Volume 59, Number 3, 2017

Pages 785-795

Oxana V. Galzitskaya, Olga M. Selivanova (Handling Associate Editor: Ewa Bienkiewicz)
Rosetta Stone for Amyloid Fibrils: The Key Role of Ring-Like Oligomers in Amyloidogenesis
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 oligomertofibril transition is the least agreed upon. Our studies of a number of amyloidogenic proteins and peptides (insulin, A 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.

Pages 797-801
Short Communication

Vijay Chandra, Veer Singh Mehta (Handling Associate Editor: Amos Korczyn)
Distribution of Types of Dementia in the First 100 Patients Seen at a Dementia Clinic in India
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.

Pages 803-814
Erin L. Richard, Donna Kritz-Silverstein, Gail A. Laughlin, Teresa T. Fung, Elizabeth Barrett-Connor, Linda K. McEvoy (Handling Associate Editor: Francesco Panza)
Alcohol Intake and Cognitively Healthy Longevity in Community-Dwelling Adults: The Rancho Bernardo Study
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.

Pages 815-849
Vincenzo Solfrizzi*, Carlo Custodero, Madia Lozupone, Bruno P. Imbimbo, Vincenzo Valiani, Pasquale Agosti, Andrea Schilardi, Alessia D’Introno, Maddalena La Montagna, Mariapaola Calvani, Vito Guerra, Rodolfo Sardone, Daniela I. Abbrescia, Antonello Bellomo, Antonio Greco, Antonio Daniele, Davide Seripa, Giancarlo Logroscino, Carlo Sabbà, Francesco Panza* *These authors contributed equally to this work.
Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer’s Disease and Late-life Cognitive Disorders: A Systematic Review
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.

Pages 851-869
Yanling Yin, Yuanyuan Zhao, Song Han, Nan Zhang, Hanyu Chen, Xiaomin Wang
Autophagy-ERK1/2-Involved Disinhibition of Hippocampal Neurons Contributes to the Pre-Synaptic Toxicity Induced by Aβ42 Exposure
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.

Pages 871-881
Hana Markova, Ross Andel, Hana Stepankova, Miloslav Kopecek, Tomas Nikolai, Jakub Hort, Catherine Thomas-Antérion, Martin Vyhnalek (Handling Associate Editor: Laura Rabin)
Subjective Cognitive Complaints in Cognitively Healthy Older Adults and Their Relationship to Cognitive Performance and Depressive Symptoms
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.

Pages 883-892
Sicong Tu, Hugo J. Spiers, John R. Hodges, Olivier Piguet, Michael Hornberger (Handling Associate Editor: Sharon Naismith)
Egocentric versus Allocentric Spatial Memory in Behavioral Variant Frontotemporal Dementia and Alzheimer’s Disease
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.

Pages 893-901
Emma Borland*, Katarina Nägga*, Peter M. Nilsson, Lennart Minthon, Erik D. Nilsson, Sebastian Palmqvist *These authors contributed equally to this work.
The Montreal Cognitive Assessment: Normative Data from a Large Swedish Population-Based Cohort
Abstract: Abstract: Background: The Montreal Cognitive Assessment (MoCA) is highly 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 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 deviation) for cognitive impairment ranged from <21 to <25 for the lowest educated and <23 to <26 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.

Pages 903-912
Paweł Muszyński, Agnieszka Kulczyńska-Przybik, Renata Borawska, Ala Litman-Zawadzka, Agnieszka Słowik, Aleksandra Klimkowicz-Mrowiec, Joanna Pera, Tomasz Dziedzic, Barbara Mroczko (Handling Associate Editor: Piotr Lewczuk)
The Relationship between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood-Brain Barrier Impairment in Alzheimer’s Disease
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.

Pages 913-927
Linjie Yu, Yi Liu, Hui Yang, Xiaolei Zhu, Xiang Cao, Jun Gao, Hui Zhao, Yun Xu
PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β
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 A-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.

Pages 929-939
Lasse M. Giil, Christian A. Vedeler, Einar K. Kristoffersen, Jan Erik Nordrehaug, Harald Heidecke, Ralf Dechend, Kai Schulze-Forster, Dominik N. Muller, Victoria S. von Goetze, Otavio Cabral-Marques, Gabriela Riemekasten, Petra Vogelsang, Staale Nygaard, Anders Lund, Dag Aarsland (Handling Associate Editor: Henrik Zetterberg)
Antibodies to Signaling Molecules and Receptors in Alzheimer’s Disease are Associated with Psychomotor Slowing, Depression, and Poor Visuospatial Function
Abstract: Background: Alzheimer’s disease (AD) is associated with several antibodies as well as signaling molecules and receptors. These may be detrimental in the presence of a disrupted blood-brain barrier (BBB). Objective: To investigate whether the levels of antibodies toward 33 signaling molecules involved in neurotransmitter, vascular, and immune functions were associated with AD and, within the AD group; cognitive function and mood. Methods: Antibodies in sera from patients with mild AD [(n=91) defined as a Mini-Mental State Examination 20 or a Clinical Dementia Rating Scale ≤ 1] and healthy controls (n=102) were measured with enzyme-linked immunosorbent assays. Levels in AD and controls were compared by Mann-Whitney test. In the AD group, associations between antibodies and psychometric test scores were analyzed by robust regression. The false discovery threshold was set to 0.05. Results: Antibodies to serotonin receptors [5-HT2AR (effect size (r)=0.21, p=0.004), 5-HT2CR (r=0.25, p=0.0005) and 5-HT7R (r=0.21, p=0.003)], vascular endothelial growth factor receptor 1 [VEGFR1 (r=0.29, p<0.001)] and immune-receptors (Stabilin-1 (r=0.23, p=0.001) and C5aR1 (r=0.21, p=0.004) were higher in AD. Psychomotor speed was associated with D1R-abs (0.49, p<0.001), depression with ETAR-abs (0.31, p<0.001), and visuospatial function with 5-HT1AR-abs (0.27, p = 0.004) despite similar antibody levels compared to controls. Conclusions: Antibody levels to VEGFR1, serotonergic receptors, and receptors in the immune system were increased in AD. Antibodies at similar levels as in controls were associated cognitive dysfunction and depression in AD.

Pages 941-949
Jia Chen*, Tao Zhang*, Shusheng Jiao, Xinfu Zhou, Jinhua Zhong, Yanjiang Wang, Juan Liu, Juan Deng, Shuiping Wang, Zhiqiang Xu *These authors contributed equally to this work.
proBDNF Accelerates Brain Amyloid-β Deposition and Learning and Memory Impairment in APPswePS1dE9 Transgenic Mice
Abstract: Background: Alzheimer’s disease (AD) is pathologically known for the amyloid-β (Aβ) deposition, neurofibrillary tangles, and neuronal loss in the brain. The precursor of brain-derived neurotrophic factor (proBDNF) before proteolysis has opposing functions to its mature form in neuronal survival and neurite growth. However, the role of proBDNF in the pathogenesis of AD remains unclear. Objective: To investigate the effects of proBDNF on neurons in vitro, and on learning and memory impairment and brain Aβ production in a transgenic AD mouse model (APPswePS1dE9). Methods: We here examined the effects of proBDNF on the viability (MTT assay) and neurite growth (morphologic measurement) of the primary neurons in vitro. After the intracerebroventricular injection of adeno-associated virus-proBDNF (AAV-proBDNF), we then investigated the learning and memory impairment (Morris water maze) and Aβ deposition in the brains of the AD mice. Results: The results showed that proBDNF could inhibit neuronal viability and neurite growth in vitro, enhance Aβ levels, and accelerate its deposition in the brain, which was consistent with the learning and memory impairment of AD mice, likely dependent on the membrane receptor of p75NTR. Conclusions: Our findings suggest that proBDNF may exert a crucially negative effect during AD pathogenesis and progression.

Pages 951-959
Atsushi Niwa, Yuichiro Ii, Akihiro Shindo, Ko Matsuo, Hidehiro Ishikawa, Akira Taniguchi, Shinichi Takase, Masayuki Maeda, Hajime Sakuma, Hiroyasu Akatsu, Yoshio Hashizume, Hidekazu Tomimoto
Comparative Analysis of Cortical Microinfarcts and Microbleeds using 3.0-Tesla Postmortem Magnetic Resonance Images and Histopathology
Abstract: Microvascular lesions including cortical microinfarctions (CMIs) and cerebral lobar microbleeds (CMBs) are usually caused by cerebral amyloid angiopathy (CAA) in the elderly and are correlated with cognitive decline. However, their radiological-histopathological coincidence has not been revealed systematically with widely used 3-Tesla (3T) magnetic resonance imaging (MRI). The purpose of the present study is to delineate the histopathological background corresponding to MR images of these lesions. We examined formalin-fixed 10-mm thick coronal brain blocks from 10 CAA patients (five were also diagnosed with Alzheimer’s disease, three with dementia with Lewy bodies, and two with CAA only) with dementia and six non CAA patients with neurodegenerative disease. Using 3T MRI, both 3D-fluid attenuated inversion recovery (FLAIR) and 3D-double inversion recovery (DIR) were examined to identify CMIs, and T2* and susceptibility-weighted images (SWI) were examined to identify CMBs. These blocks were subsequently examined histologically and immunohistochemically. In CAA patients, 48 CMIs and 6 lobar CMBs were invariably observed in close proximity to degenerated Aβ-positive blood vessels. Moreover, 16 CMIs (33%) of 48 were detected with postmortem MRI, but none were seen when the lesion size was smaller than 1 mm. In contrast, only 1 undeniable CMI was founded with MRI and histopathology in 6 non CAA patients. Small, cortical high-intensity lesions seen on 3D-FLAIR and 3D-DIR images likely represent CMIs, and low-intensity lesions in T2* and SWI correspond to CMBs with in vivo MRI. Furthermore, a close association between amyloid-laden vessels and these microvascular lesions indicated the contribution of CAA to their pathogenesis.

Pages 961-974
Gustavo Richter Vaz, Gabriela Hädrich, Juliana Bidone, Jamile Lima Rodrigues, Mariana Corrêa Falkembach, Jean-Luc Putaux, Mariana Appel Hort, José Maria Monserrat, Antônio Sergio Varela Junior, Helder Ferreira Teixeira, Ana Luiza Muccillo-Baisch, Ana Paula Horn, Cristiana Lima Dora
Development of Nasal Lipid Nanocarriers Containing Curcumin for Brain Targeting
Abstract: Background: Curcumin (CUR) has properties that can be useful for the treatment of Alzheimer’s disease. Such properties are the inhibition of amyloid-β-protein (Aβ) aggregation, Aβ-induced inflammation, and activities of β-secretase and acetylcholinesterase. However, previous studies have revealed that CUR exhibited low bioavailability and difficulties in reaching the brain. Objective: To overcome such drawbacks, this study aims at developing nasal lipid nanocarriers loaded with CUR to effectively target the brain. Methods: The lipid nanocarriers (NE) were prepared using the hot solvent diffusion associated with the phase inversion temperature methods. Physico-chemical and morphological characterizations and in vitro drug release of the nanocarriers were carried out. The CUR permeation/retention was analyzed in Franz-type diffusion cell using porcine nasal mucosa. Confocal laser scan and histopathological studies were also performed. Results: The results showed that the NE sizes ranged between 18 nm and 44 nm with negative zeta potential. The CUR content ranged from 0.24 to 1.50 mg/mL with an encapsulation efficiency of 99%. The profiles of CUR release indicated a biphasic kinetics. CUR-NE permeation across the porcine nasal mucosa was higher when compared to free CUR. These results have also been validated through an analysis on a confocal microscopy. In addition, no toxicity on the nasal mucosa has been observed in a histopathological analysis. Conclusion: These results suggest that it is possible to develop NEs with a high content of CUR and small particle size. Such an encapsulation increases the potential of CUR permeation across the porcine nasal mucosa.

Pages 975-985
Jennifer R. Gatchel, Nancy J. Donovan, Joseph J. Locascio, Aaron P. Schultz, J. Alex Becker, Jasmeer Chhatwal, Kathryn V. Papp, Rebecca E. Amariglio, Dorene M. Rentz, Deborah Blacker, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall (Handling Associate Editor: Krista Lanctôt)
Depressive Symptoms and Tau Accumulation in the Inferior Temporal Lobe and Entorhinal Cortex in Cognitively Normal Older Adults: A Pilot Study
Abstract: Background: Depressive symptoms are common in older adults and associated with increased morbidity and cognitive decline. These symptoms occur during preclinical and prodromal stages of Alzheimer’s disease (AD), but their relationship to tau, one of the main AD proteinopathies, is poorly understood. Objective: The objective of this study was to investigate the cross-sectional association between depressive symptoms and cerebral tau [18F T807 (also known as 18F-AV-1451) tau positron emission tomography (PET) imaging] in cognitively normal (CN) older adults. Methods: We measured depressive symptoms using the Geriatric Depression Scale (GDS), and in vivo cerebral tau using T807 PET in 111 CN older adults. We employed general linear regression models to evaluate the relationship of GDS score regressed on entorhinal cortex (EC) or inferior temporal (IT) tau in separate backward elimination models. Other predictors included age, sex, and in secondary analyses, amyloid (Pittsburgh Compound B PET). Results: Higher GDS was significantly associated with greater IT tau (partial r=0.188, p=0.050) and marginally associated with greater EC tau (partial r=0.183, p=0.055). In additional analyses including both linear and quadratic age terms, we found a significant U-shaped relation of GDS to age (p=0.001). Conclusions: Results suggest that IT and EC tau are modestly associated with depressive symptoms in CN older adults. Findings suggest a link between depressive symptoms and tau-mediated neurodegeneration in a region vulnerable in AD. Future longitudinal studies examining the association of more severe depressive symptoms and cerebral tau accumulation are needed to substantiate this finding and to guide prevention and treatment in AD.

Pages 987-996
Julie M. Jiang, Elizabeth K. Seng, Molly E. Zimmerman, Martin Sliwinski, Mimi Kim, Richard B. Lipton
Evaluation of the Reliability, Validity, and Predictive Validity of the Subscales of the Perceived Stress Scale in Older Adults
Abstract: Background: The Perceived Stress Scale (PSS) is made up of two subscales but is typically used as a single summary measure. However, research has shown that the two subscales may have differential properties in older adults. Objective: To evaluate the internal consistency, test-retest reliability, and the concurrent and predictive validity for development of amnestic mild cognitive impairment (aMCI) of the positively-worded (PSS-PW) and negatively-worded (PSS-NW) subscale scores of the PSS in older adults. Methods: We recruited community residing older adults free of dementia from the Einstein Aging Study. Reliability of the PSS-PW and PSS-NW was assessed using Cronbach’s alpha for internal consistency and intraclass correlation for one year test-retest reliability. Concurrent validity was evaluated by examining the relationship between the PSS subscales and depression, anxiety, neuroticism, and positive and negative affect. Predictive validity was assessed using multivariate Cox regression analyses to examine the relationship between baseline PSS-PW and PSS-NW score and subsequent onset of aMCI. Results: Both PSS-PW and PSS-NW showed adequate internal consistency and retest reliabilities. Both the PSS-PW and PSS-NW were associated with depression, neuroticism, and negative affect. The PSS-NW was uniquely associated with anxiety while the PSS-PW was uniquely associated with positive affect. Only the PSS-PW was associated with a statistically significant increased risk of incident aMCI (HR = 1.27; 95% CI: 1.06-1.51 for every 5-point increase in PSS-PW). Conclusions: Evaluating the separate effects of the two PSS subscales may reveal more information than simply using a single summation score. Future research should investigate the PSS-PW and PSS-NW as separate subscales.

Pages 997-1007
Oriol Turró-Garriga, Laia Calvó-Perxas, Joan Vilalta-Franch, Marta Hernández-Ferràndiz, Margarita Flaqué, Marta Linares, Marta Cullell, Jordi Gich, Isabel Casas, Héctor Perkal, Josep Garre-Olmo, on behalf of the Registry of Dementia of Girona Study Group (ReDeGi Study Group) (Handling Associate Editor: Brandy Callahan)
Adherence to Clinical Practice Guidelines during Dementia Work-Up in a Real-World Setting: A Study from the Registry of Dementias of Girona
Abstract: Background: There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia. Objective: Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007-2011 and 2012-2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes. Methods: Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI). Results: The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007-2011 to 8.5 points in 2012-2015 (Cohen’s d=0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases. Conclusion: The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases.

Pages 1009-1015
Cinzia Bussè, Pasquale Anselmi, Sara Pompanin, Giovanni Zorzi, Federica Fragiacomo, Giulia Camporese, Gian Antonio Di Bernardo, Carlo Semenza, Paolo Caffarra, Annachiara Cagnin (Handling Associate Editor: Daniela Galimberti)
Specific Verbal Memory Measures May Distinguish Alzheimer’s Disease from Dementia with Lewy Bodies
Abstract: Background: Standard measures of commonly used memory tests may not be appropriate to distinguish different neurodegenerative diseases affecting memory. Objective: To study whether specific measures of verbal memory obtained with the Rey Auditory Verbal Learning test (RAVLT) could help distinguish dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD). Methods: Twenty-nine DLB and 32 AD patients participated in the study and were followed longitudinally for 3 years until the diagnosis was confirmed according to standard clinical criteria. Twenty-eight healthy elderly subjects served as controls. The following verbal memory measures were evaluated: verbal learning (VL), verbal forgetting (VF), percentage of verbal forgetting (VF%), and serial position effects of the immediate recall performance. Results: DLB and AD groups have comparable performances at the RAVLT immediate and delayed recall tasks. However, VL was higher in DLB than AD while VF% was greater in AD. With a VF% cut-off ≥75%, AD and DLB patients were differently distributed, with 58% of AD versus 21% of DLB above this cut-off. The recency effect was significant higher in AD than DLB. Discussion: DLB patients had a better performance in VL than AD, but worse VF and recency effect. These specific measures of verbal memory could be used as cognitive markers in the differential diagnosis between these two conditions.

Pages 1017-1026
Per Johansson, Erik G. Almqvist, Maria Bjerke, Anders Wallin, Jan-Ove Johansson, Ulf Andreasson, Kaj Blennow, Henrik Zetterberg, Johan Svensson
Reduced Cerebrospinal Fluid Concentration of Apolipoprotein A-I in Patients with Alzheimer’s Disease
Abstract: Background: Apolipoprotein E (ApoE) has been extensively studied in Alzheimer's disease (AD), but little is known of apolipoprotein A-I (ApoA-I) in cerebrospinal fluid (CSF). Objective: Plasma lipids as well as ApoA-I and ApoE in plasma and CSF were determined and related to Mini-Mental State Examination (MMSE) score, APOE genotype, and CSF AD biomarkers. Methods: Consecutive patients with AD (n = 29), stable mild cognitive impairment (n = 13), other dementias (n = 14), and healthy controls (n = 18) were included at a single center. Results: AD patients had higher plasma triglycerides and lower CSF ApoA-I concentration than controls (both p < 0.05). CSF ApoE concentration was reduced in other dementias (p < 0.01). In AD as well as other dementias, the ratios between CSF and plasma concentrations of both ApoA-I and ApoE were lower than those in the controls. ApoA-I and ApoE in plasma and CSF were not influenced by APOE ε4 allele distribution. In the total study population (n = 74), CSF ApoA-I correlated positively with MMSE score (r = 0.26, p < 0.05) and negatively with CSF P-tau (r = -0.25, p < 0.05). CSF ApoE correlated positively with CSF concentrations of T-tau and P-tau in the total study population and in AD patients. Conclusion: CSF ApoA-I was reduced in AD patients and associated with measures of cognitive function and AD disease status. The mechanisms underlying the decreased CSF:plasma ratios of ApoA-I and ApoE in AD and other dementias need to be explored in further studies.

Pages 1027-1035
Catherine C. Price, Cynthia Garvan, Loren Hizel, Marcos G. Lopez, Frederic T. Billings IV
Delayed Recall and Working Memory MMSE Domains Predict Delirium following Cardiac Surgery
Abstract: Background: Reduced preoperative cognition is a risk factor for postoperative delirium. The significance for type of preoperative cognitive deficit, however, has yet to be explored and could provide important insights into mechanisms and prediction of delirium. Objective: Our goal was to determine if certain cognitive domains from the general cognitive screener, the Mini-Mental State Exam (MMSE), predict delirium after cardiac surgery. Methods: Patients completed a preoperative MMSE prior to undergoing elective cardiac surgery. Following surgery, delirium was assessed throughout ICU stay using the Confusion Assessment Method for ICU delirium and the Richmond Agitation and Sedation Scale. Results: Cardiac surgery patients who developed delirium (n=137) had lower total MMSE scores than patients who did not develop delirium (n=457). In particular, orientation to place, working memory, delayed recall, and language domain scores were lower. Of these, only the working memory and delayed recall domains predicted delirium in a regression model adjusting for history of chronic obstructive pulmonary disease, age, sex, and duration of cardiopulmonary bypass. For each word not recalled on the three-word delayed recall assessment, the odds of delirium increased by 50%. For each item missed on the working memory index, the odds of delirium increased by 36%. Of the patients who developed delirium, 47% had a primary impairment in memory, 21% in working memory, and 33% in both domains. The area under the receiver operating characteristics curve using only the working memory and delayed recall domains was 0.75, compared to 0.76 for total MMSE score. Conclusion: Delirium risk is greater for individuals with reduced MMSE scores on the delayed recall and working memory domains. Research should address why patients with memory and executive vulnerabilities are more prone to postoperative delirium than those with other cognitive limitations.

Pages 1037-1044
Yachen Shi, Lihua Gu, Abdul Azeez Alsharif, Zhijun Zhang
The Distinction of Amyloid-β Protein Precursor (AβPP) Ratio in Platelet Between Alzheimer’s Disease Patients and Controls: A Systematic Review and Meta-Analysis
Abstract: To systematically assess the clinical significance of platelet amyloid-β protein precursor (AβPP) ratio between Alzheimer’s disease (AD) patients and controls. 14 articles were selected in this analysis by search of databases including PubMed and Web of Science up to December 2016. Random effects models were used to calculate the standardized mean difference (SMD). Subgroup analyses were used to detect the cause of heterogeneity. The result showed a significant drop in platelet AβPP ratio in AD patients compared to controls [SMD: -1.871; 95% CI: (-2.33,-1.41); p<0.001; I2=88.0%]. Subgroup analysis revealed races or the quality of studies may be the cause of high heterogeneity. This meta-analysis concluded that there is a close association between platelet AβPP ratio and AD. It is necessary to design a sizable sample study to further support that platelet AβPP ratio can be a biomarker of AD.

Pages 1045-1055
Alpha Tom Kodamullil, Anandhi Iyappan*, Reagon Karki*, Sumit Madan, Erfan Younesi, Martin Hofmann-Apitius *These authors contributed equally to this work.
Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models
Abstract: Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species.

Pages 1057-1065
Cláudia Y. Santos, Jason T. Machan, Wen-Chih Wu, Peter J. Snyder (Handling Associate Editor: Tim Ostrowski)
Autonomic Cardiac Function in Preclinical Alzheimer’s Disease
Abstract: To explore early autonomic cardiac changes in pre-clinical Alzheimer’s disease (AD), we have evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55-75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18F-Florbetapir) to determine amyloid positivity (Aβ+). No change in electrocardiographic measures were observed for Aβ+ participants under each testing condition, whereas Aβ- subjects showed an expected increase in vagal tone during the cognitive stress condition. These findings suggest an early relationship between cortical Aβ accumulation, a precursor to AD development, and autonomic cardiac function.

Pages 1067-1078
Meina Wu, Hui Shi, Yexin He, Li Yuan, Xuesong Qu, Jun Zhang, Zhaojun Wang, Hongyan Cai, Jinshun Qi (Handling Associate Editor: Zhiqian Tong)
Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia, and effective therapeutics are lacking. Colivelin (CLN), a novel, strong humanin derivative, is effective in vitro in preventing cell death induced by AD-causative genes and amyloid-β protein (Aβ) even at a low concentration. We recently demonstrated that intrahippocampal injection of CLN prevents Aβ25–35-induced deficits in spatial memory and synaptic plasticity in normal rats. Here, we further observed the effects of chronically intranasally (i.n.) administered CLN on cognitive behaviors and pathological hallmarks in 9-month-old APPswe/PS1dE9 (APP/PS1) AD mice using multiple behavioral tests and immunochemistry. The electrophysiological mechanism of CLN neuroprotection was also investigated by recording in vivo hippocampal long-term potentiation (LTP). CLN pretreatment effectively prevented impairments in new object recognition, working memory, and long-term spatial memory and reversed the depression of in vivo hippocampal LTP in APP/PS1 mice. Additionally, chronic application of CLN obviously reduced Aβ deposition in the hippocampus in APP/PS1 mice. These results indicate that CLN has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Aβ deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD.

Pages 1079-1096
Gisela Esquerda-Canals, Joaquim Martí-Clúa, Alejandro R. Roda, Sandra Villegas
An Intracellular Amyloid-β/AβPP Epitope Correlates with Neurodegeneration in those Neuronal Populations Early Involved in Alzheimer’s Disease
Abstract: The main histopathological hallmarks of Alzheimer's disease (AD) are the extracellular deposition of neuritic amyloid plaques, composed of amyloid-β (Aβ) peptide, and the intracellular accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau. Both traits are emulated in the 3xTg-AD mouse model. Because the relevance of this model in the bibliography and the main role of Aβ in neuronal impairment, here we have detailed the brain Aβ/AβPP distribution to subsequently quantify cellular density and intracellular burden for specific neuronal populations in the early stages of the disease. 6E10 immunoreactivity was evident in the deep layers of the cerebral cortex, in the pyramidal cell layer of the hippocampus, in the basolateral amygdala nucleus, and in the deep cerebellar nuclei macroneurons; whereas the specific neuronal populations with decreased cellular density were the large pyramidal neurons from the layers V-VI in the cerebral cortex, the pyramidal neurons from the CA2-3 region in the hippocampus, and the large neurons from the basolateral nucleus in the amygdala, apart from the already reported deep cerebellar nuclei. Interestingly, we found a strong correlation between intracellular Aβ/AβPP burden and cellular density in all these populations. In addition, behavioral testing showed the functional consequences of such a neuronal depletion. Concretely, anxious-like behavior is manifested in the corner and open-field tests, as well as cognitive functions shown to be impaired in the novel object recognition test and Morris water maze paradigm. To our knowledge, this is the first deep characterization of the specific neuronal populations affected in the 3xTg-AD mouse model.

Pages 1097-1111
Olivia C. Küster, Daria Laptinskaya, Patrick Fissler, Cathrin Schnack, Martina Zügel, Verena Nold, Franka Thurm, Sina Pleiner, Alexander Karabatsiakis, Björn von Einem, Patrick Weydt, Andre Liesener, Andreas Borta, Alexander Woll, Bastian Hengerer, Iris-Tatjana Kolassa, and Christine A.F. von Arnim (Handling Associate Editor: Thomas Leyhe)
Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway
Abstract: Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings.

Pages 1113-1122
Jodi D. Edwards*, Joel Ramirez*, Brandy L. Callahan, Sheldon W. Tobe, Paul Oh, Courtney Berezuk, Krista Lanctôt, Walter Swardfager, Sean Nestor, Alexander Kiss, Stephen Strother, Sandra E. Black, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Antihypertensive Treatment is associated with MRI-Derived Markers of Neurodegeneration and Impaired Cognition: A Propensity-Weighted Cohort Study
Abstract: Background: Hypertension is an important risk factor for Alzheimer’s disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid. Objective: The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication. Methods: We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N=886; mean age=75.0) from the Alzheimer’s Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition. Results: Individuals treated with ARBs showed larger hippocampal volumes (R2=0.83, p=0.05) and brain parenchymal fraction (R2=0.83, p=0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2=0.83, p=0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p<0.05). Conclusions: Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD.

Pages 1123-1137
Lindsey I. Sinclair, Seth Love
Effect of APOE Genotype on Synaptic Proteins in Earlier Adult Life
Abstract: Background: Possession of APOE 4 is a strong risk factor for late-onset Alzheimer’s disease and is associated with loss of synaptic proteins in the elderly even in the absence of Alzheimer’s disease. Objective: We hypothesized that ε4 allele possession in non-demented adults aged under-75 would also be associated with alterations in the levels of synaptic proteins. Methods: We measured synaptophysin, PSD95, drebrin, SNAP-25, and septin 7 by ELISA in hippocampus and superior temporal gyrus from 103 adults aged <75 without dementia. Corresponding gene expression was measured by RT-PCR. Results: There was no evidence that ε4 affected levels of the proteins measured. Instead we found an increase in post-synaptic proteins in the hippocampi of those with an 32 genotype. The evidence was strongest for drebrin (p=0.011). There was some evidence of increased synaptic protein gene expression in ε4 carriers. Conclusions: People with an APOE ε32 genotype have a reduced risk of Alzheimer’s disease. It may be relevant that they have a higher level of post-synaptic proteins in the hippocampus even in earlier adulthood.