Journal of Alzheimer's Disease - Volume 63, issue 2

Authors: Yasar, Sevil | Varma, Vijay R. | Harris, Gregory C. | Carlson, Michelle C.

Article Type: Research Article

Abstract: Background: Emerging evidence suggests a possible role of the renin angiotensin system in the pathophysiologic process of Alzheimer’s disease, of which angiotensin converting enzyme-1 (ACE-1) and angiotensin II (ANGII) are important proteins. Few studies evaluated associations between blood ACE-1 and none between ANGII levels, and cognition. Objective: Our pilot study was aimed to examine associations between blood ACE-1 and ANG II levels and cognitive function in non-demented participants at baseline and over a 1-year period. Methods: 56 participants were included from the Brain Health Substudy of the Baltimore Experience Corps Study. Linear regression analysis, adjusting for …confounders, was used to determine associations between baseline ACE-1 and ANGII, and baseline and 1-year follow-up measures of psychomotor and processing speed, executive function, verbal learning memory and working memory, and whether these associations were mediated by blood pressure. Results: Participants were predominantly female (75%), African-American (93%), with mean age of 67.8 years and education of 14.3 years. There were no associations between baseline ACE-1 or ANGII levels and cognitive function; however, there were significant association between baseline ACE-1 levels and 1-year follow-up Trail Making Test, Part A (β= 0.003, p  = 0.04) and Digit Span (β= –0.001, p  = 0.02). Conclusions: In this cognitively intact sample, elevated ACE-1 levels were associated with worse processing speed and working memory after 1 year. Findings from this pilot study suggest that changes in the RAS are associated with alterations in cognitive function warranting further assessment of the role of RAS in neurodegenerative disorders. Show more

Keywords: Angiotensin II, angiotensin converting enzyme-1, cognition, cohort study

DOI: 10.3233/JAD-170944

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 655-664, 2018

Authors: Gourmaud, Sarah | Thomas, Priscilla | Thomasseau, Sylvie | Tible, Marion | Abadie, Claire | Paquet, Claire | Hugon, Jacques

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by accumulations of amyloid-β (Aβ42 ) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n  = 6–9 per group). Cognitive deficits and brain lesions were assessed …using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice. Show more

Keywords: Alzheimer’s disease, cell death, JNK, memory, mice model peptide inhibitor, therapeutic

DOI: 10.3233/JAD-171099

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 665-674, 2018

Authors: Heymann, Petra | Gienger, Regine | Hett, Andreas | Müller, Stephan | Laske, Christoph | Robens, Sibylle | Ostermann, Thomas | Elbing, Ulrich

Article Type: Research Article

Abstract: Based on the knowledge of art therapy, we developed a new neuropsychological drawing test in order to identify individuals with mild cognitive impairment (MCI) as well as dementia patients and healthy controls (HC). By observing a variety of drawing characteristics of 92 participants with a mean age of 67.7, art therapy and dementia experts discriminate HC from MCI, early dementia of the Alzheimer-type (eDAT), and moderate dementia of the Alzheimer-type (mDAT) by the process analysis of tree drawings on a digitizing tablet. The art therapist’s average categorical rating of healthy and MCI or demented individuals matched the clinical diagnosis by …88%. In a first small study, we analyzed interrater reliability, sensitivity, specificity, negative and positive predicted values of our tree drawing test (TDT) in comparison with the clock drawing test (CDT). Similar values of moderate interrater reliability were found for the TDT (0.56) as well as for the CDT (0.54). A significant high sensitivity of 0.9 within this binary impairment scale (HC versus impaired or demented) can be demonstrated. Substantial values for the specificity (0.67) could be obtained that however remain under a perfect value of the CDT (1.0). Considering 31 individuals that received the clinical diagnosis “impaired or demented” the TDT shows a higher recognition rate for the MCI group than the CDT. Furthermore in 8 of 12 borderline cases of clinical diagnosis, the outcome of the TDT diagnosis was consistent with the final clinical result. Show more

Keywords: Art therapist raters, dichotomous classification, drawing characteristics, early Alzheimer’s disease, mild cognitive impairment, neuropsychological drawing test, screening, tablet-based

DOI: 10.3233/JAD-170946

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 675-687, 2018

Authors: Chao, Fenglei | Jiang, Lin | Zhang, Yi | Zhou, Chunni | Zhang, Lei | Tang, Jing | Liang, Xin | Qi, Yingqiang | Zhu, Yanqing | Ma, Jing | Tang, Yong

Article Type: Research Article

Abstract: The risk of cognitive decline during Alzheimer’s disease (AD) can be reduced if physical activity is maintained; however, the specific neural events underlying this beneficial effect are still uncertain. To quantitatively investigate the neural events underlying the effect of running exercise on middle-aged AD subjects, 12-month-old male APP/PS1 mice were randomly assigned to a control group or running group, and age-matched non-transgenic littermates were used as a wild-type group. AD running group mice were subjected to a treadmill running protocol (regular and moderate intensity) for four months. Spatial learning and memory abilities were assessed using the Morris water maze. Hippocampal …amyloid plaques were observed using Thioflavin S staining and immunohistochemistry. Hippocampal volume, number of neurons, and number of newborn cells (BrdU+ cells) in the hippocampus were estimated using stereological techniques, and newborn neurons were observed using double-labelling immunofluorescence. Marked neuronal loss in both the CA1 field and dentate gyrus (DG) and deficits in both the neurogenesis and survival of new neurons in the DG of middle-aged APP/PS1 mice were observed. Running exercise could improve the spatial learning and memory abilities, reduce amyloid plaques in the hippocampi, delay neuronal loss, induce neurogenesis, and promote the survival of newborn neurons in the DG of middle-aged APP/PS1 mice. Exercise-induced protection of neurons and adult neurogenesis within the DG might be part of the important structural basis of the improved spatial learning and memory abilities observed in AD mice. Show more

Keywords: BrdU+ cell, neuron, newborn neuron, running exercise, transgenic AD mice

DOI: 10.3233/JAD-171017

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 689-703, 2018

Authors: Zolezzi, Juan M. | Lindsay, Carolina B. | Serrano, Felipe G. | Ureta, Roxana C. | Theoduloz, Cristina | Schmeda-Hirschmann, Guillermo | Inestrosa, Nibaldo C.

Article Type: Research Article

Abstract: Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer’s disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result …that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD. Show more

Keywords: Amyloid-β, diterpenes, ferruginol, jatrophone, junicedric acid, neuroprotection

DOI: 10.3233/JAD-170701

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 705-723, 2018

Authors: Nouriziabari, Bardia | Sarkar, Susmita | Tanninen, Stephanie E. | Dayton, Robert D. | Klein, Ronald L. | Takehara-Nishiuchi, Kaori

Article Type: Research Article

Abstract: Trace eyeblink conditioning is a hippocampus-dependent associative learning paradigm which is impaired in patients with Alzheimer’s disease (AD) and animal AD models. Learning in this paradigm accompanies changes in oscillatory activity in forebrain regions, some of which are loci of pathogenic changes in prodromal AD stages. These observations motivated us to examine how cortical event-related potentials (ERPs) during this paradigm are affected by two features of the asymptomatic, AD-related brain abnormality, entorhinal tau accumulation and mild cholinergic deficit. Adult rats received viral overexpression of P301L mutant human tau in the entorhinal cortex, low-dose scopolamine treatment, or both. Electroencephalograms were recorded …with epidural electrodes on the surface of the frontal, parietal, and temporal cortices during differential and reversal trace eyeblink conditioning. All rats developed conditioned responses to one of two stimuli (auditory or visual) paired with mild eyelid shock (CS+), but not to the other stimulus presented alone (CS-). They were also able to adjust the response when the stimulus contingency was reversed. With learning, the amplitude of several ERP components in the frontal and temporal cortices came to differentiate the CS+ from CS-. Scopolamine affected the learning-related change in temporal P2 and other learning-unrelated components in three regions. Entorhinal tau overexpression primary affected the amplitude of temporal visual ERPs and learning-unrelated frontal and temporal auditory ERP components. The double manipulation only affected two components of temporal auditory ERPs. Thus, cortical ERPs during differential associative learning are sensitive to asymptomatic brain abnormality associated with AD. Show more

Keywords: Acetylcholine, associative learning, EEG, ERPs, rats, scopolamine, tau, viral vector

DOI: 10.3233/JAD-171033

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 725-740, 2018

Authors: van Santen, Joeke | Dröes, Rose-Marie | Holstege, Marije | Henkemans, Olivier Blanson | van Rijn, Annelies | de Vries, Ralph | van Straten, Annemieke | Meiland, Franka

Article Type: Research Article

Abstract: Background: Physical exercise benefits functioning, health, and well-being. However, people living with dementia in particular hardly engage in exercise. Exergaming (exercise and gaming) is an innovative, fun, and relatively safe way of exercising in a virtual reality or gaming environment. It may help people living with dementia overcome barriers they can experience regarding regular exercise activities. Objective: This systematic literature review aims to provide an overview of the cost-effectiveness of exergaming and its effects on physical, cognitive, emotional, and social functioning, as well as the quality of life in people living with dementia. Methods: PubMed, Embase, …Cinahl, PsycINFO, the Cochrane Library, and the Web of Science Core Collection were searched. Selection of studies was carried out by at least two independent researchers. Results: Three studies were found to be eligible and were included in this review. Two of these showed some statistically significant effects of exergaming on physical, cognitive, and emotional functioning in people living with dementia, although based on a very small sample. No articles were found about the cost-effectiveness of exergaming. Conclusions: Only a few controlled studies have been conducted into the effectiveness of exergaming, and these show very little significant benefits. More well-designed studies are necessary to examine the effects of exergaming. Show more

Keywords: Cognition, dementia, exercise, neuropsychiatry, play, quality of life, review

DOI: 10.3233/JAD-170667

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 741-760, 2018

Authors: Li, Mengzhu | Liu, Enjie | Zhou, Qiuzhi | Li, Shihong | Wang, Xin | Liu, Yanchao | Wang, Lin | Sun, Dongsheng | Ye, Jinwang | Gao, Yuan | Yang, Xifei | Liu, Jianjun | Yang, Ying | Wang, Jian-Zhi

Article Type: Research Article

Abstract: The transient receptor potential cation (TRPC) channels are widely expressed in nervous system but their functions remain largely unclear. Here, we found that TRPC1 deletion did not affect learning and memory in physiological conditions, while it aggravated learning and memory deficits induced by amyloid-β (Aβ), the major component of the senile plaques observed in the brains of Alzheimer’s disease (AD). Further studies demonstrated that TRPC1 deletion did not affect cell apoptosis in physiological condition, but it exacerbated the Aβ-induced cell death in mouse hippocampus. Moreover, the level of TRPC1 was decreased in AD cell and mouse models, and upregulation of …TRPC1 decreased Aβ levels with attenuation of apoptosis in the cells stably overexpressing amyloid-β protein precursor (AβPP). Finally, the transmembrane domain of TRPC1 could bind to AβPP and thus decreased Aβ production. These findings indicate that loss of TRPC1 exacerbates Aβ-induced memory deficit and cell apoptosis, though it does not impair cognitive function or induce cell death in physiological conditions. Show more

Keywords: Alzheimer’s disease, amyloid-β, apoptosis, cognitive impairment, transient receptor potential channels

DOI: 10.3233/JAD-180077

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 761-772, 2018

Authors: Wang, Jen-Hung | Wu, Ya-Ju | Tee, Boon Lead | Lo, Raymond Y.

Article Type: Research Article

Abstract: Background: Little is known about the distribution of medical comorbidities in Alzheimer’s disease (AD). Objective: We aimed to describe the comorbidity pattern of AD in a nested case-control study. Methods: Incident AD cases were identified by International Classification of Diseases codes in a random sample of 2 million individuals in Taiwan National Health Insurance program during 2001–2011. We further restricted cases to those treated with AD drugs of approved reimbursement. We sampled a set of age- and sex-matched control subjects (2:1 ratio) and employed conditional logistic regression to estimate the associations between pre-specified 14 comorbidities and …AD. The clusters of multiple chronic diseases were then identified by exploratory factor analysis. Results: A total of 2,618 AD cases were identified during 2001–2011 with a mean age of 76.1 years and female preponderance (59%). The most common 5 comorbidities in AD were hypertension (55.1%), osteoarthritis (38.2%), depression (32.3%), diabetes mellitus (DM) (25.7%), and cerebrovascular disease (CVD) (22.7%). After adjusting for age and sex, DM, osteoporosis, depression, and CVD were significantly associated with AD. The number of comorbidity was 3-fold greater in the AD group. The cluster of hypertension, DM, and hyperlipidemia was the most common combination in old age, whereas the cluster osteoarthritis and osteoporosis was the only multimorbidity pattern significantly associated with AD. Conclusion: Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, comorbidity, dementia, nested case-control studies

DOI: 10.3233/JAD-170786

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 773-781, 2018

Authors: Fantoni, Enrico R. | Chalkidou, Anastasia | O’ Brien, John T. | Farrar, Gill | Hammers, Alexander

Article Type: Research Article

Abstract: Background: Amyloid PET (aPET) imaging could improve patient outcomes in clinical practice, but the extent of impact needs quantification. Objective: To provide an aggregated quantitative analysis of the value added by aPET in cognitively impaired subjects. Methods: Systematic literature searches were performed in Embase and Medline until January 2017. 1,531 cases over 12 studies were included (1,142 cases over seven studies in the primary analysis where aPET was the key biomarker; the remaining cases included as defined groups in the secondary analysis). Data was abstracted by consensus among two observers and assessed for bias. Clinical utility …was measured by diagnostic change, diagnostic confidence, and patient management before and after aPET. Three groups were further analyzed: control patients for whom feedback of aPET scan results was delayed; aPET Appropriate Use Criteria (AUC+) cases; and patients undergoing additional FDG/CSF testing. Results: For 1,142 cases with only aPET, 31.3% of diagnoses were revised, whereas 3.2% of diagnoses changed in the delayed aPET control group (p  < 0.0001). Increased diagnostic confidence following aPET was found for 62.1% of 870 patients. Management changes with aPET were found in 72.2% of 740 cases and in 55.5% of 299 cases in the control group (p  < 0.0001). The diagnostic value of aPET in AUC+ patients or when FDG/CSF were additionally available did not substantially differ from the value of aPET alone in the wider population. Conclusions: Amyloid PET contributed to diagnostic revision in almost a third of cases and demonstrated value in increasing diagnostic confidence and refining management plans. Show more

Keywords: Alzheimer’s disease, amyloid PET, dementia, diagnostic confidence, differential diagnosis, impact, patient management, quantitative, systematic review, utility

DOI: 10.3233/JAD-171093

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 783-796, 2018