhanced Raman scattering spectroscopy, coherent anti-Stokes Raman scattering spectroscopy, and confocal Raman microspectroscopy, that could be used for the diagnosis of AD. These techniques have shown the potential to detect AD biomarkers, such as the amyloid-β peptide and the tau protein, or the neurotransmitters involved in the disease (e.g., Glutamate and γ -Aminobutyric acid), or the typical structural alterations in specific …brain areas. The possibility to detect the specific biomarkers in liquid biopsies and to obtain high resolution 3D microscope images of the affected area make the Raman spectroscopy a valuable ally in the early diagnosis and monitoring of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, brain tissue, diagnosis, Raman spectroscopy, tau protein

DOI: 10.3233/JAD-161238

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1145-1156, 2017

Authors: Liu, Xin-jun | Wei, Jun | Shang, Ying-hui | Huang, Han-chang | Lao, Feng-xue

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a dementia disease with neuronal loss and synaptic impairment. This impairment is caused, at least partly, by the generation of two main AD hallmarks, namely the hyperphosphorylated tau protein comprising neurofibrillary tangles and senile plaques containing amyloid-β (Aβ) peptides. The amyloid-β protein precursor (AβPP) and glycogen synthase kinase-3β (GSK3β) are two main proteins associated with AD and are closely correlated with these hallmarks. Recently, both of the proteins were reported to be modulated by endoplasmic reticulum stress (ERS) and are involved in the pathogenesis of AD. The mechanism of ERS plus the modulation of AβPP processing …and GSK3β activity by ERS in AD are summarized and explored in this review. Show more

Keywords: Alzheimer’s disease, amyloid-β, apoptosis, endoplasmic reticulum stress, neurofibrillary tangles

DOI: 10.3233/JAD-161111

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1157-1170, 2017

Authors: Esquerda-Canals, Gisela | Montoliu-Gaya, Laia | Güell-Bosch, Jofre | Villegas, Sandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology. …Then, transgenic mouse lines harboring mutated human genes at several loci such as APP , PSEN1 , APOE ɛ 4 , and ob (leptin) are reviewed. Therefore, not only the accumulation of the Aβ peptide is emulated but also cholesterol and insulin metabolism. Further novel information about the disease will allow for the development of more accurate animal models, which in turn will undoubtedly be helpful for bringing preclinical research closer to clinical trials in humans. Show more

Keywords: Alzheimer’s disease, amyloid-β, animal models, apoE, APP, ob mutation, PS1

DOI: 10.3233/JAD-170045

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1171-1183, 2017

Authors: Gazzina, Stefano | Archetti, Silvana | Alberici, Antonella | Bonomi, Elisa | Cosseddu, Maura | Di Lorenzo, Diego | Padovani, Alessandro | Borroni, Barbara

Article Type: Short Communication

Abstract: Progranulin is a multifunctional growth factor mainly expressed in neurons and microglia. Loss-of-function mutations in the Granulin (GRN) gene are causative of frontotemporal dementia with TAR DNA-binding protein-43 inclusions. We reported the case of a 51-year-old male patient affected by sporadic agrammatic variant of primary progressive aphasia, in whom we identified a novel heterozygous deletion in the exon 6 (g.10338_39delAG, p.Arg161GlyfsX36). Plasma progranulin levels were significantly reduced and in silico analysis predicted a premature termination codon. This case expands our knowledge on GRN mutations in frontotemporal dementia.

Keywords: Frontotemporal dementia, granulin, mutation, progranulin

DOI: 10.3233/JAD-170066

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1185-1189, 2017

Authors: Wingbermühle, Robin | Wen, Ke-xin | Wolters, Frank J. | Ikram, M. Arfan | Bos, Daniel

Article Type: Short Communication

Abstract: The association of smoking with preclinical cognitive decline remains unclear and may be modified by the APOE ɛ 4 genotype. In 5,705 participants (mean age: 63.9±9.1 years; 57.4% women) from the population-based Rotterdam Study, we investigated the relationship between smoking and cognitive decline over a 5.5-year period and examined potential effect modification by APOE ɛ 4 genotype. We found that current smoking was related to decline in global cognition [difference compared to never smoking: –0.06 (95% C.I.–0.10;–0.01)], as well as decline on specific cognitive tests including the Letter Digit Substitution Task, the 15-Word Learning Test, and …the Purdue Pegboard. We found no evidence for effect modification by APOE ɛ 4 genotype on this relation. Show more

Keywords: APOE ɛ4 genotype, cognitive decline, epidemiology, smoking

DOI: 10.3233/JAD-170063

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1191-1195, 2017

Authors: Anstey, Kaarin J. | Eramudugolla, Ranmalee | Chopra, Sidhant | Price, Jasmine | Wood, Joanne M.

Article Type: Research Article

Abstract: Background: With population aging, drivers with mild cognitive impairment (MCI) are increasing; however, there is little evidence available regarding their safety. Objective: We aimed to evaluate risk of unsafe on-road driving performance among older adults with MCI. Method: The study was a cross-sectional observational study, set in Canberra, Australia. Participants were non-demented, current drivers (n  = 302) aged 65 to 96 years (M  = 75.7, SD = 6.18, 40% female) recruited through the community and primary and tertiary care clinics. Measures included a standardized on-road driving test (ORT), a battery of screening measures designed to evaluate older driver safety …(UFOV® , DriveSafe, Multi-D), a neurocognitive test battery, and questionnaires on driving history and behavior. Results: Using Winblad criteria, 57 participants were classified as having MCI and 245 as cognitively normal (CN). While the MCI group had a significantly lower overall safety rating on the ORT (5.61 versus 6.05, p  = 0.03), there was a wide range of driving safety scores in the CN and MCI groups. The MCI group performed worse than the CN group on the off-road screening tests. The best fitting model of predictors of ORT performance across the combined sample included age, the Multi-D, and DriveSafe, classifying 90.4% of the sample correctly. Conclusion: Adults with MCI exhibit a similar range of driving ability to CN adults, although on average they scored lower on off-road and on-road assessments. Driving specific tests were more strongly associated with safety ratings than traditional neuropsychological tests. Show more

Keywords: Driving safety, mild cognitive impairment, neuropsychological assessment, older drivers, on-road drivingperformance

DOI: 10.3233/JAD-161209

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1197-1205, 2017

Authors: Yin, Huajing | Wang, Weiping | Yu, Wenwen | Li, Jiang | Feng, Nan | Wang, Ling | Wang, Xiaoliang

Article Type: Research Article

Abstract: In the present study, the progressive alteration of cognition and the mechanisms of reduction in long-term potentiation (LTP) in spontaneous obese KK-Ay type 2 diabetic mice were investigated. In the study, 3-, 5-, and 7-month-old KK-Ay mice were used. The results indicated that KK-Ay mice showed cognitive deficits in the Morris water maze test beginning at the age of 3 months. LTP was significantly impaired in KK-Ay mice during whole study period (3 to 7 months). The above deficits were reversible at an early stage (3 to 5 months old) by diet intervention. Moreover, we found the underlying mechanisms of …LTP impairment in KK-Ay mice might be attributed to abnormal phosphorylation or expression of postsynaptic glutamate receptor subunits instead of alteration of basal synaptic transmission. The expression levels of NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptors (NMDARs) were unchanged while the Tyr-dependent phosphorylation of both NR2A and NR2B subunits were significantly reduced in KK-Ay mice. The level of p-Src expression mediating this process was decreased, and the level of αCaMKII autophosphorylation was also reduced. Meanwhile, the GluR1 of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) was decreased, and GluR2 was significantly increased. These data suggest that deficits in synaptic plasticity in KK-Ay mice may arise from the abnormal phosphorylation of the NR2 subunits and the alteration of subunit composition of AMPARs. Diet intervention at an early stage of diabetes might alleviate the cognitive deficits and LTP reduction in KK-Ay mice. Show more

Keywords: AMPA receptor, diabetic encephalopathy, KK-Ay mice, long-term potentiation, NMDA receptor, type 2 diabetes mellitus

DOI: 10.3233/JAD-160858

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1207-1220, 2017

Authors: Shinagawa, Shunichiro | Shigenobu, Kazue | Tagai, Kenji | Fukuhara, Ryuji | Kamimura, Naoto | Mori, Takaaki | Yoshiyama, Kenji | Kazui, Hiroaki | Nakayama, Kazuhiko | Ikeda, Manabu

Article Type: Research Article

Abstract: Although violations of laws, such as shoplifting, are considered to be common in frontotemporal dementia (FTD) patients, there have been few studies on this subject and the frequencies and types of such violations have not been clarified. The objective of this study was to conduct a retrospective investigation of FTD patients in the psychiatry departments of multiple institutions to determine the types and frequencies of any law violations and compare them with those of AD patients. All patients were examined between January 2011 and December 2015 at the specialized dementia outpatient clinics of 10 facilities (5 psychiatry departments of university …hospitals, 5 psychiatric hospitals). According to diagnostic criteria, 73 behavior variant FTD (bvFTD) patients, 84 semantic variant of primary progressive aphasia (svPPA) patients, and 255 age- and sex-matched AD subjects as the control group were selected. The findings revealed a higher rate of law violations in the bvFTD and svPPA patients before the initial consultation as compared to the AD group (bvFTD: 33%, svPPA: 21%, AD: 6%) and that many patients had been referred due to such violations. Laws had been broken 4 times or 5 or more times in several cases in the FTD group before the initial consultation. Regarding rates for different types of violation, in bvFTD subjects, the highest rate was for theft, followed by nuisance acts and hit and run. In svPPA, theft had the highest rate, followed by ignoring road signs. There was no gender difference in law violations but they were more frequent when the disease was severe at the initial consultation in the FTD group. As the rates of law violations after the initial consultation were lower than before it, interventions were considered to have been effective. These findings may be useful for future prevention as well as to the legal system. Show more

Keywords: Behavioral symptoms, frontotemporal dementia, legal system, violation of laws

DOI: 10.3233/JAD-170028

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1221-1227, 2017

Authors: Czaja, Sara J. | Loewenstein, David A. | Sabbag, Samir A. | Curiel, Rosie E. | Crocco, Elizabeth | Harvey, Philip D.

Article Type: Research Article

Abstract: Background: Recent findings indicate that impairments in functional performance do occur among individuals diagnosed with mild cognitive impairment (MCI). Most assessment strategies for everyday competence are associated with challenges with reliability, are typically in paper and pencil format, or require in-person administration by a trained professional. Objective: This paper reports on a novel technology-based assessment battery of everyday competence that includes ecologically valid simulations of daily activities important to independence. Methods: The sample included 85 non-cognitively impaired older adults aged 65+ and 62 older adults diagnosed with amnestic MCI (aMCI). Participants completed standard measures of …cognitive abilities and the computerized battery of everyday tasks, which included simulations of a doctor’s visit; and medication and financial management tasks. Results: The older adults with aMCI performed significantly poorer on all three tasks in the everyday task battery. Performance on these measures were also moderately correlated with standard measures of cognitive abilities and showed good test-retest reliability. Conclusions: The results show that it is feasible to use a technology-based assessment battery of everyday tasks with both non-cognitively impaired older adults and older adults with MCI. The use of this type of battery can overcome many of the logistic constraints associated with current functional assessment protocols. Show more

Keywords: Assessment, cognition, everyday competence, mild cognitive impairment, technology

DOI: 10.3233/JAD-161183

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1229-1238, 2017