Journal of Alzheimer's Disease - Volume 59, issue 3

Authors: Galzitskaya, Oxana V. | Selivanova, Olga M.

Article Type: Review Article

Abstract: Deeper understanding of processes of protein misfolding, aggregation, formation of oligomers, protofibrils, and fibrils is crucial for the development of future medicine in treatment of amyloid-related diseases. While numerous reports illuminate the field, the above processes are extremely complex, as they depend on many varying parameters, such as the peptide concentration, temperature, pH, presence of metal ions, lipids, and organic solvents. Different mechanisms of amyloid fibril formation have been proposed, but the process of the oligomer−to−fibril transition is the least agreed upon. Our studies of a number of amyloidogenic proteins and peptides (insulin, Aβ peptides, the Bgl2 protein from the …yeast cell wall), as well as their amyloidogenic fragments, have allowed us to propose a model of the fibril structure generation. We have found that the main building block of fibrils of any morphology is a ring-like oligomer. The varying models of interaction of ring oligomers with each other revealed in our studies make it possible to explain their polymorphism. Crucially, the amino acid sequence determines the oligomer structure for the given protein/peptide. Show more

Keywords: Alzheimer’s disease, amyloid-β, insulin, nucleus, ring-like oligomers, seeds

DOI: 10.3233/JAD-170230

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 785-795, 2017

Authors: Chandra, Vijay | Mehta, Veer Singh

Article Type: Short Communication

Abstract: The aim of our study was to determine if the distribution of types of dementia could explain the reported lower prevalence of dementia in India. The study is an observational study of the first 100 cases of dementia. All patients were evaluated clinically and with blood tests and MRI of the brain. The causes of dementia were: Lewy body dementia (22%), depression (20%), Alzheimer’s disease (13%), and mild cognitive impairment (18%). Other dementias were less common. The distribution of dementia types in this series is different from that reported globally. The observation of Lewy body dementia being the most common …cause of dementia needs to be verified. Show more

Keywords: Alzheimer’s disease, dementia, depression, frontotemporal lobar degeneration, India, Lewy body dementia, mild cognitive impairment

DOI: 10.3233/JAD-170251

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 797-801, 2017

Authors: Richard, Erin L. | Kritz-Silverstein, Donna | Laughlin, Gail A. | Fung, Teresa T. | Barrett-Connor, Elizabeth | McEvoy, Linda K.

Article Type: Research Article

Abstract: To better understand the association of alcohol intake with cognitively healthy longevity (CHL), we explored the association between amount and frequency of alcohol intake and CHL among 1,344 older community-dwelling adults. Alcohol intake was assessed by questionnaire in 1984–1987. Cognitive function was assessed in approximate four-year intervals between 1988 and 2009. Multinomial logistic regression, adjusting for multiple lifestyle and health factors, was used to examine the association between alcohol consumption and CHL (living to age 85 without cognitive impairment), survival to age 85 with cognitive impairment (MMSE score >1.5 standard deviations below expectation for age, sex, and education), or death before …age 85. Most participants (88%) reported some current alcohol intake; 49% reported a moderate amount of alcohol intake, and 48% reported drinking near-daily. Relative to nondrinkers, moderate and heavy drinkers (up to 3 drinks/day for women and for men 65 years and older, up to 4 drinks/day for men under 65 years) had significantly higher adjusted odds of survival to age 85 without cognitive impairment (p ’s < 0.05). Near-daily drinkers had 2-3 fold higher adjusted odds of CHL versus living to at least age 85 with cognitive impairment (odds ratio (OR) = 2.06; 95% confidence interval (CI): 1.21, 3.49) or death before 85 (OR = 3.24; 95% CI: 1.92, 5.46). Although excessive drinking has negative health consequences, these results suggest that regular, moderate drinking may play a role in cognitively healthy longevity. Show more

Keywords: Alcohol drinking, aging, cognitive impairment, cohort study, longevity

DOI: 10.3233/JAD-161153

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 803-814, 2017

Authors: Solfrizzi, Vincenzo | Custodero, Carlo | Lozupone, Madia | Imbimbo, Bruno P. | Valiani, Vincenzo | Agosti, Pasquale | Schilardi, Andrea | D’Introno, Alessia | La Montagna, Maddalena | Calvani, Mariapaola | Guerra, Vito | Sardone, Rodolfo | Abbrescia, Daniela I. | Bellomo, Antonello | Greco, Antonio | Daniele, Antonio | Seripa, Davide | Logroscino, Giancarlo | Sabbá, Carlo | Panza, Francesco

Article Type: Research Article

Abstract: In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014–2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging–Alzheimer’s Association guidelines for Alzheimer’s disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes …in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. Show more

Keywords: Alzheimer’s disease, dementia, dietary pattern, food groups, foods, healthy diet, Mediterranean diet, macronutrients, micronutrients, mild cognitive impairment

DOI: 10.3233/JAD-170248

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 815-849, 2017

Authors: Yin, Yanling | Zhao, Yuanyuan | Han, Song | Zhang, Nan | Chen, Hanyu | Wang, Xiaomin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most frequent cause of progressive cognitive decline in the elderly population. To date, there is still no effective treatment for AD, requiring more underlying mechanisms. In the present study, we investigated the effects of Aβ42 on the inhibitory synaptic transmission in the cultured hippocampal neurons, and explored the possible mechanism. The frequency, but not amplitude, of miniature inhibitory post-synaptic currents was significantly suppressed by Aβ42 , indicating that Aβ42 played its role in inhibitory transmitter release at the pre-synaptic sites. Aβ42 had no effect on miniature excitatory …post-synaptic currents, suggesting GABAergic synapses are more susceptible to Aβ42 exposure. However, the number of GABAergic neurons or synapses was not influenced, suggesting the corresponding stage may be a preclinical one. The effect of Aβ42 can be mimicked by PD98059 (an inhibitor of ERK1/2) and blocked by curcumin (an activator of MEK), which reveals Aβ-involved influence is via the decreased phosphorylation of MAPK-ERK1/2. In addition, synaptophysin is confirmed to be a downstream protein of MAPK-ERK1/2 at the pre-synaptic site. At the same time, suppressed autophagy was observed after Aβ42 exposure, and the activation of autophagy increased pERK1/2 level and salvaged the disinhibition of hippocampal neurons. These data suggest that diminished GABAergic tone likely starts from the preclinical stage of AD, so some GABAergic stress test may be effective for identifying cognitively normal elder adults. Strategies against the dysfunction of autophagy should be adopted in the early stage of AD because of its initial effects. Show more

Keywords: Alzheimer’s disease, autophagy, LC3, MAPK/ERK1/2, miniature inhibitory post-synaptic currents, synaptophysin

DOI: 10.3233/JAD-170246

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 851-869, 2017

Authors: Markova, Hana | Andel, Ross | Stepankova, Hana | Kopecek, Miloslav | Nikolai, Tomas | Hort, Jakub | Thomas-Antérion, Catherine | Vyhnalek, Martin

Article Type: Research Article

Abstract: Background: Subjective cognitive complaints (SCCs) may be an early marker of prodromal Alzheimer’s disease. Objectives: Using a 10-item yes/no SCCs questionnaire (Le Questionnaire de Plainte Cognitive [QPC]), we evaluated the prevalence and distribution of SCCs in cognitively healthy Czech older adults and examined total score and specific QPC items in relation to depressive symptomology and cognitive performance. Methods: A sample of 340 cognitively healthy older community-dwelling volunteers aged 60 or older from the third wave of the longitudinal project National Normative Study of Cognitive Determinants of Healthy Aging, who underwent a comprehensive neuropsychological assessment and completed …the QPC and the 15-item Geriatric Depression Scale (GDS-15). Regression analysis was controlled for age when GDS-15 was the outcome and for age and GDS-15 with cognitive domains as the outcome. Results: 71% reported 1 + SCCs, with prevalence of individual complaints ranging from 4% to 40%. The number of SCCs was associated with GDS-15 (p  < 0.001). Personality change (p < 0.001) and Limitation in daily activities (p = 0.002) were significantly associated with higher GDS-15 score and Spatial orientation difficulties (p = 0.019) and Impression of worse memory in comparison to peers (p  = 0.012) were significantly associated with lower memory performance. Conclusions: We identified some cognitive complaints that were very common in our sample. Overall, a higher number of SCCs in well cognitively functioning individuals was most closely related to depressive symptomatology, while some specific complaints reflected lower memory performance and should be considered when screening for people at risk of cognitive decline. Show more

Keywords: Aging, cognitive functioning, depressive symptoms, prodromal Alzheimer’s disease, subjective cognitive complaints

DOI: 10.3233/JAD-160970

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 871-881, 2017

Authors: Tu, Sicong | Spiers, Hugo J. | Hodges, John R. | Piguet, Olivier | Hornberger, Michael

Article Type: Research Article

Abstract: Background: Diagnosis of behavioral variant frontotemporal dementia (bvFTD) can be challenging, in particular when patients present with significant memory problems, which can increase the chance of a misdiagnosis of Alzheimer’s disease (AD). Growing evidence suggests spatial orientation is a reliable cognitive marker able to differentiate these two clinical syndromes. Objective: Assess the integrity of egocentric and allocentric heading orientation and memory in bvFTD and AD, and their clinical implications. Method: A cohort of 22 patients with dementia (11 bvFTD; 11 AD) and 14 healthy controls were assessed on the virtual supermarket task of spatial orientation and …a battery of standardized neuropsychological measures of visual and verbal memory performance. Results: Judgements of egocentric and allocentric heading direction were differentially impaired in bvFTD and AD, with AD performing significantly worse on egocentric heading judgements than bvFTD. Both patient cohorts, however, showed similar degree of impaired allocentric spatial representation, and associated hippocampal pathology. Conclusions: The findings suggest egocentric heading judgements offer a more sensitive discriminant of bvFTD and AD than allocentric map-based measures of spatial memory. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, hippocampus, orientation

DOI: 10.3233/JAD-160592

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 883-892, 2017

Authors: Borland, Emma | Nägga, Katarina | Nilsson, Peter M. | Minthon, Lennart | Nilsson, Erik D. | Palmqvist, Sebastian

Article Type: Research Article

Abstract: Background: The Montreal Cognitive Assessment (MoCA) has a high sensitivity for detecting cognitive dysfunction. Swedish normative data does not exist and international norms are often derived from populations where cognitive impairment has not been screened for and not been thoroughly assessed to exclude subjects with dementia or mild cognitive impairment. Objective: To establish norms for MoCA and develop a regression-based norm calculator based on a large, well-examined cohort. Methods: MoCA was administered on 860 randomly selected elderly people from a population-based cohort from the EPIC study. Cognitive dysfunction was screened for and further assessed at a …memory clinic. After excluding cognitively impaired participants, normative data was derived from 758 people, aged 65–85. Results: MoCA cut-offs (–1 to –2 standard deviations) for cognitive impairment ranged from <25 to <21 for the lowest educated and <26 to <24 for the highest educated, depending on age group. Significant predictors for MoCA score were age, sex and level of education. Conclusion: We present detailed normative MoCA data and cut-offs according to the DSM-5 criteria for cognitive impairment based on a large population-based cohort of elderly individuals, screened and thoroughly investigated to rule out cognitive impairment. Level of education, sex, and age should be taken in account when evaluating MoCA score, which is facilitated by our online regression-based calculator that provide percentile and z-score for a subject’s MoCA score. Show more

Keywords: Cognitively healthy elderly, excluding cognitively impaired, Montreal Cognitive Assessment, normative, population-based, representative, Swedish

DOI: 10.3233/JAD-170203

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 893-901, 2017

Authors: Muszyński, Paweł | Kulczyńska-Przybik, Agnieszka | Borawska, Renata | Litman-Zawadzka, Ala | Słowik, Agnieszka | Klimkowicz-Mrowiec, Aleksandra | Pera, Joanna | Dziedzic, Tomasz | Mroczko, Barbara

Article Type: Research Article

Abstract: Background: It is known that YKL-40— a marker of glial inflammation, and VILIP-1— a marker of neuronal injury, reflect functional and structural changes in AD brains, although there is limited data concerning their potential influence on blood-brain barrier (BBB) homeostasis. Objective: Therefore, the aim of our study was to investigate the relationship between markers of inflammation and degeneration in the central nervous system (CNS) of patients with AD and mild cognitive impairment (MCI) as well as immunological response in CNS and BBB function. Methods: Cerebrospinal fluid (CSF) concentrations of proteins tested were determined in 45 AD …patients, 18 MCI subjects, and 23 non-demented controls using ELISA method. Results: CSF concentrations of YKL-40 were significantly higher in MCI and AD patients, whereas CSF levels of VILIP-1 were statistically higher in the AD group as compared to the subjects without cognitive deficits. Elevated concentrations of YKL-40 correlated significantly with increased albumin quotient and decreased Aβ42/40 ratio in AD patients and with IgG quotient in the total study group. We did not find a relationship between VILIP-1 and immunological parameters reflecting BBB dysfunction and humoral immune response. Conclusion: Our findings indicate that YKL-40 may contribute to decreased stability and increased permeability of BBB in AD patients. It is assumed that YKL-40 is implicated in the development of brain barriers, although its precise mechanism of action in the BBB disruption remains unrevealed. Further studies on larger groups of patients are required to confirm our hypothesis. Show more

Keywords: Alzheimer’s disease, blood-brain barrier disruption, cerebrospinal fluid, humoral immune response in the CNS, mild cognitive impairment, neuroinflammation, neurodegeneration

DOI: 10.3233/JAD-170220

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 903-912, 2017

Authors: Yu, Linjie | Liu, Yi | Yang, Hui | Zhu, Xiaolei | Cao, Xiang | Gao, Jun | Zhao, Hui | Xu, Yun

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer’s disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated. The open field test, Morris water maze test, and fear condition test revealed that …PSD-93 overexpression ameliorated spatial memory deficits in APP/PS1 mice. The facilitation of long-term potentiation induction was observed in APP/PS1 mice after PSD-93 overexpression. The expression of somatostatin receptor 4 (SSTR4) and neprilysin was increased, while the amyloid plaque load and Aβ levels were decreased in the brains of APP/PS1 mice. Moreover, PSD-93 interacted with SSTR4 and affected the level of SSTR4 on cell membrane, which was associated with the ubiquitination. Together, these findings suggest that PSD-93 attenuates spatial memory deficits and decreases amyloid levels in APP/PS1 mice, which might be associated with Aβ catabolism, and overexpression of PSD-93 might be a potential therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, postsynaptic density protein 93, somatostatin receptor 4

DOI: 10.3233/JAD-170320

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 913-927, 2017