Investigation on the Role of BDNF in the Benefits of Blueberry Extracts for the Improvement of Learning and Memory in Alzheimer's Disease Mouse Model. - Tan, Long; Yang, Hongpeng; Pang, Wei; Li, Haiqiang; Liu, Wei; Sun, Shoudan; Song, Nan; Zhang, Wanqi; Jiang, Yugang (J Alzheimers Dis, 2017)
BACKGROUND: Blueberry (BB) can provide a wide range of antioxidant benefits for AD. There is evidence that BB extracts could improve brain functions. However, the details are still unknown. OBJECTIVE: In the present study, we aimed to investigate the possible mechanism involved in the improvement of learning and memory capacity from BB extracts in AD. METHODS: APP/PS1 transgenic mice were fed BB extracts for 16 weeks. The capacity of learning and memory was assessed by Morris water maze (MWM) test, and long-term potentiation (LTP) was determined to evaluate hippocampal neuronal plasticity at the end of administration. Pathological changes in the brain were observed, and the expressions of brain-derived neurotrophic factor (BDNF) and extracellular signal-related kinase (ERK1/2) were determined to explore the mechanism of BB extract-induced benefits. RESULTS: AD mice exhibited more difficulties to learn and remember the exact position of the platform in the MWM test. The data showed that AD mice lacked effective learning in the platform search. In contrast, AD mice exhibited better performance both in the training phase and probe test of MWM after the BB treatment. Moreover, LTP was enhanced and the neuron loss was alleviated with BB treatment, while we did not find any obvious effect on the elimination of amyloid-β. In the AD mice, the expression of ERK1/2 was significantly increased (p < 0.05), while the level of BDNF was decreased (p < 0.05). CONCLUSIONS: BB treatment was beneficial for the improvement of learning and memory of AD, and these effects might be related to the regulation of BDNF.

Kidins220 Correlates with Tau in Alzheimer's Disease Brain and Cerebrospinal Fluid. - Gamir-Morralla, Andrea; Belbin, Olivia; Fortea, Juan; Alcolea, Daniel; Ferrer, Isidro; Lleo, Alberto; Iglesias, Teresa (J Alzheimers Dis, 2017)
Identification of neurodegeneration-monitoring biomarkers would be of great clinical value for Alzheimer's disease (AD) diagnosis. Using N- or C-terminal antibodies, we studied the pro-survival synaptic effector, Kidins220, in the brain and cerebrospinal fluid (CSF) of controls and AD patients. Only the N-terminal antibody showed a positive correlation between Kidins220 and phosphorylated tau in AD brains. Using this antibody, Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. This study highlights the potential of Kidins220 as a CSF biomarker in AD.

The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins. - Bharadwaj, Prashant; Wijesekara, Nadeeja; Liyanapathirana, Milindu; Newsholme, Philip; Ittner, Lars; Fraser, Paul; Verdile, Giuseppe (J Alzheimers Dis, 2017)
A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aβ and hyperphosphorylated tau may also have roles in pancreatic β-cell dysfunction and in reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet β-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to β-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aβ to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβ and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes.

Lipid Peroxidation Markers in Coronary Artery Disease Patients with Possible Vascular Mild Cognitive Impairment. - Suridjan, Ivonne; Herrmann, Nathan; Adibfar, Alex; Saleem, Mahwesh; Andreazza, Ana; Oh, Paul I; Lanctôt, Krista L (J Alzheimers Dis, 2017)
This study examined associations between lipid peroxidation markers and cognition, and associations between these markers and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia. Lipid peroxidation products were measured in serum in 118 patients (29 possible vascular mild cognitive impairment and 89 controls). Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated. Cognitive performance was assessed before and at completion of a 24-week exercise intervention program. A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, and cardiopulmonary fitness (main effect of group F (3,102) = 2.957, p = 0.036). Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p = 0.03) and executive function (F (1, 64) = 5.219, p = 0.026) performance. Similarly, higher ratios of 8-ISO/LPH (F (1, 65) = 6.592, p = 0.013) and (8-ISO+4-HNE) to LPH (F (1, 65) = 3.857, p = 0.054), were associated with less improvement in executive function performance over a 24-week exercise intervention. Lipid peroxidation may be a biomarker of early vascular cognitive impairment, and elevated lipid peroxidation might limit the cognitive benefits of exercise in this high-risk population.

A Lipidomics Approach to Assess the Association Between Plasma Sphingolipids and Verbal Memory Performance in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation: A C18:0 Signature for Cognitive Response to Exercise. - Saleem, Mahwesh; Herrmann, Nathan; Dinoff, Adam; Mielke, Michelle M; Oh, Paul I; Shammi, Prathiba; Cao, Xingshan; Venkata, Swarajya Lakshmi Vattem; Haughey, Norman J; Lanctôt, Krista L (J Alzheimers Dis, 2017)
BACKGROUND: Early subtle deficits in verbal memory, which may indicate early neural risk, are common in patients with coronary artery disease (CAD). While exercise can improve cognition, cognitive response to exercise is heterogeneous. Sphingolipids have been associated with the development and progression of CAD, and impairments in sphingolipid metabolism may play roles in neurodegeneration and in the neural adaptation response to exercise. OBJECTIVE: In this study, change in plasma concentrations of sphingolipids was assessed in relation to change in verbal memory performance and in other cognitive domains among CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program. METHODS: Patients with CAD (n = 120, mean age = 64±6 y, 84% male, years of education = 16±3) underwent CR with neuropsychological assessments and blood collected at baseline, 3-, and 6-months. Z-scores based on age, gender, and education were combined for verbal memory, visuospatial memory, processing speed, executive function, and global cognition tasks to calculate cognitive domain Z-scores. Plasma sphingolipid concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Mixed models were used to identify sphingolipids significantly associated with performance in verbal memory and other cognitive domains, adjusting for potential confounders. RESULTS: A decrease in ceramide C18:0 concentration was significantly associated with improvement in verbal memory performance (b[SE] = -0.51 [0.25], p = 0.04), visuospatial memory (b[SE] = -0.44 [0.22], p = 0.05), processing speed (b[SE] = -0.89 [0.32], p = 0.007), and global cognition (b[SE] = -1.47 [0.59], p = 0.01) over 6 months of CR. CONCLUSIONS: Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in patients with CAD.

Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes. - Del Prete, Dolores; Suski, Jan M; Oulès, Bénédicte; Debayle, Delphine; Gay, Anne Sophie; Lacas-Gervais, Sandra; Bussiere, Renaud; Bauer, Charlotte; Pinton, Paolo; Paterlini-Bréchot, Patrizia; Wieckowski, Mariusz R; Checler, Frédéric; et al. (J Alzheimers Dis, 2017)
Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

Logopenic Aphasia due to a Strategic Stroke: New Evidence from a Single Case. - Riancho, Javier; Pozueta, Ana; Santos, Miguel; Lage, Carmen; Carril, José M; Banzo, Ignacio; Martínez-Rodriguez, Isabel; Gorno-Tempini, Marilu; Sánchez-Juan, Pascual (J Alzheimers Dis, 2017)
Among primary progressive aphasias (PPAs), logopenic variant PPA (lv-PPA) is usually related to Alzheimer's disease. Although it has been widely clinically and pathologically evaluated, the topography in LPA is still controversial. We report a patient presenting with a logopenic syndrome due to a strategic lesion located in the superior and middle temporal gyrus and compare our findings with those of a PiB-PET positive lv-PPA patient matched by age, gender, and education. We consider that our study provides new anatomical clues to better understand the cognitive mechanisms underlying the logopenic syndrome.
Keywords: Aphasia; Atrophy; Brain; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Stroke

Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model. - Waldron, Ann-Marie; Wyffels, Leonie; Verhaeghe, Jeroen; Richardson, Jill C; Schmidt, Mark; Stroobants, Sigrid; Langlois, Xavier; Staelens, Steven (J Alzheimers Dis, 2017)
We aimed to monitor the timing of amyloid-β deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer's disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-β is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. - Kramberger, Milica G; Auestad, Bjørn; Garcia-Ptacek, Sara; Abdelnour, Carla; Olmo, Josep Garre; Walker, Zuzana; Lemstra, Afina W; Londos, Elisabet; Blanc, Frédéric; Bonanni, Laura; McKeith, Ian; Winblad, Bengt; et al. (J Alzheimers Dis, 2017)
BACKGROUND/OBJECTIVE: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients. METHODS: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features. RESULTS: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features. CONCLUSIONS: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Cognition Disorders; Cohort Studies; Female; Humans; International Cooperation; Lewy Body Disease; Male; Mental Status Schedule; Middle Aged

Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala713Thr Mutation Carrier. - Lombardi, Gemma; Berti, Valentina; Tedde, Andrea; Bagnoli, Silvia; Piaceri, Irene; Polito, Cristina; Lucidi, Giulia; Ferrari, Camilla; Ginestroni, Andrea; Moretti, Marco; Pupi, Alberto; Nacmias, Benedetta; et al. (J Alzheimers Dis, 2017)
According to the literature, the APP Ala713Thr mutation is associated with Alzheimer's disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.
Keywords: Alanine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Brain; Ethylene Glycols; Humans; Male; Middle Aged; Mutation; Peptide Fragments; Positron-Emission Tomography; Threonine

Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer's Disease. - Chen, Yaohua; Sillaire, Adeline Rollin; Dallongeville, Jean; Skrobala, Emilie; Wallon, David; Dubois, Bruno; Hannequin, Didier; Pasquier, Florence (J Alzheimers Dis, 2017)
BACKGROUND: Determinants of early-onset Alzheimer's disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation. OBJECTIVE: The objective of this study was to assess the putative association between VRFs and EOAD. METHODS: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses. RESULTS: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; p < 0.0001), were less likely to be regular alcohol consumers (p < 0.0001), had a lower body mass index (-2 kg/m2; p < 0.0004), and a lower mean systolic blood pressure (-6.2 mmHg; p = 0.0036). The prevalence of APOE ɛ4 allele was higher in participants with dementia than in controls (50% versus 29.4%; p = 0.0002), as was the prevalence of depression (48% versus 32%; p < 0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; p = 0.03). CONCLUSION: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD.

Meta-Analysis of Parkinson's Disease and Alzheimer's Disease Revealed Commonly Impaired Pathways and Dysregulation of NRF2-Dependent Genes. - Wang, Qian; Li, Wen-Xing; Dai, Shao-Xing; Guo, Yi-Cheng; Han, Fei-Fei; Zheng, Jun-Juan; Li, Gong-Hua; Huang, Jing-Fei (J Alzheimers Dis, 2017)
Many lines of evidence suggest that Parkinson's disease (PD) and Alzheimer's disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD.

Metabolic and Growth Rate Alterations in Lymphoblastic Cell Lines Discriminate Between Down Syndrome and Alzheimer's Disease. - Coskun, Pinar; Helguera, Pablo; Nemati, Zahra; Bohannan, Ryan C; Thomas, Jean; Samuel, Schriner E; Argueta, Jocelyn; Doran, Eric; Wallace, Douglas C; Lott, Ira T; Busciglio, Jorge (J Alzheimers Dis, 2017)
BACKGROUND: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer's disease (AD) and these alterations in mitochondria occur systemically in both conditions. OBJECTIVE: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls. METHODS: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy. RESULTS: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS. CONCLUSION: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes.

A Metal-Free Method for Producing MRI Contrast at Amyloid-β. - Hilt, Silvia; Tang, Tang; Walton, Jeffrey H; Budamagunta, Madhu; Maezawa, Izumi; Kálai, Tamás; Hideg, Kálmán; Singh, Vikrant; Wulff, Heike; Gong, Qizhi; Jin, Lee-Way; Louie, Angelique; et al. (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a  fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of spin-labeled fluorene into live mice resulted in good brain penetration, with the compound able to generate contrast 24-h post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by MRI.

A Method for Diagnosing Alzheimer's Disease Based on Salivary Amyloid-β Protein 42 Levels. - Lee, Moonhee; Guo, Jian-Ping; Kennedy, Krista; McGeer, Edith G; McGeer, Patrick L (J Alzheimers Dis, 2017)
We have developed a non-invasive method of diagnosing Alzheimer's disease (AD), which can also predict the risk of its future onset. It is based on measuring salivary levels of amyloid-β protein terminating at position 42 (Aβ42). Brain deposits of this peptide are characteristic of AD. Biomarker studies indicate that such brain deposits commence a decade or more prior to clinical onset of the disease. We report here that Aβ42 is produced in all peripheral organs tested, thus establishing the generality of its production. We used this information to develop simple and sensitive tests to determine salivary Aβ42 levels. The levels were first stabilized by adding thioflavin S as an anti-aggregation agent and sodium azide as an anti-bacterial agent. We then quantitated the Aβ42 in a series of samples with ELISA type tests. Control cases showed almost identical levels of salivary Aβ42 regardless of sex or age. All AD cases secreted levels of Aβ42 more than double those of controls. Individuals at elevated risk of developing AD secreted levels comparable to the AD cases. The results establish that salivary Aβ42 levels can be used to diagnose AD as well as to predict the risk of its future onset.

MicroRNA Profile in Patients with Alzheimer's Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples. - Riancho, Javier; Vázquez-Higuera, José Luis; Pozueta, Ana; Lage, Carmen; Kazimierczak, Martha; Bravo, María; Calero, Miguel; Gonalezález, Andrea; Rodríguez, Eloy; Lleo, Alberto; Sánchez-Juan, Pascual (J Alzheimers Dis, 2017)
BACKGROUND: MicroRNAs have been postulated as potential biomarkers for Alzheimer's disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders. OBJECTIVE: i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients. METHODS: A panel of 760 microRNAs was analyzed in the CSF of 10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls. RESULTS: Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects. CONCLUSION: These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers.

MicroRNAs in Human Cerebrospinal Fluid as Biomarkers for Alzheimer's Disease. - Lusardi, Theresa A; Phillips, Jay I; Wiedrick, Jack T; Harrington, Christina A; Lind, Babett; Lapidus, Jodi A; Quinn, Joseph F; Saugstad, Julie A (J Alzheimers Dis, 2017)
BACKGROUND: Currently available biomarkers of Alzheimer's disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD. OBJECTIVE: Investigate miRNAs in CSF obtained from living donors as biomarkers for AD. METHODS: We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated. RESULTS: We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80-0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84. CONCLUSIONS: CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification.

Midlife Metabolic Profile and the Risk of Late-Life Cognitive Decline. - Tortelli, Rosanna; Lozupone, Madia; Guerra, Vito; Barulli, Maria Rosaria; Imbimbo, Bruno P; Capozzo, Rosa; Grasso, Alessandra; Tursi, Marianna; Di Dio, Cristina; Sardone, Rodolfo; Giannelli, Gianluigi; Seripa, Davide; et al. (J Alzheimers Dis, 2017)
Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

The Mild Behavioral Impairment Checklist (MBI-C): A Rating Scale for Neuropsychiatric Symptoms in Pre-Dementia Populations. - Ismail, Zahinoor; Agüera-Ortiz, Luis; Brodaty, Henry; Cieslak, Alicja; Cummings, Jeffrey; Fischer, Corinne E; Gauthier, Serge; Geda, Yonas E; Herrmann, Nathan; Kanji, Jamila; Lanctôt, Krista L; Miller, David S; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described. OBJECTIVE: To develop an instrument based on ISTAART-AA MBI criteria. METHODS: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults. RESULTS: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician. CONCLUSION: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes.

Mitochondrial Abnormalities and Synaptic Loss Underlie Memory Deficits Seen in Mouse Models of Obesity and Alzheimer's Disease. - Martins, Isaura V A; Rivers-Auty, Jack; Allan, Stuart M; Lawrence, Catherine B (J Alzheimers Dis, 2017)
Obesity is associated with impaired memory in humans, and obesity induced by high-fat diets leads to cognitive deficits in rodents and in mouse models of Alzheimer's disease (AD). However, it remains unclear how high-fat diets contribute to memory impairment. Therefore, we tested the effect of a high-fat diet on memory in male and female control non-transgenic (Non-Tg) and triple-transgenic AD (3xTgAD) mice and determined if a high-fat diet caused similar ultrastructural abnormalities to those observed in AD. Behavior was assessed in mice on control or high-fat diet at 4, 8, or 14 months of age and ultrastructural analysis at 8 months of age. A high-fat diet increased body weight, fat weight, and insulin levels with some differences in these metabolic responses observed between Non-Tg and 3xTgAD mice. In both sexes, high-fat feeding caused memory impairments in Non-Tg mice and accelerated memory deficits in 3xTgAD mice. In 3xTgAD mice, changes in hippocampal mitochondrial morphology were observed in capillaries and brain neuropil that were accompanied by a reduction in synapse number. A high-fat diet also caused mitochondria abnormalities and a reduction in synapse number in Non-Tg mice, but did not exacerbate the changes seen in 3xTgAD mice. Our data demonstrate that a high-fat diet affected memory in Non-Tg mice and produced similar impairments in mitochondrial morphology and synapse number comparable to those seen in AD mice, suggesting that the detrimental effects of a high-fat diet on memory might be due to changes in mitochondrial morphology leading to a reduction in synaptic number.

Modulating the Balance of Synaptic and Extrasynaptic NMDA Receptors Shows Positive Effects against Amyloid-β-Induced Neurotoxicity. - Huang, Yan; Shen, Wei; Su, Jie; Cheng, Bin; Li, Dong; Liu, Gang; Zhou, Wen-Xia; Zhang, Yong-Xiang (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect. In Aβ ICV-injected animals, the combination of ifenprodil and D-cycloserine (a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests (nest building, novel object recognition, and Morris water maze) than ifenprodil (Morris water maze) or D-cycloserine (nest building) alone. Signal pathway analysis showed that Aβ disturbed the GluN2A/GluN2B-related pathway. The ratio of GluN2A to GluN2B decreased in Aβ-treated animals, and TORC dephosphorylation and ERK1/2 activation, which could be initiated by GluN2A, also decreased in the hippocampal tissues of Aβ-treated animals. As a result, the activation of CREB and the content of brain-derived BDNF decreased. The combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone, indicating that Aβ-induced toxicology was mediated both by functionally inhibiting GluN2A and enhancing GluN2B. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Aβ-induced neurotoxicity, suggesting that modulation of the balance between GluN2A and GluN2B could be a potential strategy for AD drug development and therapy.
Keywords: Amyloid beta-Peptides; Animals; Antimetabolites; Cycloserine; Disease Models, Animal; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Locomotion; Male; Maze Learning; N-Methylaspartate; Nesting Behavior; Neurotoxicity Syndromes; Peptide Fragments; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recognition (Psychology); Signal Transduction; Synapses

Modulation of AβPP and GSK3β by Endoplasmic Reticulum Stress and Involvement in Alzheimer's Disease. - Liu, Xin-Jun; Wei, Jun; Shang, Ying-Hui; Huang, Han-Chang; Lao, Feng-Xue (J Alzheimers Dis, 2017)
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.

Mortality Risk after Diagnosis of Early-Onset Alzheimer's Disease versus Late-Onset Alzheimer's Disease: A Propensity Score Matching Analysis. - Chang, Ki Jung; Hong, Chang Hyung; Lee, Kang Soo; Kang, Dae Ryong; Lee, Jeong Dong; Choi, Seong Hye; Kim, Seong Yoon; Na, Duk L; Seo, Sang Won; Kim, Do-Kwan; Lee, Yunhwan; Chung, Young Ki; et al. (J Alzheimers Dis, 2017)
BACKGROUND/OBJECTIVE: We aimed to compare the risk of mortality in patients with early-onset Alzheimer's disease (EOAD) versus those with late-onset AD (LOAD) using a large number of study subjects. We applied propensity score matching (PSM) to minimize confounding biases in the comparison between EOAD and LOAD. METHODS: We obtained data from elderly Korean subjects with AD (n = 3,611) at baseline from the CREDOS cohort study, which was conducted from November 2005 to July 2013. We conducted PSM to reduce the bias due to confounding variables related to survival in patients with AD. The risks of mortality associated with EOAD and LOAD were evaluated by Cox proportional hazard analyses, controlling for relevant covariates. RESULTS: After propensity score matching, 312 subjects with EOAD and 624 subjects with LOAD were selected for further analysis. The Cox proportional hazard analysis showed that patients with EOAD are at a greater risk for mortality compared to those with LOAD (Hazard Ratio: 2.01, 95% CI: 1.01-4.00, p-value: 0.04) when controlling for the direct effect of aging on mortality. The results did not change after adjusting for age at diagnosis, general cognitive function, nutritional factor related to body mass index, and physical disability using activities of daily living. The results support the assumption that EOAD takes a more malignant course than LOAD. CONCLUSIONS: Our results provide support for the idea that EOAD takes a clinical course that is distinct from that of LOAD, especially as pertains to the risk of mortality.

Motor Phenotype in Neurodegenerative Disorders: Gait and Balance Platform Study Design Protocol for the Ontario Neurodegenerative Research Initiative (ONDRI). - Montero-Odasso, Manuel; Pieruccini-Faria, Frederico; Bartha, Robert; Black, Sandra E; Finger, Elizabeth; Freedman, Morris; Greenberg, Barry; Grimes, David A; Hegele, Robert A; Hudson, Christopher; Kleinstiver, Peter W; Lang, Anthony E; et al. (J Alzheimers Dis, 2017)
BACKGROUND: The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled. OBJECTIVE: To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients. METHODS: Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm. RESULTS: Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics. CONCLUSIONS: As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.

mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. - Lee, Han-Kyu; Kwon, Bumsup; Lemere, Cynthia A; de la Monte, Suzanne; Itamura, Kyohei; Ha, Austin Y; Querfurth, Henry W (J Alzheimers Dis, 2017)
Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42, mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD.

A Multi-Cohort Study of ApoE ɛ4 and Amyloid-β Effects on the Hippocampus in Alzheimer's Disease. - Khan, Wasim; Giampietro, Vincent; Banaschewski, Tobias; Barker, Gareth J; Bokde, Arun L W; Büchel, Christian; Conrod, Patricia; Flor, Herta; Frouin, Vincent; Garavan, Hugh; Gowland, Penny; Heinz, Anreas; et al. (J Alzheimers Dis, 2017)
The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer's disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n = 1,781), we compared the effect of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n = 1,387) was also used to compared hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in ɛ4 carriers with positron emission tomography Aβ who were dichotomized (Aβ+/Aβ-) using previous cut-offs. We found a linear reduction in hippocampal volumes with ɛ4 carriers possessing the smallest volumes, ɛ3 carriers possessing intermediate volumes, and ɛ2 carriers possessing the largest volumes. Moreover, AD and MCI ɛ4 carriers possessed the smallest hippocampal volumes and control ɛ2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ɛ4 and Aβ+ had the lowest hippocampal volumes when compared to Aβ- ɛ4 carriers, suggesting a synergistic relationship between APOE ɛ4 and Aβ. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ɛ4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.

Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-α and IL-1β in an Aβ25-35-induced Rat Model of Alzheimer's Disease. - Li, Lin; Xu, Shaofeng; Liu, Lifei; Feng, Rentian; Gong, Yongxiang; Zhao, Xuyang; Li, Jiang; Cai, Jie; Feng, Nan; Wang, Ling; Wang, Xiaoliang; Peng, Ying (J Alzheimers Dis, 2017)
The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

The Multimerization State of the Amyloid-β42 Amyloid Peptide Governs its Interaction Network with the Extracellular Matrix. - Salza, Romain; Lethias, Claire; Ricard-Blum, Sylvie (J Alzheimers Dis, 2017)
The goals of this work were i) to identify the interactions of amyloid-β (Aβ)42 under monomeric, oligomeric, and fibrillar forms with the extracellular matrix (ECM) and receptors, ii) to determine the influence of Aβ42 supramolecular organization on these interactions, and iii) to identify the molecular functions, biological processes, and pathways targeted by Aβ42 in the ECM. The ECM and cell surface partners of Aβ42 and its supramolecular forms were identified with protein and glycosaminoglycan (GAG) arrays (81 molecules in triplicate) probed by surface plasmon resonance imaging. The number of partners of Aβ42 increased upon its multimerization, ranging from 4 for the peptide up to 53 for the fibrillar aggregates. The peptide interacted only with ECM proteins but their percentage among Aβ42 partners decreased upon multimerization. Aβ42 and its supramolecular forms recognized different molecular features on their partners, and the partners of Aβ42 fibrillar forms were enriched in laminin IV-A, N-terminal, and EGF-like domains. Aβ42 oligomerization triggered interactions with receptors, whereas Aβ42 fibrillogenesis promoted binding to GAGs, proteoglycans, enzymes, and growth factors and the ability to interact with perineuronal nets. Fibril aggregation bind to further membrane proteins including tumor endothelial marker-8, syndecan-4, and discoidin-domain receptor-2. The partners of the Aβ42 supramolecular forms are enriched in proteins contributing to cell growth and/or maintenance, involved in integrin cell surface interactions and expressed in kidney cancer, preadipocytes, and dentin. In conclusion, the supramolecular assembly of Aβ42 governs its ability to interact in vitro with ECM proteins, remodeling and crosslinking ECM enzymes, proteoglycans, and receptors.

Multimodal Cognitive Enhancement Therapy for Patients with Mild Cognitive Impairment and Mild Dementia: A Multi- Center, Randomized, Controlled, Double-Blind, Crossover Trial. - Han, Ji Won; Lee, Hyeonggon; Hong, Jong Woo; Kim, Kayoung; Kim, Taehyun; Byun, Hye Jin; Ko, Ji Won; Youn, Jong Chul; Ryu, Seung-Ho; Lee, Nam-Jin; Pae, Chi-Un; Kim, Ki Woong (J Alzheimers Dis, 2017)
We developed and evaluated the effect of Multimodal Cognitive Enhancement Therapy (MCET) consisting of cognitive training, cognitive stimulations, reality orientation, physical therapy, reminiscence therapy, and music therapy in combination in older people with mild cognitive impairment (MCI) or mild dementia. This study was a multi-center, double-blind, randomized, placebo-controlled, two-period cross-over study (two 8-week treatment phases separated by a 4-week wash-out period). Sixty-four participants with MCI or dementia whose Clinical Dementia Rating was 0.5 or 1 were randomized to the MCET group or the mock-therapy (placebo) group. Outcomes were measured at baseline, week 9, and week 21. Fifty-five patients completed the study. Mini-Mental State Examination (effect size = 0.47, p = 0.013) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (effect size = 0.35, p = 0.045) scores were significantly improved in the MCET compared with mock-therapy group. Revised Memory and Behavior Problems Checklist frequency (effect size = 0.38, p = 0.046) and self-rated Quality of Life - Alzheimer's Disease (effect size = 0.39, p = 0.047) scores were significantly improved in the MCET compared with mock-therapy. MCET improved cognition, behavior, and quality of life in people with MCI or mild dementia more effectively than conventional cognitive enhancing activities did.

Neural Correlates of Self-Reference Effect in Early Alzheimer's Disease. - Gaubert, Malo; Villain, Nicolas; Landeau, Brigitte; Mézenge, Florence; Egret, Stéphanie; Perrotin, Audrey; Belliard, Serge; de la Sayette, Vincent; Eustache, Francis; Desgranges, Béatrice; Chételat, Gaël; Rauchs, Géraldine (J Alzheimers Dis, 2017)
Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer's disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

Neurocognitive and Behavioral Indexes for Identifying the Amnestic Subtypes of Mild Cognitive Impairment. - Cid-Fernández, Susana; Lindín, Mónica; Díaz, Fernando (J Alzheimers Dis, 2017)
Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer's disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants).

Neurofibrillary Tangles of Aβx-40 in Alzheimer's Disease Brains. - Lacosta, Ana-María; Insua, Daniel; Badi, Hassnae; Pesini, Pedro; Sarasa, Manuel (J Alzheimers Dis, 2017)
The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-β (Aβ) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of Aβ is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for Aβx-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or Aβx-40 in AD.

Nitrosylation of Vesicular Transporters in Brain of Amyloid Precursor Protein/Presenilin 1 Double Transgenic Mice. - Wang, Ying; Zhou, Zhu; Tan, Hua; Zhu, Shenghua; Wang, Yiran; Sun, Yingxia; Li, Xin-Min; Wang, Jun-Feng (J Alzheimers Dis, 2017)
Nitric oxide can attack thiol groups of cysteine residues in proteins and induce protein cysteine S-nitrosylation. Cholinergic and glutamatergic systems are dysregulated in Alzheimer's disease. Vesicular acetylcholine transporter (VAChT) and vesicular glutamate transporter 1 (VGLUT1) are important in packaging acetylcholine and glutamate into vesicles, which is an important step for neurotransmission. Previously we found that VAChT and VGLUT1 can be nitrosylated and that S-nitrosylation of these transporters inhibits vesicular uptake of acetylcholine and glutamate. To understand the role of VAChT and VGLUT1 nitrosylation in the pathophysiological development of Alzheimer's disease, we analyzed nitrosylation of VAChT and VGLUT1 in brain of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice, an animal model for Alzheimer's disease. Using a Morris water maze test, we found that 9- and 12-month-old APP/PS1 mice showed memory deficit, compared to wild type mice. We further found that total protein nitrosylation was increased in frontal cortex and hippocampus of 9- and 12-month-old APP/PS1 mice. Although nitrosylation of VAChT and VGLUT1 was not changed in hippocampus of 9- and 12-month-old APP/PS1 mice, nitrosylation of VAChT and VGLUT1 was significantly increased in frontal cortex of APP/PS1 mice at these ages. We also found that nitrosylation of VAChT and VGLUT1 was increased in hippocampus (but not frontal cortex) of 3-month-old APP/PS1 mice. These findings suggest that nitrosylation of VAChT and VGLUT1 may be associated with dysfunctional acetylcholinergic and glutamatergic neurotransmission in Alzheimer's disease.

No Genetic Overlap Between Circulating Iron Levels and Alzheimer's Disease. - Lupton, Michelle K; Benyamin, Beben; Proitsi, Petroula; Nyholt, Dale R; Ferreira, Manuel A; Montgomery, Grant W; Heath, Andrew C; Madden, Pamela A; Medland, Sarah E; Gordon, Scott D; Lovestone, Simon; Tsolaki, Magda; et al. (J Alzheimers Dis, 2017)
Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.

Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization. - Lewczuk, Piotr; Lelental, Natalia; Lachmann, Ingolf; Holzer, Max; Flach, Katharina; Brandner, Sebastian; Engelborghs, Sebastiaan; Teunissen, Charlotte E; Zetterberg, Henrik; Molinuevo, José Luis; Mroczko, Barbara; Blennow, Kaj; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF). OBJECTIVE: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF. METHODS: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method. RESULTS: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. CONCLUSION: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.

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. - Küster, Olivia C; Laptinskaya, Daria; Fissler, Patrick; Schnack, Cathrin; Zügel, Martina; Nold, Verena; Thurm, Franka; Pleiner, Sina; Karabatsiakis, Alexander; von Einem, Björn; Weydt, Patrick; Liesener, André; et al. (J Alzheimers Dis, 2017)
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.

A Novel Method for Direct Assessment of Everyday Competence Among Older Adults. - Czaja, Sara J; Loewenstein, David A; Sabbag, Samir A; Curiel, Rosie E; Crocco, Elizabeth; Harvey, Philip D (J Alzheimers Dis, 2017)
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.

Occupational Attainment as Risk Factor for Progression from Mild Cognitive Impairment to Alzheimer's Disease: A CREDOS Study. - Myung, Woojae; Lee, Chunsoo; Park, Jin Hong; Woo, Sook-Young; Kim, Seonwoo; Kim, Sangha; Chung, Jae Won; Kang, Hyo Shin; Lim, Shinn-Won; Choi, Junbae; Na, Duk L; Kim, Seong Yoon; et al. (J Alzheimers Dis, 2017)
High occupational attainment has been known as a marker of cognitive reserve. Previous studies in the general population have shown that high occupational attainment is associated with reduced risk of Alzheimer's disease (AD). However, few studies have assessed the effect of occupational attainment on the clinical course of mild cognitive impairment (MCI). In this study, we evaluated whether individuals with high occupational attainment show more frequent progression from MCI to AD. Participants (n = 961) with MCI were recruited from a nationwide, hospital-based multi-center cohort, and were followed for up to 60 months (median: 17.64, interquartile range [12.36, 29.28]). We used Cox regression for competing risks to analyze the effect of occupational attainment on development of AD, treating dementia other than AD as a competing risk. Among the 961 individuals with MCI, a total of 280 (29.1%) converted to dementia during the follow-up period. The risk of progression to AD was higher in the individuals with high occupational attainment after controlling for potential confounders (hazard ratio = 1.83, 95% confidence interval = 1.25-2.69, p = 0.002). High occupational attainment in individuals with MCI is an independent risk factor for higher progression rate of MCI to AD. This result suggests that the protective effect of high occupational attainment against cognitive decline disappears in the MCI stage, and that careful assessment of occupational history can yield important clinical information for prognosis in individuals with MCI.

One-Year Evolution of Behavioral and Psychological Symptoms of Dementia in Patients Initially Hospitalized in Cognitive Behavioral Units: The EVITAL Prospective Cohort. - Rouch, Isabelle; Pongan, Elodie; Trombert, Béatrice; Fabre, Florence; Auguste, Nicolas; Sellier, Claire; Freulon, Magalie; Jacqueline, Sophie; Federico, Denis; Mouchoux, Christelle; Martin-Gaujard, Géraldine; Krolak-Salmon, Pierre; et al. (J Alzheimers Dis, 2017)
BACKGROUND: The 2008-2012 French Alzheimer's Plan has provided hospital Cognitive and Behavioral Units (CBU) to improve the management of patients with productive behavioral and psychological symptoms of dementia (BPSD). Little is known concerning the behavioral outcome of these patients after discharge. OBJECTIVE: The present study investigated the long-term evolution of BPSD over one year after CBU discharge. METHODS: The EVITAL cohort included 221 participants admitted to the CBUs of 3 French hospitals. BPSD were collected using the Neuropsychiatric Inventory (NPI) at admission and 3, 6, and 12 months after hospitalization. The global NPI score evolution was assessed using a linear mixed-effect model. A four-factor model of the NPI including behavioral dyscontrol, psychosis, mood, and agitation subscores was also analyzed. RESULTS: Our analysis focused on 148 patients followed up during 12 months and evaluated at each visit. The global NPI score was 48.5 (SD 21.7) at baseline, 28.8 (SD 18.7) at 3-month, 23.2 (SD 16.4) at 6-month and 20.9 (SD 15.9) at 12-month follow-up. The score significantly decreased from baseline to follow-up (F = 109.3 p < 0.0001). Moreover, the decrease was observed for each NPI subscores. The Clinical Dementia Rating (CDR) scale score was significantly linked to the baseline NPI score (t = 2.76, p = 0.009). Conversely, the NPI decline was observed whatever the CDR level. CONCLUSION: The present study showed a decrease in the global NPI score and all its subscores during the year following the CBU hospitalization, regardless of the initial CDR score.

Optical Coherence Tomography Reveals Retinal Neuroaxonal Thinning in Frontotemporal Dementia as in Alzheimer's Disease. - Ferrari, Laura; Huang, Su-Chun; Magnani, Giuseppe; Ambrosi, Alessandro; Comi, Giancarlo; Leocani, Letizia (J Alzheimers Dis, 2017)
BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are leading causes of cognitive decline. Optical coherence tomography (OCT) allows the measurement of thickness of retinal neuroaxonal layers. While in AD and mild cognitive impairment (MCI), retinal nerve fiber layer (RNFL) thinning is frequently reported, less information is available on ganglion cell layer-inner plexiform layer (GCL-IPL). Data on FTD are lacking. OBJECTIVE: To obtain cross-sectional information on RNFL and GCL-IPL thickness among MCI, AD, FTD, and healthy controls (HC), and their correlations with dementia severity. METHODS: Peripapillary OCT scans were obtained in 27 MCI, 39 AD, 17 FTD, 49 HC using high-definition Heidelberg Spectral-domain OCT, with RNFL and GCL-IPL thickness measurement. Statistical analysis tested group effects and correlation with gender, disease duration and severity (Mini-Mental State Examination, MMSE). RESULTS: RNFL showed a significant group effect [F(4,132) = 3.786, p = 0.006], being reduced versus controls in MCI (p = 0.033), moderate AD (p = 0.025), and FTD (p < 0.001), and versus mild AD in FTD (p = 0.042). GCL-IPL showed a significant group effect as well [F(4,121) = 5.104, p < 0.001], with reduction in moderate AD versus HC (p < 0.001), MCI (p = 0.037), and mild AD (p = 0.009); in FTD versus HC (p = 0.002) and mild AD (p = 0.038). In AD, GCL-IPL correlated with MMSE (r = 0.487, p = 0.003), without significant effects of age, gender, or disease duration. CONCLUSION: Retinal neuroaxonal thinning occurs in MCI/AD consistently with previous reports, as well as in FTD. Correlation with disease severity in AD suggests that retinal and brain neurodegeneration may occur in parallel to some extent, and prompts larger studies aimed at providing surrogate endpoints for clinical trials in AD.

Overexpression of Kinesin Superfamily Motor Proteins in Alzheimer's Disease. - Hares, Kelly; Miners, James Scott; Cook, Amelia Jane; Rice, Claire; Scolding, Neil; Love, Seth; Wilkins, Alastair (J Alzheimers Dis, 2017)
Defects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer's disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-β protein precursor (AβPP), and amyloid-β (Aβ) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains. Expression of KIF5A, KIF1B, and KIF21B at gene and protein level was significantly increased in AD. KIF5A protein expression correlated inversely with the levels of AβPP and soluble Aβ in AD brains. Upregulation of KIFs may be an adaptive response to impaired axonal transport in AD.

Overexpression of Ubiquilin-1 Alleviates Alzheimer's Disease-Caused Cognitive and Motor Deficits and Reduces Amyloid-β Accumulation in Mice. - Adegoke, Oludotun O; Qiao, Fangfang; Liu, Yanying; Longley, Kirsty; Feng, Shelley; Wang, Hongmin (J Alzheimers Dis, 2017)
Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer's disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology has not been determined in animal models. To understand the function of Ubqln1 in vivo, we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the AβPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-β 40 (Aβ40) and Aβ42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aβ plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AβPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory, but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders.

Palmitate Increases β-site AβPP-Cleavage Enzyme 1 Activity and Amyloid-β Genesis by Evoking Endoplasmic Reticulum Stress and Subsequent C/EBP Homologous Protein Activation. - Marwarha, Gurdeep; Rostad, Stephen; Lilek, Jaclyn; Kleinjan, Mason; Schommer, Jared; Ghribi, Othman (J Alzheimers Dis, 2017)
Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer's disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) were shown to inversely correlate with cognitive function. However, the cellular mechanisms by which sFFA may increase the risk for AD are not well known. Endoplasmic reticulum (ER) stress has emerged as one of the signaling pathways initiating and fostering the neurodegenerative changes in AD by increasing the aspartyl protease β-site AβPP cleaving enzyme 1 (BACE1) and amyloid-β (Aβ) genesis. In this study, we determined the extent to which palmitate increases BACE1 and Aβ levels in vitro and in vivo as well as the potential role of ER stress as cellular mechanism underlying palmitate effects. We demonstrate, in palmitate-treated SH-SY5Y neuroblastoma cells and in the hippocampi of palmitate-enriched diet-fed mice, that palmitate evokes the activation of the C/EBP Homologous Protein (CHOP), a transcription factor that is specifically responsive to ER stress. Induction of CHOP expression is associated with increased BACE1 mRNA, protein and activity levels, and subsequent enhanced amyloidogenic processing of amyloid-β protein precursor (AβPP) that culminates in a substantial increase in Aβ genesis. We further show that CHOP is an indispensable molecular mediator of palmitate-induced upregulation in BACE1 activity and Aβ genesis. Indeed, we show that Chop-/- mice and CHOP knocked-down SH-SY5Y neuroblastoma cells do not exhibit the same commensurate degree of palmitate-induced increase in BACE1 expression levels and Aβ genesis.
Keywords: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cell Line, Tumor; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Gene Expression Regulation; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuroblastoma; Palmitates; RNA, Messenger; Signal Transduction; Transcription Factor CHOP; Transcription Factors; Transfection

PCSK9 Promotes oxLDL-Induced PC12 Cell Apoptosis Through the Bcl-2/Bax-Caspase 9/3 Signaling Pathway. - Liu, Lu-Shan; Bai, Xue-Qin; Gao, Ya; Wu, Qi; Ren, Zhong; Li, Qing; Pan, Li-Hong; He, Ni-Ya; Peng, Juan; Tang, Zhi-Han (J Alzheimers Dis, 2017)
BACKGROUND: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases. OBJECTIVE: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer's disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL). METHODS: Cultured PC12 cells were serum-starved and incubated with different concentrations of oxLDL for 24 h. Intracytoplasmic lipid droplets were observed by oil red O staining. Morphological assessment of apoptotic cells was performed using Hoechst 33258 staining and flow cytometry analysis. The expression of mRNA and protein was detected by reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses, respectively. Transfection of small interfering RNA (siRNA) into PC12 cells was conducted using HiperFect Transfection Reagent. Concentrations of Aβ40 and Aβ42 were detected by enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Intracellular lipid content, the number of apoptotic cells, and PCSK9 expression were increased in PC12 cells after oxLDL treatment. Transfection with PCSK9 siRNA reduced the oxLDL-induced apoptosis of PC12 cells. We further confirmed the involvement of Bcl-2/Bax-Caspase (9, 3) signaling pathway in the regulation of PC12 cells apoptosis.β-Secretase 1, another target gene of PCSK9, was downregulated in PC12 cells in response to oxLDL treatment. Aβ40 and Aβ42 contents were also decreased. CONCLUSION: PCSK9 promotes oxLDL-induced PC12 cell apoptosis through the Bcl-2/Bax-Caspase 9/3 signaling pathway.
Keywords: Amyloid beta-Peptides; Analysis of Variance; Animals; Apoptosis; bcl-2-Associated X Protein; Caspases; Culture Media, Serum-Free; Dose-Response Relationship, Drug; Flow Cytometry; Lipid Metabolism; Lipoproteins, LDL; PC12 Cells; Peptide Fragments; Proprotein Convertase 9; Proto-Oncogene Proteins c-bcl-2; Rats; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Transfection

Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing. - Hu, Chen; Xu, Junjie; Zeng, Linlin; Li, Ting; Cui, Mei-Zhen; Xu, Xuemin (J Alzheimers Dis, 2017)
Presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer-2 (Pen-2) have been considered the minimal essential subunits required to form an active γ-secretase complex. Besides PS, which has been widely believed to function as the catalytic subunit of the complex, the functional roles of the other subunits in the γ-secretase complex remain debatable. In the current study, we set out to determine the role of Pen-2 in γ-secretase activity. To this end, using knockout cells in combination with siRNA and immunoprecipitation approaches, our results revealed that Pen-2 together with presenilin are sufficient to form a functionally active enzyme to process Notch. Specifically, our data demonstrated that Pen-2 plays a crucial role in substrate binding, a mechanism by which Pen-2 contributes directly to the catalytic mechanism of γ-secretase activity. Our data also suggested that there may be different requirements for components to process AβPP and Notch. This information would be important for therapeutic strategy aimed at inhibition or modulation of γ-secretase activity.

People with Dementia Can Learn Compensatory Movement Maneuvers for the Sit-to-Stand Task: A Randomized Controlled Trial. - Werner, Christian; Wiloth, Stefanie; Lemke, Nele Christin; Kronbach, Florian; Jansen, Carl-Philipp; Oster, Peter; Bauer, Jürgen M; Hauer, Klaus (J Alzheimers Dis, 2017)
BACKGROUND: A complex motor skill highly relevant to mobility in everyday life (e.g., sit-to-stand [STS] transfer) has not yet been addressed in studies on motor learning in people with dementia (PwD). OBJECTIVE: To determine whether a dementia-specific motor learning exercise program enables PwD to learn compensatory STS maneuvers commonly taught in geriatric rehabilitation therapy to enhance patients' STS ability. METHODS: Ninety-seven patients with mild-to-moderate dementia (Mini-Mental State Examination: 21.9±2.9 points) participated in a double-blinded, randomized, placebo-controlled trial with 10-week intervention and 3-month follow-up period. The intervention group (IG, n = 51) underwent a motor learning exercise program on compensatory STS maneuvers specifically designed for PwD. The control group (CG, n = 46) performed a low-intensity motor placebo activity. Primary outcomes were scores of the Assessment of Compensatory Sit-to-stand Maneuvers in People with Dementia (ACSID), which covers the number of recalled and initiated, and of effectively performed compensatory STS maneuvers. Secondary outcomes included temporal and kinematic STS characteristics measured by a body-fixed motion sensor (BFS, DynaPort® Hybrid). RESULTS: The IG significantly improved in all ACSID scores compared to the CG (p < 0.001). Secondary analysis confirmed learning effects for all BFS-based outcomes (p < 0.001-0.006). Learning gains were sustained during follow-up for most outcomes. CONCLUSION: People with mild-to-moderate dementia can learn and retain compensatory STS maneuvers in response to a dementia-specific motor learning exercise program. This is the first study that demonstrated preserved motor learning abilities in PwD by using a motor skill highly relevant to everyday life.

PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI). - Rafii, Michael S; Lukic, Ana S; Andrews, Randolph D; Brewer, James; Rissman, Robert A; Strother, Stephen C; Wernick, Miles N; Pennington, Craig; Mobley, William C; Ness, Seth; Matthews, Dawn C (J Alzheimers Dis, 2017)
BACKGROUND: Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimer's disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations. OBJECTIVES: 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI. METHODS: Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures. RESULTS: All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures. CONCLUSIONS: Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy.

PET Tau and Amyloid-β Burden in Mild Alzheimer's Disease: Divergent Relationship with Age, Cognition, and Cerebrospinal Fluid Biomarkers. - Koychev, Ivan; Gunn, Roger N; Firouzian, Azadeh; Lawson, Jennifer; Zamboni, Giovanna; Ridha, Basil; Sahakian, Barbara J; Rowe, James B; Thomas, Alan; Rochester, Lynn; Ffytche, Dominic; Howard, Robert; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Combining PET amyloid-β (Aβ) and tau imaging may be critical for tracking disease progression in Alzheimer's disease (AD). OBJECTIVE: We sought to characterize the relationship between Aβ and tau ligands as well as with other measures of pathology. METHODS: We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with Aβ ([18F]AV45) and tau ([18F]AV1451) ligands at baseline. RESULTS: 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical Aβ associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not Aβ. CONCLUSION: The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker- the CSF total tau/Aβ ratio.

Physical Activity in Midlife is not Associated with Cognitive Health in Later Life Among Cognitively Normal Older Adults. - Gross, Alden L; Lu, Haidong; Meoni, Lucy; Gallo, Joseph J; Schrack, Jennifer A; Sharrett, A Richey (J Alzheimers Dis, 2017)
BACKGROUND: Links between physical activity and dementia are based primarily on cross-sectional data or studies with unsatisfactory follow-up. OBJECTIVE: We leveraged three decades of follow-up from an established cohort to determine whether physical activity in midlife is associated with late-life cognition and dementia. METHODS: The Johns Hopkins Precursors study (n = 646) enrolled participants from 1948-1964 and administered questions about physical activity, from which we calculated metabolic equivalents (MET h/day), and exercise from 1978-present. Cognitive tests were administered in 2008. Dementia was adjudicated through 2011. To characterize associations with midlife physical activity, we used linear regression for cognitive tests and Cox proportional hazards models for dementia onset. Models adjusted for age, sex, smoking, diabetes, and hypertension. RESULTS: No physical activity measure from 1978 was associated with late-life cognition or onset of dementia. Both MET h/day (β= 0.007, 95% CI: 0.002, 0.013) and regular exercise (β= 0.357, 95% CI: 0.202, 0.513) in 2006, however, were associated with better cognition in 2008. CONCLUSION: Findings from this 30-year cohort study that physical activity measured recently, but not in mid-life, is associated with late-life cognition fits with null findings from randomized trials and other observational studies with extensive follow-up. Cross-sectional findings may be misleading due to reverse causation.

Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels. - den Hoedt, Sandra; Janssen, Carola I F; Astarita, Giuseppe; Piomelli, Daniele; Leijten, Frank P J; Crivelli, Simone M; Verhoeven, Adrie J M; De Vries, Helga E; Walter, Jochen; Martinez-Martinez, Pilar; Sijbrands, Eric J G; Kiliaan, Amanda J; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ɛ4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD. OBJECTIVE: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet. METHODS: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR. RESULTS: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice. CONCLUSION: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.

Polymorphonuclear Neutrophil Functions are Differentially Altered in Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease Patients. - Le Page, Aurélie; Lamoureux, Julie; Bourgade, Karine; Frost, Eric H; Pawelec, Graham; Witkowski, Jacek M; Larbi, Anis; Dupuis, Gilles; Fülöp, Tamás (J Alzheimers Dis, 2017)
The mechanisms of neurodegeneration in Alzheimer's disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n = 13), patients with mild AD (mAD, n = 15), and healthy elderly controls (n = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1β, IL-12p70) and chemokine (MIP-1α, MIP-1β, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development.

Precuneus Failures in Subjects of the PSEN1 E280A Family at Risk of Developing Alzheimer's Disease Detected Using Quantitative Electroencephalography. - Ochoa, John Fredy; Alonso, Joan Francesc; Duque, Jon Edinson; Tobón, Carlos Andrés; Baena, Ana; Lopera, Francisco; Mañanas, Miguel Angel; Hernández, Alher Mauricio (J Alzheimers Dis, 2017)
BACKGROUND: Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer's disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-β. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD. OBJECTIVE: To examine how previous reported differences in EEG for Theta and Alpha-2 rhythms in E280A subjects are related to specific regions in cortex and could be tracked across different ages. METHODS: EEG signals were acquired during resting state from non-carriers and carriers, asymptomatic and symptomatic subjects from E280A kindred from Antioquia, Colombia. Independent component analysis (ICA) and inverse solution methods were used to locate brain regions related to differences in Theta and Alpha-2 bands. RESULTS: ICA identified two components, mainly related to the Precuneus, where the differences in Theta and Alpha-2 exist simultaneously at asymptomatic and symptomatic stages. When the ratio between Theta and Alpha-2 is used, significant correlations exist with age and a composite cognitive scale. CONCLUSION: Theta and Alpha-2 rhythms are altered in E280A subjects. The alterations are possible to track at Precuneus regions using EEG, ICA, and inverse solution methods.

Predicting Development of Amyotrophic Lateral Sclerosis in Frontotemporal Dementia. - Van Langenhove, Tim; Piguet, Olivier; Burrell, James R; Leyton, Cristian; Foxe, David; Abela, Melissa; Bartley, Lauren; Kim, Woojin S; Jary, Eve; Huang, Yue; Dobson-Stone, Carol; Kwok, John B; et al. (J Alzheimers Dis, 2017)
BACKGROUND: A proportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS). OBJECTIVE: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS. METHODS: Of 218 consecutive patients with FTD, 10.1% had a dual FTD-ALS diagnosis at presentation. The remaining 152 FTD patients with follow-up of at least 12 months were included in the present study. We calculated the rate of progression to FTD-ALS and compared the baseline characteristics of FTD patients who developed ALS to those who did not develop ALS. RESULTS: Five percent of FTD patients developed ALS. The incidence rate of ALS was 6.7/100 patient-years in patients with FTD symptoms since 1 year, which declined with duration of FTD symptoms. No FTD patients developed ALS after 5 years. Five out of 8 FTD patients who developed ALS had presented with a mixed behavioral variant FTD and progressive non-fluent aphasia (bvFTD+PNFA) phenotype, 2 with bvFTD, and 1 with PNFA. Progression to FTD-ALS was significantly more frequent in patients with bvFTD+PNFA compared to those without this phenotype (p < 0.0001, OR 38.3, 95% CI: 7.3 to 199.2), and in FTD patients who carried the C9orf72 repeat expansion compared to those without the repeat expansion (p = 0.02, OR 8.0, 95% CI: 1.7 to 38.6). CONCLUSIONS: FTD patients with a mixed bvFTD+PNFA phenotype and with a C9orf72 repeat expansion should be closely monitored for the possible development of ALS. The risk of developing ALS in FTD appears to decline with the duration of FTD symptoms.

Prediction Model of Conversion to Dementia Risk in Subjects with Amnestic Mild Cognitive Impairment: A Longitudinal, Multi-Center Clinic-Based Study. - Jang, Hyemin; Ye, Byoung Seok; Woo, Sookyoung; Kim, Sun Woo; Chin, Juhee; Choi, Seong Hye; Jeong, Jee Hyang; Yoon, Soo Jin; Yoon, Bora; Park, Kyung Won; Hong, Yun Jeong; Kim, Hee Jin; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) have an increased risk of dementia. However, conversion rate varies. Therefore, predicting the dementia conversion in these patients is important. OBJECTIVE: We aimed to develop a nomogram to predict dementia conversion in aMCI subjects using neuropsychological profiles. METHODS: A total of 338 aMCI patients from two hospital-based cohorts were used in analysis. All patients were classified into 1) verbal, visual, or both, 2) early or late, and 3) single or multiple-domain aMCI according to the modality, severity of memory dysfunction, and multiplicity of involved cognitive domains, respectively. Patients were followed up, and conversion to dementia within 3 years was defined as the primary outcome. Our patients were divided into a training data set and a validation data set. The associations of potential covariates with outcome were tested, and nomogram was constructed by logistic regression model. We also developed another model with APOE data, which included 242 patients. RESULTS: In logistic regression models, both modalities compared with visual only (OR 4.44, 95% CI 1.83-10.75, p = 0.001), late compared to early (OR 2.59, 95% CI 1.17-5.72, p = 0.019), and multiple compared to single domain (OR 3.51, 95% CI 1.62-7.60, p = 0.002) aMCI were significantly associated with dementia conversion within 3 years. A nomogram incorporating these clinical variables was constructed on the training data set and validated on the validation data set. Both nomograms with and without APOE data showed good prediction performance (c-statistics ≥ 0.75). CONCLUSIONS: This study showed that several neuropsychological profiles of aMCI are significantly associated with imminent dementia conversion, and a nomogram incorporating these clinical subtypes is simple and useful to help to predict disease progression.

Prediction of Conversion to Alzheimer's Disease with Longitudinal Measures and Time-To-Event Data. - Li, Kan; Chan, Wenyaw; Doody, Rachelle S; Quinn, Joseph; Luo, Sheng (J Alzheimers Dis, 2017)
BACKGROUND: Identifying predictors of conversion to Alzheimer's disease (AD) is critically important for AD prevention and targeted treatment. OBJECTIVE: To compare various clinical and biomarker trajectories for tracking progression and predicting conversion from amnestic mild cognitive impairment to probable AD. METHODS: Participants were from the ADNI-1 study. We assessed the ability of 33 longitudinal biomarkers to predict time to AD conversion, accounting for demographic and genetic factors. We used joint modelling of longitudinal and survival data to examine the association between changes of measures and disease progression. We also employed time-dependent receiver operating characteristic method to assess the discriminating capability of the measures. RESULTS: 23 of 33 longitudinal clinical and imaging measures are significant predictors of AD conversion beyond demographic and genetic factors. The strong phenotypic and biological predictors are in the cognitive domain (ADAS-Cog; RAVLT), functional domain (FAQ), and neuroimaging domain (middle temporal gyrus and hippocampal volume). The strongest predictor is ADAS-Cog 13 with an increase of one SD in ADAS-Cog 13 increased the risk of AD conversion by 2.92 times. CONCLUSION: Prediction of AD conversion can be improved by incorporating longitudinal change information, in addition to baseline characteristics. Cognitive measures are consistently significant and generally stronger predictors than imaging measures.

Predictors of Discharge Destinations and Three-Month Evolution of Patients Initially Hospitalized in a Cognitive Behavioral Unit. - Pongan, Elodie; Dorey, Jean-Michel; Krolak-Salmon, Pierre; Federico, Denis; Sellier, Claire; Auguste, Nicolas; Fabre, Florence; Laurent, Bernard; Trombert-Paviot, Béatrice; Rouch, Isabelle (J Alzheimers Dis, 2017)
BACKGROUND: Previous studies showed that a third of patients living at home entered an institution after hospitalization in Cognitive and Behavioral Units (CBUs). OBJECTIVE: The main objective of this study was to identify predictors of discharge destination for these patients. The secondary objective was to estimate whether institutionalization can have an impact on a patient's long-term prognosis. METHODS: The study population was selected from the EVITAL study and included 140 participants living at home before hospitalization in CBUs. Factors favoring nursing-home admission were investigated and the impact of discharge destinations (i.e., home or nursing home) on patients' prognosis was examined. RESULTS: Institutionalized patients were more likely to be women (F = 4.7; p = 0.03), with a higher dementia severity (F = 9.82; p = 0.007), often living alone (F = 19.69; p = 0.001), with a caregiver other than spouse (F = 8.93; p = 0.003), and with a higher patient quality of life (QoL) according to the caregiver (F = 11.73; p = 0.001). When using multivariate logistic linear regressions, we showed a relationship between marital status (OR = 0.19, 95% CI: 0.08-0.43, p < 0.001), dementia severity (OR = 0.15, 95% CI: 0.03-0.79, p = 0.03), QoL (OR = 0.88, 95% CI: 0.79-0.98, p = 0.017), and institutionalization. At three months, a higher overall rate of rehospitalization (F = 12.21; p < 0.001) and rehospitalization for behavioral and psychological symptoms of dementia (F = 6.76; p = 0.006) were observed for patients staying at home after CBU discharge. CONCLUSION: Our study allows for a better understanding of the institutionalization risk factors of the patients hospitalized in CBUs. Identification of these factors could help clinicians to better support patients and to help the transition to be smoother. Moreover, our results suggest that prognosis of institutionalized patients is not unfavorable when compared with patients staying at home.

Prevalence, Risk Factors, and Complaints Screening Tool Exploration of Subjective Cognitive Decline in a Large Cohort of the Chinese Population. - Hao, Lixiao; Wang, Xiaoni; Zhang, Ling; Xing, Yue; Guo, Qihao; Hu, Xiaochen; Mu, Bin; Chen, Yili; Chen, Guanqun; Cao, Jing; Zhi, Xiaodong; Liu, Jiaojiao; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Substantial studies have reported the prevalence and the affecting factors of subjective cognitive decline (SCD). The complaints screening scale has also been used for probing. However, little is known in China. OBJECTIVE: To investigate the prevalence and risk factors of SCD, and explore an SCD complaints screening scale in China. METHODS: Stratified cluster random sampling was conducted. 2,689 residents aged 60-80 years completed questionnaire 1. 814 residents were included for clinical and neuropsychological evaluations. Two standards were used to make the diagnosis of mild cognitive impairment (MCI) and SCD, and a preliminary screening rate comparison was carried out. Finally, we assessed the risk factors of SCD and the correlation between the SCD-questionnaire 9 (SCD-Q9) and the Auditory Verbal Learning Test-Long Delay Free Recall (AVLT-LR). RESULTS: 1) Standard 1 (ADNI2): the prevalence of SCD was 18.8% (95% CI = 14.7-22.9%) and zero conformed to six criteria (SCD plus). 2) Standard 2 (Jak/Bondi): the prevalence of SCD was 14.4% (95% CI = 10.7-18.1%). 3) Standard 1 had a relatively higher "false" positive rate, whereas Standard 2 had higher "false" negative rate. 4) Age, low education, fewer close friends, and daily drinking were independent risk factors for SCD progressing to MCI. 5) Total points of SCD-Q9 were negatively correlated to the value of AVLT-LR. CONCLUSIONS: The prevalence of SCD is high in the ShunYi District in Beijing, China. Age, low education, less social support, and daily drinking are independent risk factors. The brief SCD-Q9 can be used as a reference.

proBDNF Accelerates Brain Amyloid-β Deposition and Learning and Memory Impairment in APPswePS1dE9 Transgenic Mice. - Chen, Jia; Zhang, Tao; Jiao, Shusheng; Zhou, Xinfu; Zhong, Jinhua; Wang, Yanjiang; Liu, Juan; Deng, Juan; Wang, Shuiping; Xu, Zhiqiang (J Alzheimers Dis, 2017)
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 andprogression.

Prodromal Dementia with Lewy Bodies and Prodromal Alzheimer's Disease: A Comparison of the Cognitive and Clinical Profiles. - Sadiq, Dilman; Whitfield, Tim; Lee, Lean; Stevens, Tim; Costafreda, Sergi; Walker, Zuzana (J Alzheimers Dis, 2017)
BACKGROUND: Dementia must be diagnosed accurately and early in the disease course to allow pathology-specific treatments to be effective. Dementia with Lewy bodies (DLB) is often misdiagnosed as Alzheimer's disease (AD), especially at the prodromal stage. OBJECTIVE: To compare the clinical and neuropsychological profiles of Mild Cognitive Impairment (MCI) patients who, at follow-up, progressed to AD (retrospectively AD-MCI) or DLB (retrospectively DLB-MCI) or remained MCI. METHODS: This longitudinal study used an unselected sample from a memory clinic database. A total of 1,848 new patients were seen at the memory clinic between 1994-2015. Of these, 560 patients (30%) had an initial diagnosis of MCI and were considered for the study. Inclusion criteria were patients who had a diagnosis of MCI at initial assessment and a minimum of 12 months' follow-up. RESULTS: Of the 429 MCI patients with follow-up data, 164 (38%) remained MCI, 107 (25%) progressed to AD, and 21 (5%) progressed to DLB. The remainder progressed to alternative diagnoses. At baseline, DLB-MCI patients performed significantly worse on visuospatial function and letter fluency tests than both AD-MCI and stable-MCI groups, and better on episodic memory tests than the AD-MCI group. At baseline, DLB-MCI patients had a significantly higher mean UPDRS score and were more likely to have REM sleep behavior disorder and fluctuating cognition. CONCLUSION: DLB-MCI patients have a specific cognitive and neuropsychiatric profile which should alert clinicians to the possibility of prodromal DLB. This is relevant when considered in the context of early disease-specific therapy.

Proteomics Analysis of Blood Serums from Alzheimer's Disease Patients Using iTRAQ Labeling Technology. - Shen, Liming; Liao, Liping; Chen, Cheng; Guo, Yi; Song, Dalin; Wang, Yong; Chen, Youjiao; Zhang, Kaoyuan; Ying, Ming; Li, Shuiming; Liu, Qiong; Ni, Jiazuan (J Alzheimers Dis, 2017)
Alzheimer' disease (AD) is the most common form of dementia affecting up to 6% of the population over the age of 65. In order to discover differentially expressed proteins that might serve as potential biomarkers, the serums from AD patients and healthy controls were compared and analyzed using the proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). For the first time, AD biomarkers in serums are investigated in the Han Chinese population using iTRAQ labeled proteomics strategy. Twenty-two differentially expressed proteins were identified and out of which nine proteins were further validated with more sample test. Another three proteins that have been reported in the literature to be potentially associated with AD were also investigated for alteration in expression level. Functions of those proteins were mainly related to the following processes: amyloid-β (Aβ) metabolism, cholesterol transport, complement and coagulation cascades, immune response, inflammation, hemostasis, hyaluronan metabolism, and oxidative stress. These results support current views on the molecular mechanism of AD. For the first time, differential expression of zinc-alpha-2-glycoprotein (AZGP1), fibulin-1 (FBLN1), platelet basic protein (PPBP), thrombospondin-1 (THBS1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9) were detected in the serums of AD patients compared with healthy controls. These proteins might play a role in AD pathophysiology and serve as potential biomarkers for AD diagnosis. Specifically, our results strengthened the crucial role of Aβ metabolism and blood coagulation in AD pathogenesis and proteins related to these two processes may be used as peripheral blood biomarkers for AD.

PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β. - Yu, Linjie; Liu, Yi; Yang, Hui; Zhu, Xiaolei; Cao, Xiang; Gao, Jun; Zhao, Hui; Xu, Yun (J Alzheimers Dis, 2017)
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.

Psychosocial Risk and Protective Factors and Incident Mild Cognitive Impairment and Dementia in Community Dwelling Elderly: Findings from the Singapore Longitudinal Ageing Study. - Rawtaer, Iris; Gao, Qi; Nyunt, Ma Shwe Zin; Feng, Lei; Chong, Mei Sian; Lim, Wee Shiong; Lee, Tih-Shih; Yap, Philip; Yap, Keng Bee; Ng, Tze Pin (J Alzheimers Dis, 2017)
BACKGROUND: Indicators of social isolation or support such as living alone, loneliness, being married, and life satisfaction are possible psychosocial risk and protective factors for dementia. OBJECTIVE: We investigate the associations of these overlapping psychosocial factors with incident MCI-dementia (neurocognitive disorder) in a population cohort. METHODS: Using data from 1601 participants of the Singapore Longitudinal Ageing Study (SLAS) who were free of MCI or dementia at baseline and followed up to 8 years, we estimated hazards ratio (HR) of association of living alone, loneliness, being married, and high life satisfaction with incident MCI-dementia. RESULTS: In univariate analyses, individual HRs of association with incident MCI-dementia for living alone was 1.86 [1.18 - 2.95], (p = 0.008), loneliness was 1.26 [0.86 - 1.84], (p = 0.23), being married was 0.54 [0.39 - 0.75] (p < 0.0001), and being very satisfied with life was 0.59 [0.38-0.91]), (p = 0.017). Adjusted mutually for other psychosocial variables, and for age, sex, education, ethnicity, smoking, alcohol, dyslipidemia, hypertension, diabetes, central obesity, history of stroke or heart disease, APOE-ɛ4, depression, physical, social, and productive activities, only being married (0.68 [0.47-0.99], p = 0.044), and being very satisfied with life (0.61 [0.39 - 0.96], p = 0.034) remained significant variables associated with lower risks of developing MCI-dementia. CONCLUSION: Individuals who were married and those who were very satisfied with life are protected against the risk of developing MCI and dementia. Controlling for the adverse effects of being without spousal support and low life satisfaction, living alone or a feeling of loneliness were not associated with increased risk of MCI-dementia.

Pupillary Responses as a Biomarker of Early Risk for Alzheimer's Disease. - Granholm, Eric L; Panizzon, Matthew S; Elman, Jeremy A; Jak, Amy J; Hauger, Richard L; Bondi, Mark W; Lyons, Michael J; Franz, Carol E; Kremen, William S (J Alzheimers Dis, 2017)
Task-evoked pupillary responses may be a psychophysiological biomarker of early risk for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Pupil dilation during cognitive tasks reflects cognitive effort until compensatory capacity is surpassed and performance declines are manifest, and reflects activation in the locus coeruleus, where degenerative changes have been found in the earliest stages of AD. We recorded pupillary responses during digit span recall in 918 participants ages 56-66. Despite normal performance, amnestic single-domain MCI (S-MCI) participants showed greater pupil dilation than non-amnestic S-MCI and cognitively normal (CN) participants at lower cognitive loads. Multi-domain MCI (M-MCI) participants failed to modulate effort across cognitive loads and showed poorer performance. Pupillary responses differentiated MCI and CN groups. Amnestic S-MCI participants required compensatory effort to maintain performance, consistent with increased risk for decline. Greater effort in CN individuals might indicate risk for MCI. Results are consistent with dysfunction in locus coeruleus-linked brain systems. This brief task shows promise as a biomarker for early MCI and AD risk prediction.

Quantitative 3D Telomeric Imaging of Buccal Cells Reveals Alzheimer's Disease-Specific Signatures. - Garcia, Angeles; Mathur, Shubha; Kalaw, Maria Carmela; McAvoy, Elizabeth; Anderson, James; Luedke, Angela; Itorralba, Justine; Mai, Sabine (J Alzheimers Dis, 2017)
This study validates and expands on our previous work that assessed three-dimensional (3D) nuclear telomere profiling in buccal cells of Alzheimer's disease (AD) patients and non-AD controls (Mathur et al., J Alzheimers Dis 39, 35-48, 2014). While the previous study used age- and gender-matched caregiver controls, the current study consented a new cohort of 44 age- and gender-matched healthy non-caregiver controls and 44 AD study participants. 3D telomeric profiles of buccal cells of AD patients and their non-AD controls were examined with participant information blinded to the analysis. In agreement with our previous study, we demonstrate that 3D telomeric profiles allow for the distinction between AD and non-AD individuals. This validation cohort provides an indication that the total number of 3D telomeric signals and their telomere lengths may be a suitable biomarker to differentiate between AD and non-AD and between mild, moderate, and severe AD. Further studies with larger sample sizes are required to move this technology further toward the clinic.

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice. - Liu, Peng; Reichl, John H; Rao, Eshaan R; McNellis, Brittany M; Huang, Eric S; Hemmy, Laura S; Forster, Colleen L; Kuskowski, Michael A; Borchelt, David R; Vassar, Robert; Ashe, Karen H; Zahs, Kathleen R (J Alzheimers Dis, 2017)
There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.

Quantitative Magnetic Resonance Abnormalities in Creutzfeldt-Jakob Disease and Fatal Insomnia. - Grau-Rivera, Oriol; Calvo, Anna; Bargalló, Nuria; Monté, Gemma C; Nos, Carlos; Lladó, Albert; Molinuevo, José Luis; Gelpi, Ellen; Sánchez-Valle, Raquel (J Alzheimers Dis, 2017)
BACKGROUND: Quantitative neuroimaging might unveil abnormalities in prion diseases that are not perceivable at visual inspection. On the other hand, scarce studies have quantified volumetric changes in prion diseases. OBJECTIVES: We aim to characterize volumetric and diffusion tensor imaging (DTI) changes in patients with prion diseases who presented with either Creutzfeldt-Jakob disease (CJD) or fatal insomnia (FI) phenotype. METHODS: Twenty patients with prion diseases- 15 with CJD and 5 with fatal insomnia (FI)- and 40 healthy controls were examined with a 3-Tesla magnetic resonance imaging scanner. Images were segmented and normalized with SPM12. DTI maps were obtained with FMRIB Software Library. Whole-brain voxel-wise and region-of-interest analyses of volumetric and DTI changes were performed with SPM12. White matter (WM) changes were also analyzed with tract-based spatial statistics. Semiquantitive assessment of neuropathological parameters was compared with DTI metrics in thalamus from 11 patients. RESULTS: Patients with CJD and FI presented significant atrophy in thalamus and cerebellum. In CJD, mean diffusivity (MD) was decreased in striatum and increased in subcortical WM, while both increased and decreased values were observed across different thalamic nuclei. In FI, MD was increased in thalamus and cerebellum. Spongiform change and PrPSc deposition were more intense in thalamus in CJD than in FI, although no significant correlations arose with MD values in the nuclei studied. CONCLUSION: Volumetric and DTI abnormalities suggest a central common role of the thalamus in prion diseases. We report, for the first time, quantitative MRI changes in FI, and provide further evidence of WM involvement in prion diseases.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia. - Rafii, Michael S; Skotko, Brian G; McDonough, Mary Ellen; Pulsifer, Margaret; Evans, Casey; Doran, Eric; Muranevici, Gabriela; Kesslak, Patrick; Abushakra, Susan; Lott, Ira T (J Alzheimers Dis, 2017)
BACKGROUND: ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer's disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. OBJECTIVE: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. RESULTS: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. CONCLUSION: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

Rapidly Progressive Frontotemporal Dementia Associated with MAPT Mutation G389R. - Sun, Lin; Chen, Kathryn; Li, Xia; Xiao, Shifu (J Alzheimers Dis, 2017)
Frontotemporal dementia includes a large spectrum of neurodegenerative disorders. Here, we report the case of a young patient with MAPT mutation G389R, who was 27 years old when he progressively developed severe behavioral disturbances. Initially, he presented with slowly progressive personality change. After 1 year, he exhibited moderate dementia with extrapyramidal and pyramidal symptoms. MRI showed frontotemporal atrophy. He rapidly progressed to severe dementia 3 years after onset. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (c.1165G>A) of MAPT, the tau gene, resulting in a glycine to arginine substitution in the patient and two unaffected relatives. We predicted the model of mutant tau protein through I-TASSER software, and speculated the structural change of tau protein caused by mutant site. We also detected the MAPT gene transcript and methylation of samples from peripheral blood leucocytes in an attempt to explain the possible mechanisms of incomplete penetrance, although there were not positive findings. This case is remarkable because of the early onset and rapid progression of the disease.

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. - Louwersheimer, Eva; Cohn-Hokke, Petra E; Pijnenburg, Yolande A L; Weiss, Marjan M; Sistermans, Erik A; Rozemuller, Annemieke J; Hulsman, Marc; van Swieten, John C; van Duijn, Cock M; Barkhof, Frederik; Koene, Teddy; Scheltens, Philip; et al. (J Alzheimers Dis, 2017)
BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD. METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

Recent Progress in Alzheimer's Disease Research, Part 1: Pathology. - Hane, Francis T; Lee, Brenda Y; Leonenko, Zoya (J Alzheimers Dis, 2017)
The field of Alzheimer's disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer's Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the "hottest" fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, pathology, reviews amyloid-β, tau, prions, brain structure, and functional changes with AD and the neuroimmune response of AD.

Recent Progress in Alzheimer's Disease Research, Part 2: Genetics and Epidemiology. - Robinson, Morgan; Lee, Brenda Y; Hane, Francis T (J Alzheimers Dis, 2017)
This is the second part of a three-part review series reviewing the most important advances in Alzheimer's disease (AD) research since 2010. This review covers the latest research on genetics and epidemiology. Epidemiological and genetic studies are revealing important insights into the etiology of, and factors that contribute to AD, as well as areas of priority for research into mechanisms and interventions. The widespread adoption of genome wide association studies has provided compelling evidence of the genetic complexity of AD with genes associated with such diverse physiological function as immunity and lipid metabolism being implicated in AD pathogenesis.

Recent Progress in Alzheimer's Disease Research, Part 3: Diagnosis and Treatment. - Hane, Francis T; Robinson, Morgan; Lee, Brenda Y; Bai, Owen; Leonenko, Zoya; Albert, Mitchell S (J Alzheimers Dis, 2017)
The field of Alzheimer's disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer's Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the "hottest" fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, diagnosis and treatment, reviews the latest diagnostic criteria, biomarkers, imaging, and treatments in AD.
Keywords: Alzheimer Disease; Biomarkers; Biomedical Research; Humans; Neuroimaging

Recovery from Proactive Semantic Interference and MRI Volume: A Replication and Extension Study. - Loewenstein, David A; Curiel, Rosie E; DeKosky, Steven; Rosselli, Monica; Bauer, Russell; Grieg-Custo, Maria; Penate, Ailyn; Li, Chunfei; Lizagarra, Gabriel; Golde, Todd; Adjouadi, Malek; Duara, Ranjan (J Alzheimers Dis, 2017)
BACKGROUND: The rise in incidence of Alzheimer's disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain. OBJECTIVE: The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early AD, and related to a unique pattern of volumetric loss in AD prone areas. METHODS: Three different memory measures were examined relative to volumetric loss and cortical thickness among 45 participants with amnestic mild cognitive impairment. RESULTS: frPSI was uniquely associated with reduced volumes in the hippocampus (r = 0.50) precuneus (r = 0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r≥0.60) and precuneus (r = 0.50) were also observed. CONCLUSION: Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD.

Recovery from Proactive Semantic Interference in Mild Cognitive Impairment and Normal Aging: Relationship to Atrophy in Brain Regions Vulnerable to Alzheimer's Disease. - Loewenstein, David A; Curiel, Rosie E; Wright, Clinton; Sun, Xiaoyan; Alperin, Noam; Crocco, Elzabeth; Czaja, Sara J; Raffo, Arlene; Penate, Ailyn; Melo, Jose; Capp, Kimberly; Gamez, Monica; et al. (J Alzheimers Dis, 2017)
BACKGROUND: There is growing evidence that proactive semantic interference (PSI) and failure to recover from PSI may represent early features of Alzheimer's disease (AD). OBJECTIVE: This study investigated the association between PSI, recovery from PSI, and reduced MRI volumes in AD signature regions among cognitively impaired and unimpaired older adults. METHODS: Performance on the LASSI-L (a novel test of PSI and recovery from PSI) and regional brain volumetric measures were compared between 38 cognitively normal (CN) elders and 29 older participants with amnestic mild cognitive impairment (MCI). The relationship between MRI measures and performance on the LASSI-L as well as traditional memory and non-memory cognitive measures was also evaluated in both diagnostic groups. RESULTS: Relative to traditional neuropsychological measures, MCI patients' failure to recover from PSI was associated with reduced volumes in the hippocampus (rs = 0.48), precuneus (rs = 0.50); rostral middle frontal lobules (rs = 0.54); inferior temporal lobules (rs = 0.49), superior parietal lobules (rs = 0.47), temporal pole (rs = 0.44), and increased dilatation of the inferior lateral ventricle (rs = -0.49). For CN elders, only increased inferior lateral ventricular size was associated with vulnerability to PSI (rs = -0.49), the failure to recover from PSI (rs = -0.57), and delayed recall on the Hopkins Verbal Learning Test-Revised (rs = -0.48). DISCUSSION: LASSI-L indices eliciting failure to recover from PSI were more highly associated with more MRI regional biomarkers of AD than other traditional cognitive measures. These results as well as recent amyloid imaging studies with otherwise cognitively normal subjects, suggest that recovery from PSI may be a sensitive marker of preclinical AD and deserves further investigation.

Reduced Cardiovascular Functions in Patients with Alzheimer's Disease. - Jin, Wang-Sheng; Bu, Xian-Le; Wang, Ye-Ran; Li, Ling; Li, Wei-Wei; Liu, Yu-Hui; Zhu, Chi; Yao, Xiu-Qing; Chen, Yang; Gao, Chang-Yue; Zhang, Tao; Gao, Chang-Yue; et al. (J Alzheimers Dis, 2017)
Previous studies have suggested that cardiovascular functions might play a critical role in Alzheimer's disease (AD) pathogenesis. However, the relationship among heart function, blood flow of cerebral vessels, and AD remains unclear. In the present study, AD patients (n = 34) and age- and gender-matched cognitively normal controls (n = 34) were recruited. Comorbidity information was collected. The ejection fraction was measured using echocardiography, and the mean velocity, pulsatility index (PI), and resistance index (RI) of the basilar artery (BA), left terminal internal carotid artery (LTICA), and right terminal internal carotid artery (RTICA) were measured using transcranial Doppler. The lacunae, white matter changes, and plaque in the aortic arch and carotid arteries were collected from brain magnetic resonance imaging and computed tomography angiography images. Compared with normal controls, AD patients had lower ejection fractions and cerebral blood flow velocities and a higher RI and PI in the BA, LTICA, and RTICA, as well as more plaques in the aortic and carotid arteries. In the multivariate logistic regression analysis, the ejection fraction and the mean velocity of the BA and LTICA were independently associated with AD after adjusting for age, gender, education, vascular risk factors, arterial plaques, and brain ischemic lesions detected in the brain images. These findings suggest that heart function and vascular condition may play important roles in AD pathogenesis. Improving cardiovascular functions could be a promising approach for the prevention and treatment of AD.

The Relationship between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood-Brain Barrier Impairment in Alzheimer's Disease. - Muszyński, Paweł; Kulczyńska-Przybik, Agnieszka; Borawska, Renata; Litman-Zawadzka, Ala; Słowik, Agnieszka; Klimkowicz-Mrowiec, Aleksandra; Pera, Joanna; Dziedzic, Tomasz; Mroczko, Barbara (J Alzheimers Dis, 2017)
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.

The Relationship of Bilingualism Compared to Monolingualism to the Risk of Cognitive Decline or Dementia: A Systematic Review and Meta-Analysis. - Mukadam, Naaheed; Sommerlad, Andrew; Livingston, Gill (J Alzheimers Dis, 2017)
BACKGROUND: Bilingualism may contribute to cognitive reserve, protect against cognitive decline, and delay the onset of dementia. OBJECTIVE: We systematically reviewed evidence about the effect of bilingualism on subsequent cognitive decline or dementia. METHODS: We searched electronic databases and references for longitudinal studies comparing cognitive decline in people who were bilingual with those who were monolingual and evaluated study quality. We conducted meta-analyses using random effects models to calculate pooled odds ratio of incident dementia. RESULTS: We included 13/1,156 eligible articles. Meta-analysis of prospective studies of the effects of bilingualism on future dementia gave a combined Odds Ratio of dementia of 0.96 (95% CI 0.74-1.23) in bilingual participants (n = 5,527) compared to monolinguals. Most retrospective studies found that bilingual people were reported to develop symptoms of cognitive decline at a later age than monolingual participants. CONCLUSION: We did not find that bilingualism protects from cognitive decline or dementia from prospective studies. Retrospective studies are more prone to confounding by education, or cultural differences in presentation to dementia services and are therefore not suited to establishing causative links between risk factors and outcomes.

The Relationship of Brain Amyloid Load and APOE Status to Regional Cortical Thinning and Cognition in the ADNI Cohort. - Li, Chunfei; Loewenstein, David A; Duara, Ranjan; Cabrerizo, Mercedes; Barker, Warren; Adjouadi, Malek (J Alzheimers Dis, 2017)
BACKGROUND: Both amyloid (Aβ) load and APOE4 allele are associated with neurodegenerative changes in Alzheimer's disease (AD) prone regions and with risk for cognitive impairment. OBJECTIVE: To evaluate the unique and independent contribution of APOE4 allele status (E4+∖E4-), Aβ status (Amy+∖Amy-), and combined APOE4 and Aβ status on regional cortical thickness (CoTh) and cognition among participants diagnosed as cognitively normal (CN, n = 251), early mild cognitive impairment (EMCI, n = 207), late mild cognitive impairment (LMCI, n = 196), and mild AD (n = 162) from the ADNI. METHODS: A series of two-way ANCOVAs with post-hoc Tukey HSD tests, controlling independently for Aβ and APOE4 status and age were examined. RESULTS: Among LMCI and AD participants, cortical thinning was widespread in association with Amy+ status, whereas in association with E4+ status only in the inferior temporal and medial orbito-frontal regions. Among CN and EMCI participants, E4+ status, but not Amy+ status, was independently associated with increased CoTh, especially in limbic regions [e.g., in the entorhinal cortex, CoTh was 0.123 mm greater (p = 0.002) among E4+ than E4-participants]. Among CN and EMCI, both E4+ and Amy+ status were independently associated with cognitive impairment, which was greatest among those with combined E4 + and Amy+ status. CONCLUSION: Decreased CoTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4 + status is associated with increased CoTh, in medial and inferior temporal regions, although cognitive impairment at this state is independently associated with Amy+ and E4 + status. These findings imply a unique pathophysiological mechanism for E4 + status in AD and its progression.

The Relationships Between Components of Metabolic Syndrome and Mild Cognitive Impairment Subtypes: A Cross-Sectional Study of Japanese Older Adults. - Bae, Seongryu; Shimada, Hiroyuki; Lee, Sangyoon; Makizako, Hyuma; Lee, Sungchul; Harada, Kazuhiro; Doi, Takehiko; Tsutsumimoto, Kota; Hotta, Ryo; Nakakubo, Sho; Park, Hyuntae; Suzuki, Takao (J Alzheimers Dis, 2017)
BACKGROUND: The associations between components of metabolic syndrome (MetS) and mild cognitive impairment (MCI) subtypes remain unclear. OBJECTIVE: The study aim was to identify the prevalence of MetS for MCI subtypes and to investigate sex differences in the association between MetS and MCI subtypes in older Japanese adults. METHODS: The study analyzed data from 3,312 men and women aged 70 years or more. MetS was diagnosed according to International Diabetes Federation criteria. Participants completed cognitive tests and were categorized into normal cognition, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The associations between MetS and its components and MCI subtypes were analyzed using multiple logistic regression. RESULTS: MetS prevalence was greater in participants with naMCI (men: p = 0.030; women: p = 0.040). Participants with naMCI showed higher odds ratios (OR) of MetS (men: 2.45, 95% confidence intervals (CI): 1.13-5.32; women: OR: 1.94, 95% CI: 1.12-3.39) compared with participants with normal cognition. MetS was not associated with aMCI. Analysis of MetS components showed that raised glucose (OR: 1.62, 95% CI: 1.19-2.22) and reduced high-density lipoprotein cholesterol (OR: 1.97, 95% CI: 1.25-3.12) were associated with naMCI in men. In women, raised blood pressure (OR: 1.42, 95% CI: 1.03-1.94) and raised glucose (OR: 1.32, 95% CI: 1.02-1.71) were associated with naMCI. CONCLUSION: MetS was associated only with naMCI regardless of sex, which suggests etiologic differences in MCI subtypes. We also found sex differences in the relationship between naMCI risk and MetS and its components.

Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review. - 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; et al. (J Alzheimers Dis, 2017)
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.

Relative Incidence of Seizures and Myoclonus in Alzheimer's Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia. - Beagle, Alexander J; Darwish, Sonja M; Ranasinghe, Kamalini G; La, Alice L; Karageorgiou, Elissaios; Vossel, Keith A (J Alzheimers Dis, 2017)
BACKGROUND: Patients with Alzheimer's disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown. OBJECTIVE: To determine incidence of seizures and myoclonus in the three most common neurodegenerative dementias: AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). METHODS: Our institution's medical records were reviewed for new-onset unprovoked seizures and myoclonus in patients meeting criteria for AD (n = 1,320), DLB (n = 178), and FTD (n = 348). Cumulative probabilities of developing seizures and myoclonus were compared between diagnostic groups, whereas age-stratified incidence rates were determined relative to control populations. RESULTS: The cumulative probability of developing seizures after disease onset was 11.5% overall, highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10-fold in AD and DLB, and 6-fold in FTD. Relative seizure rates increased with earlier age-at-onset in AD (age <50, 127-fold; 50-69, 21-fold; 70+, 2-fold) and FTD (age <50, 53-fold; 50-69, 9-fold), and relative myoclonus rates increased with earlier age-at-onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset. CONCLUSIONS: Seizures and myoclonus occur with greater incidence in patients with AD, DLB, and FTD than in the general population, but rates vary with diagnosis, suggesting varied pathomechanisms of network hyperexcitability. Patients often experience these symptoms early in disease, suggesting hyperexcitability could be an important target for interventions.

Risk of Mortality Associated with Antipsychotic Monotherapy and Polypharmacy Among Community-Dwelling Persons with Alzheimer's Disease. - Koponen, Marjaana; Taipale, Heidi; Lavikainen, Piia; Tanskanen, Antti; Tiihonen, Jari; Tolppanen, Anna-Maija; Ahonen, Riitta; Hartikainen, Sirpa (J Alzheimers Dis, 2017)
We aimed to analyze the risk of non-cancer mortality according to duration of antipsychotic use and to compare the risk associated with polypharmacy and monotherapy among community-dwellers with Alzheimer's disease (AD). The risk of mortality between most frequently used antipsychotic drugs was compared. Data from a nationwide register-based MEDALZ study that included all 70,718 community-dwellers newly diagnosed with AD during 2005-2011 in Finland was utilized. Death, excluding cancer as direct cause of death, was extracted from Causes of Death Register. Incident antipsychotic use was compared with time without antipsychotics with Cox proportional hazard models. Antipsychotic use was associated with an increased risk of mortality (adjusted hazard ratio [aHR] 1.61; 95% Confidence Interval [CI] 1.53-1.70). The absolute difference in mortality rate was 4.58 (95% CI 4.53-4.63) deaths per 100 person-years. The risk of mortality was increased from the first days of use and attenuated gradually but remained increased even after two years of use (aHR 1.30; 95% CI 1.16-1.46). Compared with nonuse, antipsychotic polypharmacy (aHR 2.88; 95% CI 2.38-3.49) was associated with an increased risk of mortality than monotherapy (aHR 1.57; 95% CI 1.49-1.66). Haloperidol was associated with higher risk of mortality (aHR 1.52; 95% CI 1.14-2.02) and quetiapine with lower risk (aHR 0.84; 95% CI 0.75-0.94) compared with risperidone. In conclusion, the findings support current treatment guidelines on having a high threshold for antipsychotic initiation among persons with AD. Antipsychotic polypharmacy and long-term use should be avoided and drug choice should be weighed against risk/benefit evidence.

The Road Less Traveled: Alternative Pathways for Action-Verb Processing in Parkinson's Disease. - Abrevaya, Sofía; Sedeño, Lucas; Fitipaldi, Sol; Pineda, David; Lopera, Francisco; Buritica, Omar; Villegas, Andrés; Bustamante, Catalina; Gomez, Diana; Trujillo, Natalia; Pautassi, Ricardo; Ibáñez, Agustín; et al. (J Alzheimers Dis, 2017)
Action verbs are critically embodied in motor brain networks. In Parkinson's disease (PD), damage to the latter compromises access to such words. However, patients are not fully incapable of processing them, as their performance is far from floor level. Here we tested the hypothesis that action-verb processing in PD may rely on alternative disembodied semantic circuits. Seventeen PD patients and 15 healthy controls listened to action verbs and nouns during functional MRI scanning. Using cluster-mass analysis with a permutation test, we assessed task-related functional connectivity considering seeds differentially engaged by action and non-action words (namely, putamen and M1 versus posterior superior temporal lobe, respectively). The putamen seed showed reduced connectivity within the basal ganglia in patients for both lexical categories. However, only action verbs recruited different cortical networks in each group. Specifically, the M1 seed exhibited more anterior connectivity for controls and more posterior connectivity for patients, with no differences in the temporal seed. Moreover, the patients' level of basal ganglia atrophy positively correlated with their reliance on M1-posterior connectivity during action-verb processing. PD patients seem to have processed action verbs via non-motor cortical networks subserving amodal semantics. Such circuits may afford alternative pathways to process words when default embodied mechanisms are disturbed. Moreover, the greater the level of basal ganglia atrophy, the greater the patients' reliance on this alternative route. Our findings offer new insights into differential neurofunctional mechanisms recruited to process action semantics in PD.

S-Adenosylmethionine Attenuates Oxidative Stress and Neuroinflammation Induced by Amyloid-β Through Modulation of Glutathione Metabolism. - Li, Qian; Cui, Jing; Fang, Chen; Liu, Min; Min, Guowen; Li, Liang (J Alzheimers Dis, 2017)
Oxidative stress and neuroinflammation are mainly involved in the pathogenic mechanisms of Alzheimer's disease (AD). Amyloid-β (Aβ), the main component of senile plaques, is a kind of strong inducer of oxidative stress. Glutathione is an endogenous antioxidant protecting cells from oxidative injury. S-adenosylmethionine (SAM) produced in the methionine cycle is the primary methyl donor and the precursor of glutathione. In this study, the Aβ intrahippocampal injection rat model and cultured SH-SY5Y cells were used to explore the neuroprotective effect of SAM. We found that SAM could protect cells against Aβ-induced cellular injury by inhibition of oxidative stress and neuroinflammation. SAM administration could increase the endogenous antioxidant glutathione and potentiate the antioxidant enzymes activities. SAM might act as an antioxidant and be a potential candidate therapy for AD patients.

Is Salivary Chromogranin A a Valid Psychological Stress Biomarker During Sensory Stimulation in People with Advanced Dementia? - Valdiglesias, Vanessa; Maseda, Ana; Lorenzo-López, Laura; Pásaro, Eduardo; Millán-Calenti, José C; Laffon, Blanca (J Alzheimers Dis, 2017)
Salivary chromogranin A (sCgA) is gaining attention as a biomarker of psychological stress. The objective of this work was to determine whether individualized music intervention and multisensory stimulation environment (MSSE) in a Snoezelen room produce changes in sCgA in severely demented older patients, and to assess the possible existence of differences in sCgA levels between the two types of interventions. Older adults with severe dementia (n = 22) were randomly assigned to two intervention groups. They participated in MSSE or individualized music interventions in 30-min weekly sessions for 16 weeks. Levels of sCgA were evaluated before and after a session, or 30-min interval, at four different time points: before starting the trial, in the middle and end of the intervention period, and two months later. Comparison of sCgA values obtained after each session with those obtained before (or at the same hour in before trial and follow-up samplings) showed no significant differences either in the individualized music or in the MSSE group at any sampling time. Comparison between the two types of interventions, both before and after each session, in the four sampling times, did not produce any significant difference either. Furthermore, no significant correlation was obtained between agitation, anxiety, cognitive function, and dementia severity with sCgA levels. In conclusion, despite beneficial effects of both individualized music and MSSE interventions being previously reported on neuropsychiatric outcomes for older patients with dementia, sCgA seems to not be a good indicator of these benefits.

Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). - Cardoso, Bárbara R; Hare, Dominic J; Bush, Ashley I; Li, Qiao-Xin; Fowler, Christopher J; Masters, Colin L; Martins, Ralph N; Ganio, Katherine; Lothian, Amber; Mukherjee, Soumya; Kapp, Eugene A; Roberts, Blaine R (J Alzheimers Dis, 2017)
Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete.

Selenomethionine Attenuates the Amyloid-β Level by Both Inhibiting Amyloid-β Production and Modulating Autophagy in Neuron-2a/AβPPswe Cells. - Zhang, Zhong-Hao; Wu, Qiu-Yan; Chen, Chen; Zheng, Rui; Chen, Yao; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a complex and progressive neurological disorder, and amyloid-β (Aβ) has been recognized as the major cause of AD. Inhibiting Aβ production and/or enhancing the clearance of Aβ to reduce its levels are still the effective therapeutic strategies pursued in anti-AD research. In previous studies, we have reported that selenomethionine (Se-Met), a major form of selenium in animals and humans with significant antioxidant capacity, can reduce both amyloid-β (Aβ) deposition and tau hyperphosphorylation in a triple transgenic mouse model of AD. In this study, a Se-Met treatment significantly decreased the Aβ levels in Neuron-2a/AβPPswe (N2asw) cells, and the anti-amyloid effect of Se-Met was attributed to its ability to inhibit Aβ generation by suppressing the activity of BACE1. Furthermore, both the LC3-II/LC3-I ratio and the number of LC3-positive puncta were significantly decreased in Se-Met-treated cells, suggesting that Se-Met also promoted Aβ clearance by modulating the autophagy pathway. Subsequently, Se-Met inhibited the initiation of autophagy through the AKT-mTOR-p70S6K signaling pathway and enhanced autophagic turnover by promoting autophagosome-lysosome fusion and autophagic clearance. Our results further highlight the potential therapeutic effects of Se-Met on AD.

Sensing of Alzheimer's Disease and Multiple Sclerosis Using Nano-Bio Interfaces. - Hajipour, Mohammad Javad; Ghasemi, Forough; Aghaverdi, Haniyeh; Raoufi, Mohammad; Linne, Uwe; Atyabi, Fatemeh; Nabipour, Iraj; Azhdarzadeh, Morteza; Derakhshankhah, Hossein; Lotfabadi, Alireza; Bargahi, Afshar; Alekhamis, Zahra; et al. (J Alzheimers Dis, 2017)
It is well understood that patients with different diseases may have a variety of specific proteins (e.g., type, amount, and configuration) in their plasmas. When nanoparticles (NPs) are exposed to these plasmas, the resulting coronas may incorporate some of the disease-specific proteins. Using gold (Au) NPs with different surface properties and corona composition, we have developed a colorimetric sensor array for the discrimination and detection of two neurodegenerative diseases, Alzheimer's disease (AD) and multiple sclerosis (MS). Applying a variety of techniques, including UV-visible spectra, array response analyses and liquid chromatography-tandem mass spectrometry, we found the corona-NP complexes, obtained from different human serums, had distinct protein composition, including some specific proteins that are known as AD and MS biomarkers. The array responses, analyzed by chemometrics and statistical methods, demonstrate promising capabilities of the sensor to unambiguously identify and discriminate AD and MS. The developed sensor array might enable a simple, inexpensive and rapid detection/discrimination of neurodegenerative diseases.

Serum SHBG Levels are not Associated with Longitudinal Cognitive Decline in Mild Cognitive Impairment. - Lin, Katherine Amy; Rundel, Colin; Doraiswamy, P Murali (J Alzheimers Dis, 2017)
BACKGROUND: Prior studies have noted gender differences in cognition, imaging, and pathological markers in mild cognitive impairment (MCI) subjects. Sex hormone-binding globulin (SHBG), a major controlling factor in the proportion of bioavailable versus bound testosterone and estrogen, has been proposed to contribute to links between hormones and dementia, but has not yet been investigated fully in a prospective biomarker trial. OBJECTIVE: This study examined whether, among subjects with MCI, SHBG levels predict future rate of cognitive decline. METHODS: We examine the effect of gender on cognitive decline and factors modulating potential gender differences in 378 MCI subjects (134 females, 244 males) in the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1), followed for up to 8 years (mean ± SE, 4.0 ± 0.1 years). Cognition was assessed using the ADAS-cog-11. Multivariate models examined the effect of gender covarying for age, ApoE4, baseline cognition, years of education, and SHBG levels. RESULTS: MCI women declined significantly faster than men in cognition over the follow up period. Baseline SHBG levels differed significantly between men and women (p < 0.0001), and by age in men, but not by ApoE4 status. In the multivariate models, SHBG levels were not a significant predictor of cognitive decline in men or women but ApoE4 status, baseline cognition, years of education, and female gender were. CONCLUSION: SHBG levels did not influence the rate of cognitive decline in MCI. Further studies to confirm these findings and uncover other potential mechanisms of gender differences in the risk for AD may be warranted.

Sex Difference in Aerobic Exercise Efficacy to Improve Cognition in Older Adults with Vascular Cognitive Impairment: Secondary Analysis of a Randomized Controlled Trial. - Barha, Cindy K; Hsiung, Ging-Yuek R; Best, John R; Davis, Jennifer C; Eng, Janice J; Jacova, Claudia; Lee, Philip E; Munkacsy, Michelle; Cheung, Winnie; Liu-Ambrose, Teresa (J Alzheimers Dis, 2017)
Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.

SH2B1 is Involved in the Accumulation of Amyloid-β42 in Alzheimer's Disease. - Shen, Yijun; Xia, Yiling; Meng, Shiquan; Lim, Nastasia K H; Wang, Wenan; Huang, Fude (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42. Partial knockout of neuronal SH2B in the Aβ42-expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42, as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42-expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42. Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia.

Short-Term Response is not Predictive of Long-Term Response to Acetylcholinesterase Inhibitors in Old Age Subjects with Alzheimer's Disease: A "Real World" Study. - Boccardi, Virginia; Baroni, Marta; Smirne, Nicoletta; Clodomiro, Alessandra; Ercolani, Sara; Longo, Annalisa; Ruggiero, Carmelinda; Bruni, Amalia C; Mecocci, Patrizia (J Alzheimers Dis, 2017)
BACKGROUND: Most of clinical guidelines recommend discontinuing treatment with cholinesterase inhibitors (ChEIs) in patients with Alzheimer's disease (AD) who do not show an initial response to therapy as evaluated with the Mini-Mental State Examination (MMSE) scale. However, understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important in clinical practice, but evidence is limited, particularly in the old-old population. OBJECTIVE: We aimed at investigating the relationship between short-term and long-term response to ChEI therapy in old age subjects with AD in a "real life" setting. METHODS: This is a retrospective longitudinal study of 628 old age subjects (≥65 years old) with AD and treated with ChEIs over three year follow-up. The sample was divided into "young-old" (≤75 years) and "old-old" (≥76 years) according to age, and as "responder" and "non-responder" according to the initial (i.e., after three months) response to treatment. Cognitive and functional evaluation was performed by means of MMSE and ADL/IADL, respectively. RESULTS: In the long run, subjects considered as non-responders showed a lower rate of cognitive decline as compared with responders, with a mean annual decline at MMSE of 1.0 point versus 1.6 points (p < 0.0001), respectively. Old-old non-responders had a slower rate of cognitive (p < 0.0001) and functional decline (p < 0.0001) as compared with responders after three years of observation. CONCLUSION: Discontinuing ChEI treatment solely for the absence of an initial response is not appropriate, especially in old-old subjects.

Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer's Disease. - Sheng, Min; Lu, Hanzhang; Liu, Peiying; Li, Yang; Ravi, Harshan; Peng, Shin-Lei; Diaz-Arrastia, Ramon; Devous, Michael D; Womack, Kyle B (J Alzheimers Dis, 2017)
BACKGROUND: Alzheimer's disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD. OBJECTIVE: We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD. METHODS: We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained. RESULTS: Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil. CONCLUSION: Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

Sleep Apnea, Cognitive Profile, and Vascular Changes: An Intriguing Relationship. - Buratti, Laura; Viticchi, Giovanna; Baldinelli, Sara; Falsetti, Lorenzo; Luzzi, Simona; Pulcini, Alessandra; Petrelli, Cristina; Provinciali, Leandro; Silvestrini, Mauro (J Alzheimers Dis, 2017)
BACKGROUND: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes. OBJECTIVE: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors. METHODS: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients. RESULTS: At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p < 0.001) and in short-term (p = 0.02) and long-term Rey Auditory Verbal Learning Test (p < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. CONCLUSIONS: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

Sleep Deprivation Induced Plasma Amyloid-β Transport Disturbance in Healthy Young Adults. - Wei, Meng; Zhao, Beiyu; Huo, Kang; Deng, Yongning; Shang, Suhang; Liu, Jie; Li, Yanbo; Ma, Louyan; Jiang, Yu; Dang, Liangjun; Chen, Chen; Wei, Shan; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Sleep is an important physiological process and beneficial in the removal of brain metabolites and functional recovery. Prior studies have shown that sleep disorders are significant risk factors for Alzheimer's disease (AD). OBJECTIVE: The present study was designed to characterize the effect of short-term total sleep deprivation (TSD) on plasma amyloid-β (Aβ) concentrations. METHODS: A clinical trial was conducted between March 1, 2016, and April 1, 2016. Twenty volunteers (age 27.3±3.4 years) with normal cognitive function and sleeping habits were recruited from the local population. Participants underwent 24 h of TSD. Periprocedural blood samples were collected to compare the changes of plasma Aβ42, Aβ40, low-density lipoprotein receptor-related protein (sLRP-1), soluble receptors for advanced glycation end products (sRAGE), and serum superoxide dismutase (SOD) and malonaldehyde (MDA). RESULTS: TSD increased morning plasma Aβ40 levels by 32.6% (p < 0.001) and decreased the Aβ42/Aβ40 ratio by 19.3% (p < 0.001). A positive relationship was found between TSD duration and plasma Aβ40 level (r = 0.51, p < 0.001) and Aβ40/Aβ42 ratio (r = 0.25, p = 0.003). Plasma concentrations of sLRP1 (p = 0.018) and sRAGE (p = 0.001) decreased significantly after TSD. Aβ40 and Aβ42 plasma concentrations correlated with plasma levels of sLRP1 and sRAGE. Serum SOD decreased after TSD (p = 0.005), whereas serum MDA was increased (p = 0.001). CONCLUSION: Sleep deprivation can lead to an elevation of plasma Aβ40 and decrease of the Aβ42/Aβ40 ratio. The underlying mechanisms may be related to increased oxidative stress and impaired peripheral Aβ clearance as pathomechanisms of AD.
Keywords: Adult; Amyloid beta-Peptides; Female; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Male; Malondialdehyde; Peptide Fragments; Receptor for Advanced Glycation End Products; Sleep Deprivation; Superoxide Dismutase; Time Factors; Young Adult

Social Cognition in the Frontal Variant of Alzheimer's Disease: A Case Study. - Duclos, Harmony; de la Sayette, Vincent; Bonnet, Anne-Laure; Viard, Armelle; Eustache, Francis; Desgranges, Béatrice; Laisney, Mickaël (J Alzheimers Dis, 2017)
Although frontal presentations of Alzheimer's disease (fv-AD) have already been described in the literature, we still know little about patients' social cognitive abilities, especially their theory of mind (ToM). We report the case of FT, a 61-year-old woman who was diagnosed with fv-AD. Two assessments of social cognition, using a false-belief task, the Reading the Mind in the Eyes test, and a task probing knowledge of social norms, were performed one year apart. FT exhibited cognitive ToM and social knowledge deficits from the onset. Affective ToM was initially preserved, but deteriorated as the disease progressed.

SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk. - Liu, Guiyou; Sun, Jing-Yi; Xu, Meiling; Yang, Xiao-Yi; Sun, Bao-Liang (J Alzheimers Dis, 2017)
A recent study sequenced the full coding region of SORL1 in 1,255 early-onset Alzheimer's disease (EOAD) cases and 1,938 control individuals, and investigated the contribution of genetic variability in SORL1 to EOAD risk in a European cohort. This study identified six common variants and five low frequency variants in the SORL1 coding sequence. However, none of these 11 variants was significantly associated with EOAD risk after adjusting for multiple testing. We consider whether these 11 SORL1 variants identified in European EOAD contribute to late-onset Alzheimer's disease (LOAD) risk in individuals of European ancestry. Here, we investigated these 11 SORL1 variants identified in European EOAD and LOAD risk in individuals of European ancestry using a large-scale LOAD GWAS. Our results indicate that three genetic variants rs2070045, rs2276412, and rs17125548 as well as their tagged genetic variants contribute to LOAD risk in European population. We further investigate whether these variants could affect SORL1 expression using multiple expression quantitative trait loci (eQTLs) datasets. Our findings suggest that three genetic variants rs2070045, rs1699102, and rs3824968 could significantly regulate SORL1 expression in human brain tissues. We believe that our findings further provide important supplementary information about the involvement of the SORL1 variants in LOAD risk.

Sporadic Cases with Novel Mutations and Pedigree in Hereditary Leukoencephalopathy with Axonal Spheroids. - Wu, Liyong; Liu, Jia; Sha, Longze; Wang, Xianling; Li, Jieying; Dong, Jing; Jia, Jianping (J Alzheimers Dis, 2017)
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant hereditary disease, featured by cerebral white matter degeneration with demyelination and axonal spheroids. We collected three gene-confirmed HDLS cases in our neurodegenerative clinic. Two HDLS cases were sporadic with novel mutations, while another case had a family history with previously described mutations. All three cases suffered memory problems with white matter lesions and pyramid signs. No obvious clinical differences were observed between sporadic and familial HDLS cases. Distinct features, such as subcortical calcification in brain computed tomography and asymmetric abnormal MRI signal along the pyramid tracts throughout brainstem and spinal cord (cervical, thoracic, and lumbar segments), were observed in one sporadic case with novel mutation. Therefore, the interactions of genotype-phenotype still need to be further investigated.

Subjective Memory Impairment and Gait Variability in Cognitively Healthy Individuals: Results from a Cross-Sectional Pilot Study. - Beauchet, Olivier; Launay, Cyrille P; Chabot, Julia; Levinoff, Elise J; Allali, Gilles (J Alzheimers Dis, 2017)
BACKGROUND: Increased stride time variability has been associated with memory impairment in mild cognitive impairment. Subjective memory impairment (SMI) is considered the earliest clinical stage of Alzheimer's disease (AD). The association between increased stride time variability and SMI has not been reported. OBJECTIVE: This study aims to examine the association of stride time variability while performing single and dual tasking with SMI in cognitively healthy individuals (CHI). METHODS: A total of 126 CHI (15 without SMI, 69 with SMI expressed by participants, 10 with SMI expressed by participant's relative, and 32 with SMI expressed by both participants and their relatives) were included in this cross-sectional study. The coefficient of variation (CoV) of stride time and walking speed were recorded under usual condition and while counting backwards. Age, gender, body mass index, number of drugs taken daily, use of psychoactive drugs, fear of falling, history of previous falls, and walking speed were used as covariates. RESULTS: The multiple linear regression models showed that greater CoV of stride time while counting backwards, but not while single tasking, was associated with a participant's relative SMI (p = 0.038). CONCLUSION: This study found a specific association between SMI expressed by a participant's relative and a greater CoV of stride time (i.e., worse performance) while dual tasking, suggesting that the association between gait variability and memory may be present in the earliest stages of memory impairment. Thus, gait variability under dual-task in individuals with SMI expressed by their relatives can be a potential biomarker of AD.

Successful Object Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer's Disease. - Ochoa, John Fredy; Alonso, Joan Francesc; Duque, Jon Edinson; Tobón, Carlos Andrés; Mañanas, Miguel Angel; Lopera, Francisco; Hernández, Alher Mauricio (J Alzheimers Dis, 2017)
BACKGROUND: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer's disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. OBJECTIVE: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. METHODS: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. RESULTS: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. CONCLUSION: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD.

Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications. - Crivelli, Simone M; Paulus, Andreas; Markus, Jozef; Bauwens, Matthias; Berkes, Dusan; De Vries, Helga E; Mulder, Monique T; Walter, Jochen; Mottaghy, Felix M; Losen, Mario; Martinez-Martinez, Pilar (J Alzheimers Dis, 2017)
Ceramide levels are increased in blood and brain tissue of Alzheimer's disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/μmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain.

A Systematic Review of Longitudinal Studies Which Measure Alzheimer's Disease Biomarkers. - Lawrence, Emma; Vegvari, Carolin; Ower, Alison; Hadjichrysanthou, Christoforos; De Wolf, Frank; Anderson, Roy M (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment or cure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causation in the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number of quantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers. The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however, not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma amyloid-β and tau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans, in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonly used diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in a representative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, we suggest directions in which research could move in order to advance our understanding of this complex disease, including repeat biomarker measurements, standardization and increased sample sizes.

Tai Chi Chuan and Baduanjin Increase Grey Matter Volume in Older Adults: A Brain Imaging Study. - Tao, Jing; Liu, Jiao; Liu, Weilin; Huang, Jia; Xue, Xiehua; Chen, Xiangli; Wu, Jinsong; Zheng, Guohua; Chen, Bai; Li, Ming; Sun, Sharon; Jorgenson, Kristen; et al. (J Alzheimers Dis, 2017)
The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS-CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults.

Targeted Metabolomic Analysis of Soluble Lysates from Platelets of Patients with Mild Cognitive Impairment and Alzheimer's Disease Compared to Healthy Controls: Is PC aeC40:4 a Promising Diagnostic Tool? - Oberacher, Herbert; Arnhard, Kathrin; Linhart, Caroline; Diwo, Angela; Marksteiner, Josef; Humpel, Christian (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system. The use of biological fluids in AD diagnosis remains limited to the analysis of specific protein biomarkers in cerebrospinal fluid. However, metabolomic analysis has recently revealed several metabolites in plasma, especially phosphatidylcholines (PC), as putative biomarkers specific for AD. Following on previous reports of platelet abnormalities in AD, we hypothesized that platelets metabolites released in plasma may offer new biomarkers in AD. The aim of the present study was to apply targeted metabolomics to compare metabolites in soluble lysates of platelets from healthy controls (CO), patients with mild cognitive impairment (MCI), and patients with AD in a cohort of 90 subjects. We could target 163 metabolites and quantitative data were obtained for 91 metabolites. Among these, the lipid PC aeC40:4 significantly differentiated AD from CO (p = 0.0009), while four other lipids (PC aaC32:0, PC ae C32:2, PC aeC34:1, and SM(OH)C14:1) differentiated patients with MCI from CO. The combination of three phosphatidylcholines (PC aeC32:2, PC aeC34:1, PCaaC36:5), two lyso-phosphatidylcholines (lysoPC aC18:1, lysoPC aC16:0), and one sphingomyelin (SM(OH) C14:1) constructed a valuable prediction model using the C4.5 decision tree. The diagnosis accuracy for AD versus CO and MCI was 85%. In a blinded follow up conversion study (10 patients with a second blood collection after 9 months), we could verify the clinical diagnosis in 19 out of 20 cases. We propose that soluble platelet PCaeC40:4 is a promising marker to diagnose AD with a cut-off of <0.30μM and that platelets undergo metabolic processes during AD progression.

Tau Pathology Promotes the Reorganization of the Extracellular Matrix and Inhibits the Formation of Perineuronal Nets by Regulating the Expression and the Distribution of Hyaluronic Acid Synthases. - Li, Yin; Li, Ze-Xu; Jin, Tan; Wang, Zhan-You; Zhao, Pu (J Alzheimers Dis, 2017)
Hyaluronic acid (HA) is the backbone of the extracellular matrix (ECM) and provides biochemical and physical support to aggrecan-based perineuronal nets (PNNs), which are associated with the selective vulnerability of neurons in Alzheimer's disease (AD). Here, we showed that HA synthases (HASs), including Has1, Has2, and Has3, were widely expressed in murine central nervous system. All types of HASs were localized to cell bodies of neurons; only Has1 existed in the membranes of neural axons. By using TauP301S transgenic (Tg) mouse model, we found that the axonal-localization of Has1 was abolished in TauP301S overexpressed mouse brain, and the redistribution of Has1 was also observed in human AD brains, suggesting that the localization of Has1 is dependent on intact microtubules which are regulated partially by the phosphorylation and dephosphorylation cycles of tau proteins. Furthermore, Has1 was reduced and Has3 was increased in TauP301S Tg mouse brain, resulting in the upregulation of shorter-chain HA in the ECM. These findings suggest that by abolishing the axonal-localization of Has1 and promoting the expression of Has3 and the synthesis of shorter-chain HA, the tau pathology breaks the balance of ECM components, promotes the reorganization of the ECM, and inhibits the formation of PNNs in the hippocampus, and then regulates neuronal plasticity during the progression of AD.

Tau Platelets Correlate with Regional Brain Atrophy in Patients with Alzheimer's Disease. - Slachevsky, Andrea; Guzmán-Martínez, Leonardo; Delgado, Carolina; Reyes, Pablo; Farías, Gonzalo A; Muñoz-Neira, Carlos; Bravo, Eduardo; Farías, Mauricio; Flores, Patricia; Garrido, Cristian; Becker, James T; Lopez, Oscar L; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Intracellular neurofibrillary tangles are part of the core pathology of Alzheimer's disease (AD), which are mainly composed of hyperphosphorylated tau protein. OBJECTIVES: The purpose of this study is to determine whether high molecular weight (HMW) or low molecular weight (LMW) tau protein levels, as well as the ratio HMW/LMW, present in platelets correlates with brain magnetic resonance imaging (MRI) structural changes in normal and cognitively impaired subjects. METHODS: We examined 53 AD patients and 37 cognitively normal subjects recruited from two Memory Clinics at the Universidad de Chile. Tau levels in platelets were determined by immunoreactivity and the MRI scans were analyzed using voxel-based morphometry in 41 AD patients. RESULTS: The HMW/LMW tau ratio was statistically different between controls and AD patients, and no associations were noted between HMW or LMW tau and MRI structures. In a multivariate analysis controlled for age and education level, the HMW/LMW tau ratio was associated with reduced volume in the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region. CONCLUSIONS: This exploratory study showed that HMW/LMW tau ratio is significantly higher in AD patients than control subjects, and that it is associated with specific brain regions atrophy. Determination of peripheral markers of AD pathology can help understanding the pathophysiology of neurodegeneration in AD.

TMEM230 Accumulation in Granulovacuolar Degeneration Bodies and Dystrophic Neurites of Alzheimer's Disease. - Siedlak, Sandra L; Jiang, Yinfei; Huntley, Mikayla L; Wang, Luwen; Gao, Ju; Xie, Fei; Liu, Jingyi; Su, Bo; Perry, George; Wang, Xinglong (J Alzheimers Dis, 2017)
Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson's disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer's disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD.

Topological Alterations and Symptom-Relevant Modules in the Whole-Brain Structural Network in Semantic Dementia. - Ding, Junhua; Chen, Keliang; Zhang, Weibin; Li, Ming; Chen, Yan; Yang, Qing; Lv, Yingru; Guo, Qihao; Han, Zaizhu (J Alzheimers Dis, 2017)
BACKGROUND: Semantic dementia (SD) is characterized by a selective decline in semantic processing. Although the neuropsychological pattern of this disease has been identified, its topological global alterations and symptom-relevant modules in the whole-brain anatomical network have not been fully elucidated. OBJECTIVE: This study aims to explore the topological alteration of anatomical network in SD and reveal the modules associated with semantic deficits in this disease. METHODS: We first constructed the whole-brain white-matter networks of 20 healthy controls and 19 patients with SD. Then, the network metrics of graph theory were compared between these two groups. Finally, we separated the network of SD patients into different modules and correlated the structural integrity of each module with the severity of the semantic deficits across patients. RESULTS: The network of the SD patients presented a significantly reduced global efficiency, indicating that the long-distance connections were damaged. The network was divided into the following four distinctive modules: the left temporal/occipital/parietal, frontal, right temporal/occipital, and frontal/parietal modules. The first two modules were associated with the semantic deficits of SD. CONCLUSION: These findings illustrate the skeleton of the neuroanatomical network of SD patients and highlight the key role of the left temporal/occipital/parietal module and the left frontal module in semantic processing.

Trajectories of Multidimensional Caregiver Burden in Chinese Informal Caregivers for Dementia: Evidence from Exploratory and Confirmatory Factor Analysis of the Zarit Burden Interview. - Li, Dan; Hu, Nan; Yu, Yueyi; Zhou, Aihong; Li, Fangyu; Jia, Jianping (J Alzheimers Dis, 2017)
BACKGROUND: Despite its popularity, the latent structure of 22-item Zarit Burden Interview (ZBI) remains unclear. There has been no study exploring how caregiver multidimensional burden changed. OBJECTIVE: The aim of the work was to validate the latent structure of ZBI and to investigate how multidimensional burden evolves with increasing global burden. METHODS: We studied 1,132 dyads of dementia patients and their informal caregivers. The caregivers completed the ZBI and a questionnaire regarding caregiving. The total sample was randomly split into two equal subsamples. Exploratory factor analysis (EFA) was performed in the first subsample. In the second subsample, confirmatory factor analysis (CFA) was conducted to validate models generated from EFA. The mean of weighted factor score was calculated to assess the change of dimension burden against the increasing ZBI total score. RESULTS: The result of EFA and CFA supported that a five-factor structure, including role strain, personal strain, incompetency, dependency, and guilt, had the best goodness-of-fit. The trajectories of multidimensional burden suggested that three different dimensions (guilt, role strain and personal strain) became the main subtype of burden in sequence as the ZBI total score increased from mild to moderate. Factor dependency contributed prominently to the total burden in severe stage. CONCLUSION: The five-factor ZBI is a psychometrically robust measure for assessing multidimensional burden in Chinese caregivers. The changes of multidimensional burden have deepened our understanding of the psychological characteristics of caregiving beyond a single total score and may be useful for developing interventions to reduce caregiver burden.

Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus. - Leino, Marina; Popova, Svetlana N; Alafuzoff, Irina (J Alzheimers Dis, 2017)
A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer's disease (AD) related amyloid-β (Aβ) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated τ (HPτ), Aβ, α-synuclein (αS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques. HPτ in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non-diabetics when compared with diabetics in demented. A significant correlation was observed between HPτ, Aβ, αS, and pTDP43, whereas IAPP showed no association with HPτ, Aβ, and αS. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown.

Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer's Disease. - Lu, Yujiao; Dong, Yan; Tucker, Donovan; Wang, Ruimin; Ahmed, Mohammad Ejaz; Brann, Darrell; Zhang, Quanguang (J Alzheimers Dis, 2017)
Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer's disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment.

Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease. - Liu, Collin Y; Ohki, Yu; Tomita, Taisuke; Osawa, Satoko; Reed, Bruce R; Jagust, William; Van Berlo, Victoria; Jin, Lee-Way; Chui, Helena C; Coppola, Giovanni; Ringman, John M (J Alzheimers Dis, 2017)
BACKGROUND: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. OBJECTIVE: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. METHODS: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. RESULTS: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aβ42 and decreased APP and Notch intracellular domain production in vitro. CONCLUSION: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aβ.

Type 1 Diabetes Mellitus and Cognitive Impairments: A Systematic Review. - Li, Wei; Huang, Edgar; Gao, Sujuan (J Alzheimers Dis, 2017)
Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia.

Upregulated Expression of Heparanase and Heparanase 2 in the Brains of Alzheimer's Disease. - Garcia, Beatriz; Martin, Carla; Garcia-Suarez, Olivia; Muniz-Alonso, Barbara; Ordiales, Helena; Fernandez-Menendez, Santiago; Santos-Juanes, Jorge; Lorente-Gea, Laura; Castanon, Sonia; Vicente-Etxenausia, Ikerne; Pina Batista, Kelvin Manuel; Ruiz-Diaz, Irune; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer's disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity. OBJECTIVE: To analyze HPSE and HPSE2 expressions at different stages of AD. METHODS: RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain. RESULTS: Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well. CONCLUSION: Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.

Urine AD7c-NTP Predicts Amyloid Deposition and Symptom of Agitation in Patients with Alzheimer's Disease and Mild Cognitive Impairment. - Zhang, Nan; Zhang, Liling; Li, Yan; Gordon, Marc L; Cai, Li; Wang, Ying; Xing, Mengya; Cheng, Yan (J Alzheimers Dis, 2017)
BACKGROUND: Expression of neuronal thread protein (NTP), which is considered to be related to neuritic sprouting and neuronal death, may be elevated in brain tissue, cerebrospinal fluid, and even urine in patients with Alzheimer's disease (AD). OBJECTIVE: In this study, we analyzed the correlation between urine AD-associated NTP (AD7c-NTP) level, and amyloid-β (Aβ) deposition, and clinical symptoms in AD and mild cognitive impairment (MCI). METHODS: Twenty-two patients with mild to moderate AD and 8 subjects with MCI were recruited. Aβ deposition was measured with [11C]-labeled Pittsburgh compound B (PiB)-positron emission tomography (PET) in all participants. Urine AD7c-NTP levels were measured using enzyme-linked immunosorbent assay. Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI) were used to evaluate cognitive function and behavioral psychological symptoms, respectively. RESULTS: Fourteen (63.6%) of AD patients and 2 (25.0%) of MCI subjects were Aβ positive on PiB-PET. There was a significant difference in urine AD7c-NTP level between Aβ positive (2.27±2.22 ng/ml) and negative (0.55±0.60 ng/ml) subjects (p = 0.018). Using 1.46 ng/ml as a cut-off value, 68.8% of Aβ positive subjects showed elevated urine AD7c-NTP level, and 92.9% of Aβ negative subjects showed normal urine AD7c-NTP level. There were no relationships between urine AD7c-NTP level and MMSE and total NPI scores. However, AD7c-NTP level positively correlated with agitation score on NPI. CONCLUSIONS: Urine AD7c-NTP had high specificity and moderate sensitivity in predicting Aβ deposition among patients with cognitive impairment. Furthermore, urine AD7c-NTP level strongly correlated with the symptom of agitation.

Urine Formaldehyde Predicts Cognitive Impairment in Post-Stroke Dementia and Alzheimer's Disease. - Tong, Zhiqian; Wang, Weishan; Luo, Wenhong; Lv, Jihui; Li, Hui; Luo, Hongjun; Jia, Jianping; He, Rongqiao (J Alzheimers Dis, 2017)
Although Alzheimer's disease (AD) was first described over 100 years ago, there is still no suitable biomarker for diagnosing AD in easily collectable samples (e.g., blood plasma, saliva, and urine). Here, we investigated the relationship between morning urine formaldehyde concentration and cognitive impairment in patients with post-stroke dementia (PSD) or AD in this cross-sectional survey for 7 years. Cognitive abilities of the study participants (n = 577, four groups: 231 controls, 61 stroke, 65 PSD, and 220 AD) were assessed by Mini-Mental State Examination (MMSE). Morning urine formaldehyde concentrations were measured by high performance liquid chromatography (HPLC). Gender- and age-matched participants were selected from the four groups (n = 42 in each group). Both semicarbazide-sensitive amine oxidase (SSAO, a formaldehyde-generating enzyme) and formaldehyde levels in the blood and urine were analyzed by using an enzyme-linked immunosorbent assay (ELISA) and HPLC, respectively. We found that morning urine formaldehyde levels were inversely correlated with MMSE scores. The threshold value (the best Cut-Off value) of formaldehyde concentration for predicting cognitive impairment was 0.0418 mM in patients with PSD (Sensitivity: 92.3%; Specificity: 77.1%), and 0.0449 mM in patients with AD (Sensitivity: 94.1%; Specificity: 81.8%), respectively. The results of biochemical analysis revealed that the observed increase in urine formaldehyde resulted from an overexpression of SSAO in the blood. The findings suggest that measuring the concentration of formaldehyde in overnight fasting urine could be used as a potentially noninvasive method for evaluating the likelihood of ensuing cognitive impairment or dementia.

Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. - Dublin, Sascha; Walker, Rod L; Gray, Shelly L; Hubbard, Rebecca A; Anderson, Melissa L; Yu, Onchee; Montine, Thomas J; Crane, Paul K; Sonnen, Josh A; Larson, Eric B (J Alzheimers Dis, 2017)
BACKGROUND: Opioids may influence the development of Alzheimer's disease (AD). Some studies have observed AD pathology in the brains of opioid abusers. No study has examined the association between prescription opioid use and dementia-related neuropathologic changes. OBJECTIVE: To examine the relationship between prescription opioid or NSAID use and dementia-related neuropathologic changes. METHODS: Within a community-based autopsy cohort (N = 420), we ascertained opioid and nonsteroidal anti-inflammatory drug (NSAID) use over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDDs). A neuropathologist assessed outcomes including neuritic plaques, neurofibrillary tangles, and macroscopic infarcts. Outcome measures were dichotomized using established cutpoints. We used modified Poisson regression to calculate adjusted relative risks (RR) and 95% confidence intervals (CI), accounting for participant characteristics and using weighting to account for possible selection bias related to selection into the autopsy sample. RESULTS: Heavier opioid exposure was not associated with greater neuropathologic changes. For neuritic plaques, the adjusted RR [95% CI] was 0.99 [0.64-1.47] for 91+ TSDDs of opioids versus little to no use, and for neurofibrillary tangles, 0.97 [0.49-1.78]. People with heavy NSAID use had higher risk of neuritic plaques (RR 1.39 [1.01-1.89]) than those with little to no use, as we have previously reported. Neither opioid nor NSAID use was associated with higher risk of macroscopic infarcts or with Lewy body disease. CONCLUSION: Prescription opioid use is not associated with dementia-related neuropathologic changes, but heavy NSAID use may be. More research is needed examining chronic pain, its pharmacologic treatments, and neuropathologic changes.

Utility of Molecular and Structural Brain Imaging to Predict Progression from Mild Cognitive Impairment to Dementia. - Lan, Martin J; Ogden, R Todd; Kumar, Dileep; Stern, Yaakov; Parsey, Ramin V; Pelton, Gregory H; Rubin-Falcone, Harry; Pradhaban, Gnanavalli; Zanderigo, Francesca; Miller, Jeffrey M; Mann, J John; Devanand, D P (J Alzheimers Dis, 2017)
This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11C]PIB) and one with fluorodeoxyglucose ([18F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11C]PIB binding potential (BPND) than HCs in multiple brain regions, and lower hippocampus volumes. [11C]PIB BPND, [18F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11C]PIB BPND and then hippocampus volume. [11C]PIB BPND and [18F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11C]PIB BPND, but did not add predictive power when combined with the [18F]FDG SUVR data. This work suggests that PET imaging with both [11C]PIB and [18F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options.

The Utility of the Cognitive Function Instrument (CFI) to Detect Cognitive Decline in Non-Demented Older Adults. - Li, Clara; Neugroschl, Judith; Luo, Xiaodong; Zhu, Carolyn; Aisen, Paul; Ferris, Steven; Sano, Mary (J Alzheimers Dis, 2017)
BACKGROUND: Subjective cognitive complaint is a sensitive marker of decline. OBJECTIVE: This study aimed to (1) examine reliability of subjective cognitive complaint using the Cognitive Function Instrument (CFI), and (2) assess the utility of the CFI to detect cognitive decline in non-demented elders. METHODS: Data from a four-year longitudinal study at multiple Alzheimer's Disease Cooperative Study (ADCS) sites were extracted (n = 644). Of these, 497 had Clinical Dementia Rating (CDR) global scores of 0 and 147 had a CDR of 0.5. Mean age and education were 79.5±3.6 and 15.0±3.1 years, respectively. All participants and their study partners completed the subject and study partner CFI yearly. Modified Mini-Mental State Exam (mMMSE) and Free and Cued Selective Reminding Test (FCSRT) were administered. Scores below the predetermined cut-off scores on either measure at annual visit were triggers for a full diagnostic evaluation. Cognitive decline was defined by the absence/presence of the trigger. RESULTS: Three-month test retest reliability showed that inter-class coefficients for subject and study partner CFI were 0.76 and 0.78, respectively. Generalized estimating equation method revealed that both subject and study partner CFI change scores and scores from previous year were sensitive to cognitive decline in the CDR 0 group (p < 0.05). In the CDR 0.5 group, only the study partner CFI change score predicted cognitive decline (p < 0.05). CONCLUSION: Cognitive decline was predicted differentially by CDR level with subject CFI scores providing the best prediction for those with CDR 0 while study partner CFI predicted best for those at CDR 0.5.

Validation by Magnetic Resonance Imaging of the Diagnostic Potential of a Heptapeptide-Functionalized Imaging Probe Targeted to Amyloid-β and Able to Cross the Blood-Brain Barrier. - André, Séverine; Ansciaux, Emilie; Saidi, Elamine; Larbanoix, Lionel; Stanicki, Dimitri; Nonclercq, Denis; Vander Elst, Luce; Laurent, Sophie; Muller, Robert N; Burtea, Carmen (J Alzheimers Dis, 2017)
The diagnosis of Alzheimer's disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls'-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

Validation of the Spanish Version of the LASSI-L for Diagnosing Mild Cognitive Impairment and Alzheimer's Disease. - Matías-Guiu, Jordi A; Curiel, Rosie E; Rognoni, Teresa; Valles-Salgado, María; Fernández-Matarrubia, Marta; Hariramani, Roshan; Fernández-Castro, Alejandro; Moreno-Ramos, Teresa; Loewenstein, David A; Matías-Guiu, Jorge (J Alzheimers Dis, 2017)
BACKGROUND: The Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) is a novel cognitive test that measures recovery from proactive semantic interference, which may be an early cognitive marker of Alzheimer's disease (AD). OBJECTIVE: To generate normative data for a Spaniard population and to validate the LASSI-L for the diagnosis of amnestic mild cognitive impairment (aMCI) and mild AD. METHODS: We performed a cross-sectional study in which 97 healthy participants, 34 with aMCI, and 33 with mild AD were studied with LASSI-L and a comprehensive neuropsychological protocol. The overlapping strategy analysis was used to maximize the sample size and to provide age- and education-adjusted normative data using a logistic regression analysis. RESULTS: Internal consistency was 0.932. Convergent validity with the Free and Cued Selective Reminding Test was moderate. LASSI-L raw scores were correlated with age and years of education, but not gender. The area under the curve for discriminating between healthy controls and aMCI was 0.909, and between healthy controls and mild AD was 0.986. LASSI-L sub-scores representing maximum storage capacity, recovery from proactive interference, and delayed recall yielded the highest diagnostic accuracy. CONCLUSIONS: The LASSI-L is a reliable and valid test for the diagnosis of aMCI and mild AD. The age and education influences on the performance of the test and normative data are provided. LASSI-L merits further studies to evaluate its ability to detect preclinical AD and predict progression to aMCI and early dementia.

Varying Degrees of Temporoparietal Hypometabolism on FDG-PET Reveal Amyloid-Positive Logopenic Primary Progressive Aphasia is not a Homogeneous Clinical Entity. - Krishnan, Kamini; Machulda, Mary M; Whitwell, Jennifer L; Butts, Alissa M; Duffy, Joseph R; Strand, Edythe A; Senjem, Matthew L; Spychalla, Anthony J; Jack, Clifford R; Lowe, Val J; Josephs, Keith A (J Alzheimers Dis, 2017)
BACKGROUND: The logopenic variant of primary progressive aphasia (lvPPA) manifests due to a breakdown of the language network with prominent hypometabolism of the left temporoparietal region. LvPPA is strongly associated with amyloid deposition, yet there is question as to whether it is a homogeneous clinical entity. OBJECTIVE: This study investigated whether differences in temporoparietal metabolic patterns on 18F fludeoxyglucose positron emission tomography (FDG-PET) could elucidate brain regions preferentially affected in lvPPA. METHOD: We used differences in FDG-PET metabolic z-scores relative to controls for means of left lateral temporal, left inferior parietal, and left superior parietal regions to classify 53 amyloid-positive lvPPA patients into temporal, parietal, or temporoparietal predominate groups. Clinical features and FDG-PET regions of hypometabolism outside of the temporoparietal region were then compared across the three groups; the latter using statistical parametric mapping. RESULTS: Of the 53 lvPPA patients, 15 were classified as temporal, 14 as temporoparietal, and 22 as parietal predominate. There were no significant differences between the groups on demographic measures, language evaluation, or apolipoprotein E genotype. Compared to the other two groups, individuals with the parietal predominate pattern had extensive hypometabolism in left frontal lobe and the precuneus. Furthermore, this group had greater behavioral dyscontrol and deficits in executive function, visuospatial skills, visual memory retention, working memory, and cognitive flexibility (Bonferronip < 0.05). CONCLUSIONS: This study demonstrates that there is clinical heterogeneity within amyloid-positive lvPPA. Patients with lvPPA with predominant parietal hypometabolism, unlike those with temporal or temporoparietal predominant hypometabolism, demonstrated widespread cognitive and behavioral changes.

Visual Selective Attention Toward Novel Stimuli Predicts Cognitive Decline in Alzheimer's Disease Patients. - Chau, Sarah A; Herrmann, Nathan; Sherman, Chelsea; Chung, Jonathan; Eizenman, Moshe; Kiss, Alex; Lanctôt, Krista L (J Alzheimers Dis, 2017)
BACKGROUND: Alzheimer's disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Using visual scanning parameters, selective attention toward novel stimuli, or novelty preference, can be measured by a non-verbal, non-invasive method that may be of value in predicting disease progression. OBJECTIVE: In this longitudinal study, we explored whether novelty preference can predict cognitive decline in AD patients. METHODS: Mild to moderate AD patients viewed slides containing both novel and repeat images. The number of fixations, the average fixation time, and the relative fixation time on the two types of images were measured by an eye-tracking system. Novelty preference was estimated by the differences between the visual scanning parameters on novel and repeat images. Cognition and attention were assessed using the Standardized Mini-Mental Status Examination (sMMSE) and the Conners' Continuous Performance Test (CPT), respectively. Cognition was re-assessed every 6 months for up to 2 years. RESULTS: Multivariate linear regressions of 32 AD patients (14 females, age = 77.9±7.8, baseline sMMSE = 22.2±4.4) indicated that reduced time spent on novel images (t = 2.78, p = 0.010) was also associated with greater decline in sMMSE scores (R2 = 0.41, Adjusted R2 = 0.35, F3,28 = 6.51, p = 0.002), adjusting for attention and baseline sMMSE. CONCLUSION: These results suggest that novelty preference, measured by visual attention scanning technology, may reflect pathophysiological processes that could predict disease progression in the cognitively-impaired.

Vitamin D and the Risk of Dementia: The Rotterdam Study. - Licher, Silvan; de Bruijn, Renée F A G; Wolters, Frank J; Zillikens, M Carola; Ikram, M Arfan; Ikram, M Kamran (J Alzheimers Dis, 2017)
BACKGROUND: Vitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results. OBJECTIVE: To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population. METHODS: Within the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimer's disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOEɛ4 carriership. RESULTS: At baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24). CONCLUSION: Lower serum vitamin D concentrations are associated with a higher incidence of dementia.

Vitamin D Insufficiency and Cognitive Function Trajectories in Older Adults: The Rancho Bernardo Study. - Laughlin, Gail A; Kritz-Silverstein, Donna; Bergstrom, Jaclyn; Reas, Emilie T; Jassal, Simerjot K; Barrett-Connor, Elizabeth; McEvoy, Linda K (J Alzheimers Dis, 2017)
BACKGROUND: Evidence of a role for vitamin D (VitD) in cognitive aging is mixed and based primarily on extreme VitD deficiency. We evaluated the association of VitD insufficiency with cognitive function in older, community-dwelling adults living in a temperate climate with year-round sunshine. METHODS: A population-based longitudinal study of 1,058 adults (median age 75; 62% women) who had cognitive function assessed and serum levels of 25-hydroxyvitaminD (25OHD) measured in 1997-99 and were followed for up to three additional cognitive function assessments over a 12-year period. RESULTS: Overall, 14% (n = 145) of participants had VitD insufficiency defined as 25OHD <30 ng/ml. Adjusting for age, sex, education, and season, VitD insufficiency was associated with poorer baseline performance on the Mini-Mental Status Exam (MMSE) (p = 0.013), Trails Making Test B (Trails B) (p = 0.015), Category Fluency (p = 0.006), and Long Term Retrieval (p = 0.019); differences were equivalent to 5 years of age. For those with VitD insufficiency, the odds of mildly impaired performance at baseline were 38% higher for MMSE (p = 0.08), 78% higher for Trails B (p = 0.017), and 2-fold higher for Category Fluency and Long Term Retrieval (both p = 0.001). VitD insufficiency was not related to the rate of cognitive decline on any test or the risk of developing impaired performance during follow-up. CONCLUSION: In this population with little VitD deficiency, even moderately low VitD was associated with poorer performance on multiple domains of cognitive function. Low VitD did not predict 12-year cognitive decline. Clinical trials are essential to establish a causal link between VitD and cognitive well-being.

White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β. - Freeze, Whitney M; Jacobs, Heidi I L; Gronenschild, Ed H; Jansen, Jacobus F A; Burgmans, Saartje; Aalten, Pauline; Clerx, Lies; Vos, Stephanie J; van Buchem, Mark A; Barkhof, Frederik; van der Flier, Wiesje M; Verbeek, Marcel M; et al. (J Alzheimers Dis, 2017)
Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.

An 18-mer Peptide Derived from Prosaposin Ameliorates the Effects of Aβ1-42 Neurotoxicity on Hippocampal Neurogenesis and Memory Deficit in Mice. - Gao, Hui-Ling; Li, Cheng; Nabeka, Hiroaki; Shimokawa, Tetsuya; Wang, Zhan-You; Cao, Ya-Ming; Matsuda, Seiji (J Alzheimers Dis, 2016)
The pathological hallmarks of Alzheimer's disease (AD) include amyloid-β (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction, and neuronal loss. The present study was performed to investigate the protective effects and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) on mice hippocampal progenitor cell proliferation, neurogenesis, and memory tasks after intracerebroventricular injection of Aβ1-42 peptide. Seven days after Aβ1-42 injection, significant proliferation of hippocampal progenitor cells and memory impairment were evident. Two weeks after Aβ1-42 peptide injection, elevated numbers of surviving 5-bromo-2-deoxyuridine cells and newly formed neurons were detected. Treatment with PS18 attenuated these effects evoked by Aβ1-42. Our data indicate that treatment with PS18 partially attenuated the increase in hippocampal neurogenesis caused by Aβ1-42-induced neuroinflammation and prevented memory deficits associated with increased numbers of activated glial cells. We observed an increase in ADAM10 and decreases in BACE1, PS1/2, and AβPP protein levels, suggesting that PS18 enhances the nonamyloidogenic AβPP cleavage pathway. Importantly, our results further showed that PS18 activated the PI3K/Akt pathway, phosphorylated GSK-3α/β, and, as a consequence, exerted a neuroprotective effect. In addition, PS18 showed a protective effect against Aβ1-42-induced neurotoxicity via suppression of the caspase pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases, such as AD.

ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies. - Boehm-Cagan, Anat; Bar, Roni; Liraz, Ori; Bielicki, John K; Johansson, Jan O; Michaelson, Daniel M (J Alzheimers Dis, 2016)
The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.

Aberrant Spontaneous Brain Activity in Patients with Mild Cognitive Impairment and concomitant Lacunar Infarction: A Resting-State Functional MRI Study. - Ni, Ling; Liu, Renyuan; Yin, Zhenyu; Zhao, Hui; Nedelska, Zuzana; Hort, Jakub; Zhou, Fei; Wu, Wenbo; Zhang, Xin; Li, Ming; Yu, Haiping; Zhu, Bin; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Lacunar infarctions (LI) have been associated with a cognitive decline and an increased risk of dementia. Whether and how the pattern of spontaneous brain activity in patients with mild cognitive impairment (MCI) differs in subjects with and without concomitant LI remains unclear. OBJECTIVE: To compare the pattern of spontaneous brain activity in MCI patients with versus those without LI using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Forty-eight MCI patients, including 22 with LI [MCI-LI] and 26 without LI [MCI-no LI], and 28 cognitive normal subjects underwent rs-fMRI post-processed using regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF) methods. RESULTS: Compared with cognitively normal subjects, the MCI-LI patients had decreased ReHo in the precuneus/cuneus (Pcu/CU) and insula; decreased ALFF in the Pcu/CU and frontal lobe; and increased ALFF and ReHo in the temporal lobe. While the MCI-no LI group had increased ReHo and ALFF in the bilateral hippocampus and parahippocampal gyrus, frontal lobe, and decreased ALFF and ReHo in the temporal lobe. Compared with the MCI-no LI patients, those with MCI-LI had decreased ALFF in the frontal lobe; decreased ReHo in the Pcu/CU and insula; and increased ALFF and ReHo in the temporal lobe (p <  0.05, AlphaSim corrected). In MCI-LI patients, the MOCA scores showed a relatively weak correlation with ALFF values in the medial frontal gyrus (r = 0.432, p = 0.045) (of borderline significance after Bonferroni correction). CONCLUSIONS: The spontaneous brain activities in MCI-LI were distinct from MCI-no LI. The probable compensatory mechanism observed in MCI-no LI might be disrupted in MCI with LI due to vascular damage.
Keywords: Aged; Aged, 80 and over; Brain; Brain Mapping; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Rest; Stroke, Lacunar

Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype. - Tramutola, Antonella; Pupo, Gilda; Di Domenico, Fabio; Barone, Eugenio; Arena, Andrea; Lanzillotta, Chiara; Broekaart, Diede; Blarzino, Carla; Head, Elizabeth; Butterfield, D Allan; Perluigi, Marzia (J Alzheimers Dis, 2016)
Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.
Keywords: Acetylation; Alzheimer Disease; Animals; Apoptosis; Blotting, Western; Disease Models, Animal; Down Syndrome; Female; Frontal Lobe; Humans; Immunoprecipitation; Male; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phenotype; Phosphorylation; Tumor Suppressor Protein p53; Young Adult

Activities of Daily Living and Depressive Symptoms in Patients with Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. - Stogmann, Elisabeth; Moser, Doris; Klug, Stefanie; Gleiss, Andreas; Auff, Eduard; Dal-Bianco, Peter; Pusswald, Gisela; Lehrner, Johann (J Alzheimers Dis, 2016)
BACKGROUND: Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest. OBJECTIVES: To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer's disease (AD). METHODS: We included 752 consecutive patients suffering from SCD, non-amnestic (naMCI) or amnestic MCI (aMCI), AD, and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed. RESULTS: SCD patients showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls-SCD-naMCI-aMCI-AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6-1.7). CONCLUSIONS: SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease.
Keywords: Activities of Daily Living; Aged; Alzheimer Disease; Cognitive Dysfunction; Depression; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Odds Ratio; Perception; Prospective Studies

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory Clinic Patients in a Prospective Cohort. - Handels, Ron L H; Joore, Manuela A; Vos, Stephanie J B; Aalten, Pauline; Ramakers, Inez H G B; Rikkert, Marcel Olde; Scheltens, Philip; Jansen, Willemijn J; Visser, Pieter-Jelle; van Berckel, Bart M N; van Domburg, Peter; Smid, Machiel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup. OBJECTIVE: This study aims to investigate the added prognostic value of AD CSF biomarkers. METHODS: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information. RESULTS: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment. CONCLUSION: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.

Administering Cognitive Tests Through Touch Screen Tablet Devices: Potential Issues. - Jenkins, Amy; Lindsay, Stephen; Eslambolchilar, Parisa; Thornton, Ian M; Tales, Andrea (J Alzheimers Dis, 2016)
Mobile technologies, such as tablet devices, open up new possibilities for health-related diagnosis, monitoring, and intervention for older adults and healthcare practitioners. Current evaluations of cognitive integrity typically occur within clinical settings, such as memory clinics, using pen and paper or computer-based tests. In the present study, we investigate the challenges associated with transferring such tests to touch-based, mobile technology platforms from an older adult perspective. Problems may include individual variability in technical familiarity and acceptance; various factors influencing usability; acceptability; response characteristics and thus validity per se of a given test. For the results of mobile technology-based tests of reaction time to be valid and related to disease status rather than extraneous variables, it is imperative the whole test process is investigated in order to determine potential effects before the test is fully developed. Researchers have emphasized the importance of including the 'user' in the evaluation of such devices; thus we performed a focus group-based qualitative assessment of the processes involved in the administration and performance of a tablet-based version of a typical test of attention and information processing speed (a multi-item localization task), to younger and older adults. We report that although the test was regarded positively, indicating that using a tablet for the delivery of such tests is feasible, it is important for developers to consider factors surrounding user expectations, performance feedback, and physical response requirements and to use this information to inform further research into such applications.

Age and its association with low insulin and high amyloid-β peptides in blood. - Li, Huajie; Zhu, Haihao; Wallack, Max; Mwamburi, Mkaya; Abdul-Hay, Samer O; Leissring, Malcolm A; Qiu, Wei Qiao (J Alzheimers Dis, 2016)
Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aβ1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD.
Keywords: Age Distribution; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Insulin; Islet Amyloid Polypeptide; Linear Models; Male; Middle Aged; Multivariate Analysis; Peptide Fragments

Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid. - Shan, Ye; Wang, Dan-Dan; Xu, Yu-Xia; Wang, Chu; Cao, Lan; Liu, Yun-Sheng; Zhu, Cui-Qing (J Alzheimers Dis, 2016)
Stress is an important risk factor of Alzheimer's disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.
Keywords: Aging; Animals; Antioxidants; Brain; Cinnamates; Corticotropin-Releasing Hormone; Depsides; Disease Models, Animal; HEK293 Cells; HSP90 Heat-Shock Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Microscopy, Immunoelectron; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Phosphorylation; Precipitating Factors; Receptors, Corticotropin; Restraint, Physical; Stress, Psychological; tau Proteins; Transfection

All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity. - Midorikawa, Akira; Leyton, Cristian E; Foxe, David; Landin-Romero, Ramon; Hodges, John R; Piguet, Olivier (J Alzheimers Dis, 2016)
BACKGROUND: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. OBJECTIVE: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). METHODS: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. RESULTS: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. CONCLUSIONS: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia.

Altered Brain Activities Associated with Neural Repetition Effects in Mild Cognitive Impairment Patients. - Yu, Jing; Li, Rui; Jiang, Yang; Broster, Lucas S; Li, Juan (J Alzheimers Dis, 2016)
Older adults with mild cognitive impairment (MCI) manifest impaired explicit memory. However, studies on implicit memory such as repetition effects in persons with MCI have been limited. In the present study, 17 MCI patients and 16 healthy normal controls (NC) completed a modified delayed-match-to-sample task while undergoing functional magnetic resonance imaging. We aim to examine the neural basis of repetition; specifically, to elucidate whether and how repetition-related brain responses are altered in participants with MCI. When repeatedly rejecting distracters, both NC and MCI showed similar behavioral repetition effects; however, in both whole-brain and region-of-interest analyses of functional data, persons with MCI showed reduced repetition-driven suppression in the middle occipital and middle frontal gyrus. Further, individual difference analysis found that activation in the left middle occipital gyrus was positively correlated with rejecting reaction time and negatively correlated with accuracy rate, suggesting a predictor of repetition behavioral performance. These findings provide new evidence to support the view that neural mechanisms of repetition effect are altered in MCI who manifests compensatory repetition-related brain activities along with their neuropathology.

Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers. - Perkins, Michelle; Wolf, Andrew B; Chavira, Bernardo; Shonebarger, Daniel; Meckel, J P; Leung, Lana; Ballina, Lauren; Ly, Sarah; Saini, Aman; Jones, T Bucky; Vallejo, Johana; Jentarra, Garilyn; et al. (J Alzheimers Dis, 2016)
The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer's disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.

Altered Executive Function in Pre-Mild Cognitive Impairment. - Seo, Eun Hyun; Kim, Hoowon; Lee, Kun Ho; Choo, Il Han (J Alzheimers Dis, 2016)
BACKGROUND: For the early detection of Alzheimer's disease (AD), there is increasing interest in pre-mild cognitive impairment (pre-MCI). OBJECTIVE: We explored the neuropsychological characteristics in a group of pre-MCI and cognitively normal (CN) elderly individuals, with the aim of providing measures sensitive to cognitive change in pre-MCI. METHODS: We included 188 CN elderly and 77 individuals with pre-MCI. All participants underwent comprehensive clinical and neuropsychological assessment. We compared 17 cognitive tests between the CN and pre-MCI groups by using one-way ANOVAs with false discovery rate correction for multiple comparisons. Pearson's correlations were also obtained between episodic memory and executive function tests in the pre-MCI group. RESULTS: The pre-MCI group showed significantly lower scores for visual immediate recall, fluency tests, and Stroop color naming in the color-word incongruent condition than the CN group (p < 0.05). Most of these executive function measures were significantly correlated with episodic memory (p < 0.05). There were no significant group-differences in other tests assessing attention, verbal memory, visuospatial ability, and language. CONCLUSION: Our findings indicate that poor executive function especially demanding inhibition and goal-directed behaviors within time limit could be the characteristics of the very early cognitive sign in the course of AD.

Altered Topology in Information Processing of a Narrated Story in Older Adults with Mild Cognitive Impairment. - Yogev-Seligmann, Galit; Oren, Noga; Ash, Elissa L; Hendler, Talma; Giladi, Nir; Lerner, Yulia (J Alzheimers Dis, 2016)
The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI.

Analysis of Cerebrospinal Fluid and [11C]PIB PET Biomarkers for Alzheimer's Disease with Updated Protocols. - Wang, Min Jeong; Yi, SangHak; Han, Jee-Young; Park, So Young; Jang, Jae-Won; Chun, In Kook; Giau, Vo Van; Bagyinszky, Eva; Lim, Kun Taek; Kang, Sung Min; An, Seong Soo A; Park, Young Ho; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Recently, a Korean research group suggested a consensus protocol, based on the Alzheimer's Disease Neuroimaging Initiative study protocol but with modifications for minimizing the confounding factors, for the evaluation of cerebrospinal fluid (CSF) biomarkers. OBJECTIVE: Here, we analyzed fluid and imaging biomarkers of Alzheimer's disease (AD) in Korean population. We used the updated protocol to propose a more accurate CSF biomarker value for the diagnosis of AD. METHODS: Twenty-seven patients with AD and 30 cognitively normal controls (NC) were enrolled. CSF was collected from 55 subjects (patients with AD = 26, NC = 29) following the Korea consensus protocol. CSF biomarkers were measured using the INNO-BIA AlzBio3 immunoassay, and Pittsburgh compound B (PIB) positron emission tomography (PET) scans were also performed. RESULTS: The cutoff values of CSF amyloid beta 1-42 (Aβ42), total tau (t-Tau), and phosphorylated tau (p-Tau) proteins were 357.1 pg/ml, 83.35 pg/ml, and 38.00 pg/ml, respectively. The cutoff values of CSF t-Tau/Aβ42 and p-Tau/Aβ42 ratio- were 0.210 (sensitivity 100%, specificity 86.21%) and 0.1350 (sensitivity 88.46%, specificity of 92.86%). The concordance rate with PIB-PET was higher using the CSF t-Tau/Aβ42 ratio (κ= 0.849, CI 0.71-0.99) than CSF Aβ42 alone (κ= 0.703, CI 0.51-0.89). CONCLUSIONS: Here, we improved controversial factors associated with the previous CSF study protocol and suggested a new cutoff value for the diagnosis of AD. Our results showed good diagnostic performance for differentiation of AD. Thus, we expect our findings could be a cornerstone in the establishment and clinical application of biomarkers for AD diagnosis.

Apathy and Attentional Biases in Alzheimer's Disease. - Chau, Sarah A; Chung, Jonathan; Herrmann, Nathan; Eizenman, Moshe; Lanctôt, Krista L (J Alzheimers Dis, 2016)
BACKGROUND: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation. OBJECTIVE: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients. METHODS: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured. RESULTS: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023). CONCLUSION: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy.
Keywords: Aged; Alzheimer Disease; Apathy; Attentional Bias; Cognition; Cross-Sectional Studies; Emotions; Eye Movement Measurements; Eye Movements; Female; Humans; Linear Models; Male; Neuropsychological Tests; Photic Stimulation; Severity of Illness Index; Social Perception

Application of the IWG-2 Diagnostic Criteria for Alzheimer's Disease to the ADNI. - Wang, Hui-Fu; Tan, Lan; Cao, Lei; Zhu, Xi-Chen; Jiang, Teng; Tan, Meng-Shan; Liu, Ying; Wang, Chong; Tsai, Richard M; Jia, Jian-Ping; Yu, Jin-Tai (J Alzheimers Dis, 2016)
BACKGROUND: The International Working Group (IWG) recently proposed the revised diagnostic criteria for Alzheimer's disease (AD) to define and refine several types of AD, and to reclassify AD-related biomarkers into diagnostic and progression markers, but its performance is not known. OBJECTIVE: This study was designed to describe the application of the revised IWG criteria in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and to ascertain whether diagnostic and progression markers show significant differences in their relationships to AD severity and progression. METHODS: Based on the requirements of the refined criteria, 857 ADNI subjects with memory evaluation and at least one pathophysiological marker (CSF or amyloid imaging biomarkers) were eligible and reclassified in this study, and we calculated the associations of diagnostic (CSF and amyloid PET) and progression markers (MRI and fluorodeoxyglucose-PET) with AD severity and progression respectively. RESULTS: The majority (84.2% ) of ADNI AD group (n = 117) and 173 MCI (37.4% ) subjects in ADNI met the definition of typical AD; and 105 cognitively normal (41.0% ) individuals were diagnosed as asymptomatic AD. Furthermore, diagnostic and progression markers showed significant differences when correlated to AD severity and progression. CONCLUSION: A large proportion of AD dementia subjects were categorized as typical AD, and the revised criteria could identify typical AD from MCI status as well as asymptomatic AD at the asymptomatic stage. Moreover, the significant differences between diagnostic and progression markers further supported the new biomarkers categorization in the refined criteria.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cognitive Dysfunction; Databases, Factual; Disease Progression; Female; Humans; Longitudinal Studies; Male; Multicenter Studies as Topic; Neuroimaging; Psychiatric Status Rating Scales; tau Proteins

Aquaporin-4 and Alzheimer's Disease. - Yang, Canhong; Huang, Xiaomin; Huang, Xiaoyu; Mai, Hantao; Li, Jie; Jiang, Tao; Wang, Xiaofeng; Lü, Tianming (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is the most common form of dementia. Although the pathogenesis of AD remains unclear, AD is thought to result from an imbalance in the production and clearance of amyloid-β protein (Aβ). Aquaporin-4 (AQP4) is the major aquaporin in the mammalian brain, is mostly expressed on astrocytic endfeet, and functions as a water transporter. However, the distribution and expression of AQP4 are altered in both AD clinical populations and animal models. Recent studies have revealed that AQP4 is important to the clearance of Aβ in brain via lymphatic clearance, transcytotic delivery, and glial degradation, as well as to the synaptic function. Thus, AQP4 likely plays an important role in the pathogenesis of AD. Further studies would provide new targets for prevention, ultimately leading to improved treatment options for AD.

Assessment and Reporting of Driving Fitness in Patients with Dementia in Clinical Practice: Data from SveDem, the Swedish Dementia Registry. - Lovas, Joel; Fereshtehnejad, Seyed-Mohammad; Cermakova, Pavla; Lundberg, Catarina; Johansson, Björn; Johansson, Kurt; Winblad, Bengt; Eriksdotter, Maria; Religa, Dorota (J Alzheimers Dis, 2016)
BACKGROUND: Driving constitutes a very important aspect of daily life and is dependent on cognitive functions such as attention, visuo-spatial skills and memory, which are often compromised in dementia. Therefore, the driving fitness of patients with dementia needs to be addressed by physicians and those that are deemed unfit should not be allowed to continue driving. OBJECTIVE: We aimed at investigating to what extent physicians assess driving fitness in dementia patients and determinant factors for revoking of their licenses. METHODS: This study includes 15113 patients with newly diagnosed dementia and driver's license registered in the Swedish Dementia Registry (SveDem). The main outcomes were reporting to the licensing authority and making an agreement about driving eligibility with the patients. RESULTS: Physicians had not taken any action in 16% of dementia patients, whereas 9% were reported to the authority to have their licenses revoked. Males (OR = 3.04), those with an MMSE score between 20-24 (OR = 1.35) and 10-19 (OR = 1.50), patients with frontotemporal (OR = 3.09) and vascular dementia (OR = 1.26) were more likely to be reported to the authority. CONCLUSION: For the majority of patients with dementia, driving fitness was assessed. Nevertheless, physicians did not address the issue in a sizeable proportion of dementia patients. Type of dementia, cognitive status, age, sex and burden of comorbidities are independent factors associated with the assessment of driving fitness in patients with dementia. Increased knowledge on how these factors relate to road safety may pave the way for more specific guidelines addressing the issue of driving in patients with dementia.

The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer's Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging. - Mielke, Michelle M; Haughey, Norman J; Han, Dingfen; An, Yang; Bandaru, Veera Venkata Ratnam; Lyketsos, Constantine G; Ferrucci, Luigi; Resnick, Susan M (J Alzheimers Dis, 2016)
BACKGROUND: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer's disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. OBJECTIVE: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype. METHODS: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. RESULTS: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ4 carriers. CONCLUSION: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

The Association Between Retinal Neuronal Layer and Brain Structure is Disrupted in Patients with Cognitive Impairment and Alzheimer's Disease. - Liu, Siwei; Ong, Yi-Ting; Hilal, Saima; Loke, Yng Miin; Wong, Tien Y; Chen, Christopher Li-Hsian; Cheung, Carol Y; Zhou, Juan (J Alzheimers Dis, 2016)
Both healthy and pathological aging due to Alzheimer's disease (AD) are associated with decreased brain grey matter volume (GMV) and disrupted white matter (WM) microstructure. Thinner macular ganglion cell-inner plexiform layer (GC-IPL) measured by spectral-domain optical coherence tomography has been reported in patients with AD and mild cognitive impairment. Emerging evidence suggested a link between thinner GC-IPL and lower GMV in subjects with no dementia using region-of-interest-based approach. However, it remains unknown whether GC-IPL thickness is associated with brain WM microstructure and how such association differed between normal and cognitively impaired subjects. Here, for subjects with no cognitive impairment (NCI), thinner GC-IPL was associated with lower WM microstructure integrity in the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tracts, anterior thalamic radiation, and cingulum regions, while it was weakly associated with lower GMV in visual cortex and cerebellum. Nevertheless, these retina-brain associations were disrupted in the presence of cognitive impairment. Correlations between GMV and GC-IPL were lost in patients with cognitive impairment but no dementia (CIND) and AD patients. GC-IPL was related to WM microstructural disruption in similar regions with decreased significance. In contrast, lower WM microstructure integrity in the fornix showed a trend of correlation with thinner GC-IPL in both CIND and AD but not NCI. Collectively, our findings suggest the possible physiological retina-brain relationship in healthy aging, which might be disrupted by disease-induced changes in patients with cognitive impairment. Longitudinal study with larger patient sample should follow to confirm the disease mechanism behind these retina-brain relationship changes.

The Associations between a Capsaicin-Rich Diet and Blood Amyloid-β Levels and Cognitive Function. - Liu, Cheng-Hui; Bu, Xian-Le; Wang, Jun; Zhang, Tao; Xiang, Yang; Shen, Lin-Lin; Wang, Qing-Hua; Deng, Bo; Wang, Xin; Zhu, Chi; Yao, Xiu-Qing; Zhang, Meng; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Capsaicin-rich diets are common worldwide. Capsaicin has been shown to have favorable effects on various diseases including atherosclerosis, cardiovascular diseases, stroke, obesity, hypertension, cancer, and gastrointestinal and inflammatory diseases. The impact of capsaicin on Alzheimer's disease (AD), which is the most common form of dementia in the elderly, remains unknown. OBJECTIVE: To investigate the correlations of capsaicin intake with cognition and blood markers of AD. METHODS: A total of 338 participants aged 40 years or older were enrolled from communities. Dietary habits regarding chili pepper consumption were collected using a Food Frequency Questionnaire (FFQ). Cognitive function was measured using the Chinese version of the Mini-Mental State Examination (MMSE). Blood amyloid-β (Aβ)40 and Aβ42 were measured with ELISA kits. RESULTS: In univariate analysis, MMSE scores (r = 0.209, p < 0.001), serum Aβ40 levels (r = -0.149, p = 0.006), the ratio of Aβ42/Aβ40 (r = 0.11, p = 0.043) and total serum Aβ levels (r = -0.097, p = 0.075), but not serum Aβ42 levels (r = 0.17, p = 0.757), were significantly correlated with total capsaicin diet scores. In multivariate analysis, total capsaicin diet scores were positively associated with MMSE scores and inversely associated with serum Aβ40 levels, and total serum Aβ levels, but not serum Aβ42 levels and the ratio of Aβ42/Aβ40, after adjustment for age, gender, educational level, smoking history, alcohol consumption, body mass index (BMI) and comorbidities. CONCLUSION: These findings suggest that a capsaicin-rich diet may exert favorable effects on AD blood biomarkers and cognitive function in middle-aged and elderly adults.

Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells. - Li, Yan; Chang, Lirong; Song, Yizhi; Gao, Xianghong; Roselli, Francesco; Liu, Jinping; Zhou, Wei; Fang, Yuan; Ling, Wei; Li, Hui; Almeida, Osborne F X; Wu, Yan (J Alzheimers Dis, 2016)
Early-stage Alzheimer's disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Aβ) and N-methyl-D-aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Aβ. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Aβ-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer's disease, in which Aβ and NMDAR play significant roles, these observations are striking since neuronal GluN2A and GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor β (β-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD.

Attitudes and Perceptions of Research in Aging and Dementia in an Urban Minority Population. - Neugroschl, Judith; Sewell, Margaret; De La Fuente, Angelica; Umpierre, Mari; Luo, Xiaodong; Sano, Mary (J Alzheimers Dis, 2016)
In dementia trials, minority participation is low. We assessed attitudes toward research in a community based urban poor minority sample of elderly adults attending senior center talks using the 7-item Research Attitudes Questionnaire (RAQ). Presentations on cognitive aging were given at senior centers, and 123 attendees completed the RAQ-7. On trust and safety questions, a significant minority (42-48%) responded neutrally or negatively. Encouragingly, on questions concerning the importance of research, 72-81% answered positively. More work can be done to capitalize on these findings to engage and foster trust, and this can be a focus of outreach.

Autobiographical Memory Performance in Alzheimer's Disease Depends on Retrieval Frequency. - Müller, Stephan; Mychajliw, Christian; Reichert, Carolin; Melcher, Tobias; Leyhe, Thomas (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures. As proposed by current theories of memory formation, this decrease is mediated by the age of the acquired knowledge. However, they cannot fully explain specific patterns of retrograde amnesia in AD. In the current study we examined an alternative approach and investigated whether the extent and severity of retrograde amnesia in AD is mediated by the frequency of memory retrieval or whether it depends on the mere age of knowledge. We compared recall of autobiographical incidents from three life periods in patients with amnestic mild cognitive impairment (aMCI), patients with early dementia of Alzheimer type (eDAT), and healthy control (HC) individuals using the Autobiographical Memory Interview. Retrieval frequency was operationalized by a paired comparison analysis. In contrast to HC individuals, recall of autobiographical incidents was impaired in patients with aMCI and eDAT following Ribot's gradient, with a reduced memory loss for remote compared to more recent life events. However, there was a strong effect of retrieval frequency on memory performance with frequently retrieved incidents memorized in more detail than less frequently retrieved episodes. Remote memories were recalled more often than recent ones. These findings suggest that more frequently retrieved autobiographical memories generally become more independent of the hippocampal complex and might thus be better protected against early hippocampal damage related to AD. Hence, the extent of retrograde amnesia in AD appears mainly mediated by the frequency of memory retrieval, which could plausibly explain why cognitive activity can effectively delay the onset of memory decline in AD.

AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders. - Ivachtchenko, Alexandre V; Lavrovsky, Yan; Okun, Ilya (J Alzheimers Dis, 2016)
Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

Behavioral and Electrophysiological Correlates of Memory Binding Deficits in Patients at Different Risk Levels for Alzheimer's Disease. - Pietto, Marcos; Parra, Mario A; Trujillo, Natalia; Flores, Facundo; García, Adolfo M; Bustin, Julian; Richly, Pablo; Manes, Facundo; Lopera, Francisco; Ibáñez, Agustín; Baez, Sandra (J Alzheimers Dis, 2016)
Deficits in visual short-term memory (VSTM) binding have been proposed as an early and specific marker for Alzheimer's disease (AD). However, no studies have explored the neural correlates of this domain in clinical categories involving prodromal stages with different risk levels of conversion to AD. We assessed underlying electrophysiological modulations in patients with mild cognitive impairment (MCI), patients in the MCI stages of familial AD carrying the mutation E280A of the presenilin-1 gene (MCI-FAD), and healthy controls. Moreover, we compared the behavioral performance and neural correlates of both patient groups. Participants completed a change-detection VSTM task assessing recognition of changes between shapes or shape-color bindings, presented in two consecutive arrays (i.e., study and test) while event related potentials (ERPs) were recorded. Changes always occurred in the test array and consisted of new features replacing studied features (shape-only) or features swapping across items (shape-color binding). Both MCI and MCI-FAD patients performed worse than controls in the shape-color binding condition. Early electrophysiological activity (100-250 ms) was significantly reduced in both clinical groups, particularly over fronto-central and parieto-occipital regions. However, shape-color binding performance and their reduced neural correlates were similar between MCI and MCI-FAD. Our results support the validity of the VSTM binding test and their neural correlates in the early detection of AD and highlight the importance of studies comparing samples at different risk for AD conversion. The combined analysis of behavioral and ERP data gleaned with the VSTM binding task can offer a valuable memory biomarker for AD.

Beneficial Effects of an Integrated Psychostimulation Program in Patients with Alzheimer's Disease. - Ibarria, Marta; Alegret, Montserrat; Valero, Sergi; Morera, Amèrica; Guitart, Marina; Cañabate, Pilar; Moreno, Mariola; Lara, Susana; Diego, Susana; Hernández, Joan; Tantinyá, Natàlia; Vera, Maribel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The existing pharmacological treatments for Alzheimer's disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied. OBJECTIVE: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP. METHODS: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years). CONCLUSIONS: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Combined Modality Therapy; Disease Progression; Female; Humans; Male; Neuropsychological Tests; Psychotherapy; Severity of Illness Index; Treatment Outcome

Best Linear Unbiased Prediction of Individual Polygenic Susceptibility to Sporadic Vascular Dementia. - Lee, Chaeyoung (J Alzheimers Dis, 2016)
Genetic factors of sporadic vascular dementia have been quite limitedly understood. Many underlying polygenes are suspected to contribute to susceptibility to sporadic vascular dementia as a typical complex disease although they have not been identified from genome-wide association studies. This study suggests a stochastic prediction of individual polygenetic susceptibility to sporadic vascular dementia using best linear unbiased prediction in a mixed model framework. The prediction shows a relative degree of individual genetic susceptibility to the disease that reflects its integrative polygenetic factors across the genome. The estimate should take into account heritability and the prevalence of sporadic vascular dementia to cope with the disease. This offers a model for application of a genetic blueprint for a complex disease to personalized preventive medicine.

Biofunctionalized Silica Nanoparticles: Standards in Amyloid-β Oligomer-Based Diagnosis of Alzheimer's Disease. - Hülsemann, Maren; Zafiu, Christian; Kühbach, Katja; Lühmann, Nicole; Herrmann, Yvonne; Peters, Luriano; Linnartz, Christina; Willbold, Johannes; Kravchenko, Kateryna; Kulawik, Andreas; Willbold, Sabine; Bannach, Oliver; et al. (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) oligomers represent a promising biomarker for the early diagnosis of Alzheimer's disease (AD). However, state-of-the-art methods for immunodetection of Aβ oligomers in body fluids show a large variability and lack a reliable and stable standard that enables the reproducible quantitation of Aβ oligomers. At present, the only available standard applied in these assays is based on a random aggregation process of synthetic Aβ and has neither a defined size nor a known number of epitopes. In this report, we generated a highly stable standard in the size range of native Aβ oligomers that exposes a defined number of epitopes. The standard consists of a silica nanoparticle (SiNaP), which is functionalized with Aβ peptides on its surface (Aβ-SiNaP). The different steps of Aβ-SiNaP synthesis were followed by microscopic, spectroscopic and biochemical analyses. To investigate the performance of Aβ-SiNaPs as an appropriate standard in Aβ oligomer immunodetection, Aβ-SiNaPs were diluted in cerebrospinal fluid and quantified down to a concentration of 10 fM in the sFIDA (surface-based fluorescence intensity distribution analysis) assay. This detection limit corresponds to an Aβ concentration of 1.9 ng l-1 and lies in the sensitivity range of currently applied diagnostic tools based on Aβ oligomer quantitation. Thus, we developed a highly stable and well-characterized standard for the application in Aβ oligomer immunodetection assays that finally allows the reproducible quantitation of Aβ oligomers down to single molecule level and provides a fundamental improvement for the worldwide standardization process of diagnostic methods in AD research.

Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab. - Russu, Alberto; Samtani, Mahesh N; Xu, Steven; Adedokun, Omoniyi J; Lu, Ming; Ito, Kaori; Corrigan, Brian; Raje, Sangeeta; Liu, Enchi; Brashear, H Robert; Styren, Scot; Hu, Chuanpu (J Alzheimers Dis, 2016)
BACKGROUND: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients. OBJECTIVE: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. METHODS: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. RESULTS: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. CONCLUSIONS: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly. - Westwood, Sarah; Leoni, Emanuela; Hye, Abdul; Lynham, Steven; Khondoker, Mizanur R; Ashton, Nicholas J; Kiddle, Steven J; Baird, Alison L; Sainz-Fuertes, Ricardo; Leung, Rufina; Graf, John; Hehir, Cristina Tan; et al. (J Alzheimers Dis, 2016)
Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

Brain Amyloid-β Plays an Initiating Role in the Pathophysiological Process of the PS1V97L-Tg Mouse Model of Alzheimer's Disease. - Wang, Wei; Lu, Lu; Wu, Qiao-Qi; Jia, Jian-Ping (J Alzheimers Dis, 2016)
Amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation are major pathophysiological events in Alzheimer's disease (AD). However, the relationships among these processes and which first exerts an effect are unknown. In the present study, we investigated age-dependent behavioral changes and the sequential pathological progression from the brain to the periphery in AD transgenic (PS1V97L-Tg) mice and their wild-type littermates. We discovered that the brain Aβ significantly increased at 6 months old, the increased brain Aβ caused memory dysfunction, and the ability of Aβ to induce tau hyperphosphorylation might be due to oxidative stress and neuroinflammatory reactions. The levels of Aβ42, total tau (t-tau), oxidative stress parameters, and proinflammatory cytokines in plasma can be used to differentiate between PS1V97L-Tg mice and their wild-type littermates at different time points. Collectively, our findings support the hypothesis that Aβ is a trigger among these pathophysiological processions and show that plasma biomarkers can reflect the condition of the AD brain.

Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK/ERK Signaling in a Middle-Aged AβPP/PS1 Mouse Model of Alzheimer's Disease. - Guillot, Florence; Kemppainen, Susanna; Lavasseur, Gregoire; Miettinen, Pasi O; Laroche, Serge; Tanila, Heikki; Davis, Sabrina (J Alzheimers Dis, 2016)
Although it is well established that insulin/IGF and BDNF signaling are dysfunctionally regulated in Alzheimer's disease, there are very few studies documenting changes in major target proteins in different murine models of the disease. We investigated a panel of proteins in the PI3K-Akt and MAPK/ERK cascades in parietal cortex, dentate gyrus and CA1 in 13-month-old AβPP/PS1 transgenic mice to determine whether amyloid pathology is associated with basal dysregulation of these proteins or following exposure to novelty. The most striking effect we found was that there was little common regulation of proteins either by pathology alone or exposure to novelty across the three structures, suggesting dysfunctional mechanisms that occur simultaneously have important structure specificity. CA1 shared certain dysfunctional regulation of proteins in the MAPK/ERK cascade, but shared dysfunctional regulation of the PI3K/Akt cascade with the dentate gyrus. Changes in ERK/CREB in transgenic mice did not result in coordinated dysfunction of the downstream transcription factor, Egr1, as it was overexpressed in a normal manner following exposure to novelty. In the PI3K-Akt cascade, there was a flagrant increase in the levels of proteins associated with inflammation, such as NFκB, and structure specific regulation of proteins associated with autophagy, such as mTOR and FOXO1 and lack of regulation of Beclin-1. Finally, Beclin-1 was increased by novelty in wild-type mice but deficient in transgenic mice. Results are interpreted in terms of structure-specific dysfunctional regulation of signaling mechanisms associated with Alzheimer's disease.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Mutation; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Presenilin-1; Signal Transduction

A Brief Computerized Paired Associate Test for the Detection of Mild Cognitive Impairment in Community-Dwelling Older Adults. - Curiel, Rosie E; Crocco, Elizabeth; Rosado, Marian; Duara, Ranjan; Greig, Maria T; Raffo, Arlene; Loewenstein, David A (J Alzheimers Dis, 2016)
BACKGROUND: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer's disease research. OBJECTIVE: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community. METHODS: Participants that were CN (n = 64) or MCI (n = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument is a brief, computerized paired associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity. RESULTS: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L. CONCLUSIONS: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research.

Butyrylcholinesterase K and Apolipoprotein E-ɛ4 Reduce the Age of Onset of Alzheimer's Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects. - De Beaumont, Louis; Pelleieux, Sandra; Lamarre-Théroux, Louise; Dea, Doris; Poirier, Judes (J Alzheimers Dis, 2016)
BACKGROUND: Genetic heterogeneity in amnestic mild cognitively impaired (aMCI) subjects could lead to variations in progression rates and response to cholinomimetic agents. Together with the apolipoprotein E4 (APOE-ɛ4) gene, butyrylcholinesterase (BCHE) has become recently one of the few Alzheimer's disease (AD) susceptibility genes with distinct pharmacogenomic properties. OBJECTIVE: To validate candidate genes (APOE/BCHE) which display associations with age of onset of AD and donepezil efficacy in aMCI subjects. METHODS: Using the Petersen et al. (2005) study on vitamin E and donepezil efficacy in aMCI, we contrasted the effects of BCHE and APOE variants on donepezil drug response using the Alzheimer's Disease Assessment Score-Cognition (ADAS-Cog) scale. Independently, we assessed the effects of APOE/BCHE genotypes on age of onset and cortical choline acetyltransferase activity in autopsy-confirmed AD and age-matched control subjects. RESULTS: Statistical analyses revealed a significant earlier age of onset in AD for APOE-ɛ4, BCHE-K*, and APOE-ɛ4/BCHE-K* carriers. Among the carriers of APOE-ɛ4 and BCHE-K*, the benefit of donepezil was evident at the end of the three-year follow-up. The responder's pharmacogenomic profile is consistent with reduced brain cholinergic activity measured in APOE-ɛ4 and BCHE-K* positive subjects. CONCLUSIONS: APOE-ɛ4 and BCHE-K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects.

Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults. - Gardener, Samantha L; Sohrabi, Hamid R; Shen, Kai-Kai; Rainey-Smith, Stephanie R; Weinborn, Michael; Bates, Kristyn A; Shah, Tejal; Foster, Jonathan K; Lenzo, Nat; Salvado, Olivier; Laske, Christoph; Laws, Simon M; et al. (J Alzheimers Dis, 2016)
Increasing evidence suggests that Alzheimer's disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18F]-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers Across the Spectrum of Lewy Body Diseases: Results from a Large Multicenter Cohort. - van Steenoven, Inger; Aarsland, Dag; Weintraub, Daniel; Londos, Elisabet; Blanc, Frédéric; van der Flier, Wiesje M; Teunissen, Charlotte E; Mollenhauer, Brit; Fladby, Tormod; Kramberger, Milica G; Bonanni, Laura; Lemstra, Afina W (J Alzheimers Dis, 2016)
BACKGROUND: Concomitant Alzheimer's disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers. OBJECTIVE: We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB). METHODS: We included 375 DLB patients, 164 Parkinson's disease (PD) patients without dementia, and 55 PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau. RESULTS: A substantial proportion of DLB patients had abnormal values for CSF Aβ42, t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF. CONCLUSION: A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation. - Renard, Dimitri; Wacongne, Anne; Ayrignac, Xavier; Charif, Mahmoud; Fourcade, Genevieve; Azakri, Souhayla; Le Floch, Anne; Bouly, Stephane; Marelli, Cecilia; Arquizan, Caroline; Hirtz, Christophe; Gabelle, Audrey; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). OBJECTIVE: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). METHODS: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). RESULTS: For the CAA-I group, statistically significant differences were: lower Aβ42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aβ40 (p <  0.001) compared to AD; lower Aβ42 (p = 0.027) compared to CAA; lower Aβ42 (p = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CONCLUSION: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cerebral Amyloid Angiopathy; Female; Humans; Inflammation; Male; Middle Aged; Retrospective Studies; tau Proteins

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Isolated Supratentorial Cortical Superficial Siderosis. - Renard, Dimitri; Gabelle, Audrey; Hirtz, Christophe; Demattei, Christophe; Thouvenot, Eric; Lehmann, Sylvain (J Alzheimers Dis, 2016)
We evaluated cerebrospinal fluid amyloid-β 1-40 (Aβ40), amyloid-β 1-42 (Aβ42), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n = 13), Alzheimer's disease patients (AD, n = 42), and controls (n = 16). Compared to controls, SS patients showed statistically significant higher t-tau (p = 0.019) and lower Aβ42 (p = 0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aβ40 compared to AD (p = 0.0063, p = 0.0004, and p = 0022, respectively), and higher p-tau compared to LH-CAA (p = 0.012).

Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation. - Carmona-Iragui, María; Fernández-Arcos, Ana; Alcolea, Daniel; Piazza, Fabrizio; Morenas-Rodriguez, Estrella; Antón-Aguirre, Sofía; Sala, Isabel; Clarimón, Jordi; Dols-Icardo, Oriol; Camacho, Valle; Sampedro, Frederic; Munuera, Josep; et al. (J Alzheimers Dis, 2016)
We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ40 and Aβ42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis.
Keywords: Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Autoantibodies; Cerebral Amyloid Angiopathy; Ethylene Glycols; Female; Humans; Magnetic Resonance Imaging; Male; Meningoencephalitis; Peptide Fragments; Positron-Emission Tomography; Statistics, Nonparametric; tau Proteins

Cerebrospinal Fluid Biomarkers in Highly Exposed PM2.5 Urbanites: The Risk of Alzheimer's and Parkinson's Diseases in Young Mexico City Residents. - Calderón-Garcidueñas, Lilian; Avila-Ramírez, José; Calderón-Garcidueñas, Ana; González-Heredia, Tonatiuh; Acuña-Ayala, Hilda; Chao, Chih-Kai; Thompson, Charles; Ruiz-Ramos, Rubén; Cortés-González, Victor; Martínez-Martínez, Luz; García-Pérez, Mario Alberto; Reis, Jacques; et al. (J Alzheimers Dis, 2016)
Exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with Alzheimer's disease (AD) risk, while Mn toxicity induces parkinsonism. Mexico City Metropolitan Area (MCMA) children have pre- and postnatal sustained and high exposures to PM2.5, O3, polycyclic aromatic hydrocarbons, and metals. Young MCMA residents exhibit frontal tau hyperphosphorylation and amyloid-β (Aβ)1 - 42 diffuse plaques, and aggregated and hyperphosphorylated α-synuclein in olfactory nerves and key brainstem nuclei. We measured total prion protein (TPrP), total tau (T-tau), tau phosphorylated at threonine 181 (P-Tau), Aβ1-42, α-synuclein (t-α-syn and d-α-synuclein), BDNF, insulin, leptin, and/or inflammatory mediators, in 129 normal CSF samples from MCMA and clean air controls. Aβ1-42 and BDNF concentrations were significantly lower in MCMA children versus controls (p = 0.005 and 0.02, respectively). TPrP increased with cumulative PM2.5 up to 5 μg/m3 and then decreased, regardless of cumulative value or age (R2 = 0.56). TPrP strongly correlated with T-Tau and P-Tau, while d-α-synuclein showed a significant correlation with TNFα, IL10, and IL6 in MCMA children. Total synuclein showed an increment in childhood years related to cumulated PM2.5, followed by a decrease after age 12 years (R2 = 0.47), while d-α-synuclein exhibited a tendency to increase with cumulated PM2.5 (R2 = 0.30). CSF Aβ1-42, BDNF, α-synuclein, and TPrP changes are evolving in young MCMA urbanites historically showing underperformance in cognitive processes, odor identification deficits, downregulation of frontal cellular PrP, and neuropathological AD and PD hallmarks. Neuroprotection of young MCMA residents ought to be a public health priority.

Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease. - Melah, Kelsey E; Lu, Sharon Yuan-Fu; Hoscheidt, Siobhan M; Alexander, Andrew L; Adluru, Nagesh; Destiche, Daniel J; Carlsson, Cynthia M; Zetterberg, Henrik; Blennow, Kaj; Okonkwo, Ozioma C; Gleason, Carey E; Dowling, N Maritza; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The immune response in Alzheimer's disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. OBJECTIVE: To determine whether neuroinflammation exacerbates neural damage in preclinical AD. METHODS: We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. RESULTS: Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. CONCLUSION: Inflammation may play a role in neural damage in preclinical AD.
Keywords: Adipokines; Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Chemokine CCL2; Chitinase-3-Like Protein 1; Diffusion Tensor Imaging; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Lectins; Male; Microglia; Middle Aged; Peptide Fragments; tau Proteins; White Matter

Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease. - Novak, Gerald; Fox, Nick; Clegg, Shona; Nielsen, Casper; Einstein, Steven; Lu, Yuan; Tudor, Iulia Cristina; Gregg, Keith; Di, Jianing; Collins, Peter; Wyman, Bradley T; Yuen, Eric; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 carriers and noncarriers, respectively, with Alzheimer's disease. OBJECTIVES: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. METHODS: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. RESULTS: For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. CONCLUSIONS: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences.
Keywords: Aged; Alzheimer Disease; Antibodies, Monoclonal, Humanized; Apolipoprotein E4; Brain; Double-Blind Method; Female; Heterozygote; Humans; Least-Squares Analysis; Magnetic Resonance Imaging; Male; Nootropic Agents; Organ Size; Severity of Illness Index; Treatment Outcome

Changes in Frailty Predict Changes in Cognition in Older Men: The Honolulu-Asia Aging Study. - Armstrong, Joshua J; Godin, Judith; Launer, Lenore J; White, Lon R; Mitnitski, Arnold; Rockwood, Kenneth; Andrew, Melissa K (J Alzheimers Dis, 2016)
BACKGROUND: As cognitive decline mostly occurs in late life, where typically it co-exists with many other ailments, it is important to consider frailty in understanding cognitive change. OBJECTIVE: Here, we examined the association of change in frailty status with cognitive trajectories in a well-studied cohort of older Japanese-American men. METHODS: Using the prospective Honolulu-Asia Aging Study (HAAS), 2,817 men of Japanese descent were followed (aged 71-93 at baseline). Starting in 1991 with follow-up health assessments every two to three years, cognition was measured using the Cognitive Abilities Screening Instrument (CASI). For this study, health data was used to construct an accumulation of deficits frailty index (FI). Using six waves of data, multilevel growth curve analyses were constructed to examine simultaneous changes in cognition in relation to changes in FI, controlling for baseline frailty, age, education, and APOE-ɛ4 status. RESULTS: On average, CASI scores declined by 2.0 points per year (95% confidence interval 1.9-2.1). Across six waves, each 10% within-person increase in frailty from baseline was associated with a 5.0 point reduction in CASI scores (95% confidence interval 4.7-5.2). Baseline frailty and age were associated both with lower initial CASI scores and with greater decline across the five follow-up assessments (p < 0.01). DISCUSSION: Cognition is adversely affected by impaired health status in old age. Using a multidimensional measure of frailty, both baseline status and within-person changes in frailty were predictive of cognitive trajectories.

Changes in Neural Connectivity and Memory Following a Yoga Intervention for Older Adults: A Pilot Study. - Eyre, Harris A; Acevedo, Bianca; Yang, Hongyu; Siddarth, Prabha; Van Dyk, Kathleen; Ercoli, Linda; Leaver, Amber M; Cyr, Natalie St; Narr, Katherine; Baune, Bernhard T; Khalsa, Dharma S; Lavretsky, Helen (J Alzheimers Dis, 2016)
BACKGROUND: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity. OBJECTIVES: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI). METHODS: Participants ( ≥ 55 y) with MCI were randomized to receive a yoga intervention or active "gold-standard" control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance. RESULTS: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex. CONCLUSION: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies.

Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease. - Rosenberg, Paul B; Lanctôt, Krista L; Herrmann, Nathan; Mintzer, Jacobo E; Porsteinsson, Anton P; Sun, Xiaoying; Raman, Rema (J Alzheimers Dis, 2016)
BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD). OBJECTIVE: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). METHODS: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline. RESULTS: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased. CONCLUSION: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

Changes of Cerebral Perfusion and Functional Brain Network Organization in Patients with Mild Cognitive Impairment. - Lou, Wutao; Shi, Lin; Wong, Adrian; Chu, Winnie C W; Mok, Vincent C T; Wang, Defeng (J Alzheimers Dis, 2016)
Disruptions of the functional brain network and cerebral blood flow (CBF) have been revealed in patients with mild cognitive impairment (MCI). However, the neurophysiological mechanism of hypoperfusion as well as the reorganization of the intrinsic whole brain network due to the neuropathology of MCI are still unclear. In this study, we aimed to investigate the changes of CBF and the whole brain network organization in MCI by using a multimodal MRI approach. Resting state ASL MRI and BOLD MRI were used to evaluate disruptions of CBF and underlying functional connectivity in 27 patients with MCI and 35 cognitive normal controls (NC). The eigenvector centrality mapping (ECM) was used to assess the whole brain network reorganization in MCI, and a seed-based ECM approach was proposed to reveal the contributions of the whole brain network on the ECM alterations. Significantly decreased perfusion in the posterior parietal cortex as well as its connectivity within the default mode network and occipital cortex were found in the MCI group compared to the NC group. The ECM analysis revealed decreased EC in the middle cingulate cortex, parahippocampal gyrus, medial frontal gyrus, and increased EC in the right calcarine sulcus, superior temporal gyrus, and supplementary motor area in the MCI group. The results of this study indicate that there are deficits in cerebral blood flow and functional connectivity in the default mode network, and that sensory-processing networks might play a compensatory role to make up for the decreased connections in MCI.

Characterization of Alzheimer's Disease and Mild Cognitive Impairment in Older Adults in Panama. - Villarreal, Alcibiades E; Grajales, Shantal; O'Bryant, Sid E; Edwards, Melissa; López, Lineth; Montalván, Astevia; Britton, Gabrielle B (J Alzheimers Dis, 2016)
Research on age-related cognitive impairment is scarce in Central America. We report factors associated with cognitive impairment among a sample of older adults in Panama diagnosed with Alzheimer's disease (AD, n = 31), mild cognitive impairment (MCI, n = 43), or no cognitive impairment (controls, n = 185). Apolipoprotein E (ApoE) genotype was assessed in a subset of cases (n = 135). Age (OR = 2.53, 95% CI = 1.03-6.17) and ApoE ɛ4 (OR = 5.14, 95% CI = 2.11-12.52) were significantly related to cognitive impairment (AD/MCI combined). Results underscore the potential of genetic screening in Panama for identifying those at risk of dementia.

Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology. - Kleinschmidt, Martin; Schoenfeld, Robby; Göttlich, Claudia; Bittner, Daniel; Metzner, Jürgen Erich; Leplow, Bernd; Demuth, Hans-Ulrich (J Alzheimers Dis, 2016)
BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively. RESULTS: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ. CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.
Keywords: Activities of Daily Living; Adolescent; Adult; Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Analysis of Variance; Apolipoproteins E; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Cytokines; Dementia; Female; Humans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Young Adult

Characterizing White Matter Tract Degeneration in Syndromic Variants of Alzheimer's Disease: A Diffusion Tensor Imaging Study. - Madhavan, Ajay; Schwarz, Christopher G; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Drubach, Daniel A; Kantarci, Kejal; Przybelski, Scott A; Reid, Robert I; Senjem, Matthew L; Gunter, Jeffrey L; Apostolova, Liana G; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Different clinical syndromes can arise from Alzheimer's disease (AD) neuropathology, including dementia of the Alzheimer's type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). OBJECTIVE: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD. METHODS: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups. RESULTS: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum. CONCLUSION: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.
Keywords: Aged; Alzheimer Disease; Aniline Compounds; Anisotropy; Aphasia, Primary Progressive; Case-Control Studies; Diffusion Tensor Imaging; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Nerve Fibers, Myelinated; Neurodegenerative Diseases; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Retrospective Studies; Thiazoles; White Matter

Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline. - Moreira, Afonso; Diógenes, Maria José; de Mendonça, Alexandre; Lunet, Nuno; Barros, Henrique (J Alzheimers Dis, 2016)
Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal Mini-Mental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease ≥ 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95% CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95% CI 0.38-0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95% CI 0.31-0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans.

Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis. - Wang, Hua-Long; Wang, Yan-Yong; Liu, Xin-Gang; Kuo, Sheng-Han; Liu, Na; Song, Qiao-Yun; Wang, Ming-Wei (J Alzheimers Dis, 2016)
Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.
Keywords: Alzheimer Disease; Cholesterol; Cognitive Dysfunction; Databases, Bibliographic; Humans; Hydroxycholesterols

Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AβPP(swe)/PS1(ΔE9) Mice. - Qiu, Hongyan; Zhong, Rujia; Liu, Hui; Zhang, Feng; Li, Song; Le, Weidong (J Alzheimers Dis, 2016)
Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AβPP(swe)/PS1(ΔE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-β protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-β(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apoptosis; Brain; Cognition Disorders; Disease Models, Animal; Humans; In Situ Nick-End Labeling; Learning Disorders; Mice; Mice, Transgenic; Mitochondrial Diseases; Mutation; Phosphorylation; Plaque, Amyloid; Presenilin-1; Reversal Learning; Sleep Deprivation; tau Proteins

Chronic Traumatic Encephalopathy Presenting as Alzheimer's Disease in a Retired Soccer Player. - Grinberg, Lea T; Anghinah, Renato; Nascimento, Camila Fernandes; Amaro, Edson; Leite, Renata P; Martin, Maria da Graça M; Naslavsky, Michel S; Takada, Leonel T; Filho, Wilson Jacob; Pasqualucci, Carlos A; Nitrini, Ricardo (J Alzheimers Dis, 2016)
The relationship between soccer and chronic traumatic encephalopathy (CTE) is not well established. We report clinicopathological correlations in an 83-year-old retired center-back soccer player, with no history of concussion, manifesting typical Alzheimer-type dementia. Examination revealed mixed pathology including widespread CTE, moderate Alzheimer's disease, hippocampal sclerosis, and TDP-43 proteinopathy. This case adds to a few CTE cases described in soccer players. Furthermore, it corroborates that CTE may present clinically as typical Alzheimer-type dementia. Further studies investigating the extent to which soccer is a risk for CTE are needed.

Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer's Disease Mouse Model. - LeVault, Kelsey R; Tischkau, Shelley A; Brewer, Gregory J (J Alzheimers Dis, 2016)
It is unclear whether pre-symptomatic Alzheimer's disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2-/- model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.
Keywords: Age Factors; Alzheimer Disease; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Brain; Chromatography, High Pressure Liquid; Chronobiology Disorders; Disease Models, Animal; Gene Expression Regulation; Glutathione; Glutathione Disulfide; Humans; Memory Disorders; Mice; Mice, Transgenic; Mutation; NADP; Nitric Oxide Synthase Type II; Oxidation-Reduction

Clinical and Demographic Factors Associated with the Cognitive and Emotional Efficacy of Regular Musical Activities in Dementia. - Särkämö, Teppo; Laitinen, Sari; Numminen, Ava; Kurki, Merja; Johnson, Julene K; Rantanen, Pekka (J Alzheimers Dis, 2016)
Recent evidence suggests that music-based interventions can be beneficial in maintaining cognitive, emotional, and social functioning in persons with dementia (PWDs). Our aim was to determine how clinical, demographic, and musical background factors influence the cognitive and emotional efficacy of caregiver-implemented musical activities in PWDs. In a randomized controlled trial, 89 PWD-caregiver dyads received a 10-week music coaching intervention involving either singing or music listening or standard care. Extensive neuropsychological testing and mood and quality of life (QoL) measures were performed before and after the intervention (n = 84) and six months later (n = 74). The potential effects of six key background variables (dementia etiology and severity, age, care situation, singing/instrument playing background) on the outcome of the intervention were assessed. Singing was beneficial especially in improving working memory in PWDs with mild dementia and in maintaining executive function and orientation in younger PWDs. Music listening was beneficial in supporting general cognition, working memory, and QoL especially in PWDs with moderate dementia not caused by Alzheimer's disease (AD) who were in institutional care. Both music interventions alleviated depression especially in PWDs with mild dementia and AD. The musical background of the PWD did not influence the efficacy of the music interventions. Our findings suggest that clinical and demographic factors can influence the cognitive and emotional efficacy of caregiver-implemented musical activities and are, therefore, recommended to take into account when applying and developing the intervention to achieve the greatest benefit.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Caregivers; Case-Control Studies; Cognition Disorders; Dementia; Executive Function; Female; Follow-Up Studies; Humans; Male; Memory, Short-Term; Middle Aged; Mood Disorders; Music Therapy; Neuropsychological Tests; Orientation; Outcome Assessment (Health Care); Psychiatric Status Rating Scales; Quality of Life

Clinical Conversion or Reversion of Mild Cognitive Impairment in Community versus Hospital Based Studies: GDEMCIS (Gwangju Dementia and Mild Cognitive Impairment Study) and CREDOS (Clinical Research Center for Dementia of South Korea). - Roh, Hyun Woong; Hong, Chang Hyung; Lee, Yunhwan; Lee, Kang Soo; Chang, Ki Jung; Kang, Dae Ryong; Lee, Jung-Dong; Choi, Seong Hye; Kim, Seong Yoon; Na, Duk L; Seo, Sang Won; Kim, Doh Kwan; et al. (J Alzheimers Dis, 2016)
BACKGROUND: In keeping with increasing interest in dementia, few recent studies suggest that clinical course of mild cognitive impairment vary across different studies with hospital-based subjects showing higher rates of conversion than community-based subjects. OBJECTIVE: The main objective of the present study was to assess whether the clinical conversion or reversion rates differ according to recruitment source. METHODS: The baseline study subjects comprised of patients who were diagnosed with mild cognitive impairment in community-based GDEMCIS or hospital-based CREDOS. The two studies had nearly the same protocol and were performed over a similar period. We used propensity score matching for baseline comparability. After that, Cox proportional hazards regression analyses were conducted to estimate the hazard ratios and 95% confidence intervals of clinical conversion or reversion. RESULTS: Based on 89 GDEMCIS subjects, 1 : 4 propensity score matching was conducted and 356 CREDOS subjects were selected. After adjusting for covariates including baseline demographics, comorbidity, depression, disability, and neuropsychological result, Cox proportional hazard regression analysis for time to clinical conversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 2.13 (95% CI, 1.08-4.21), as compared to recruitment from community-based GDEMCIS. Similarly, Cox proportional hazard regression analysis for time to reversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 0.34 (95% CI, 0.20-0.59), as compared to recruitment from community-based GDEMCIS. CONCLUSION: The present study demonstrated that even after the matching process and adjustments for baseline covariates, recruitment source greatly affected the course of mild cognitive impairment.

Clinical Impact of a Second FDG-PET in Atypical/Unclear Dementia Syndromes. - Bergeron, David; Beauregard, Jean-Mathieu; Guimond, Jean; Fortin, Marie-Pierre; Houde, Michèle; Poulin, Stéphane; Verret, Louis; Bouchard, Rémi W; Laforce, Robert (J Alzheimers Dis, 2016)
Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can greatly clarify the diagnosis and improve management.
Keywords: Adult; Brain; Dementia; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies

Clinical Utility of Amyloid PET Imaging in the Differential Diagnosis of Atypical Dementias and Its Impact on Caregivers. - Bensaïdane, Mohamed Reda; Beauregard, Jean-Mathieu; Poulin, Stéphane; Buteau, François-Alexandre; Guimond, Jean; Bergeron, David; Verret, Louis; Fortin, Marie-Pierre; Houde, Michèle; Bouchard, Rémi W; Soucy, Jean-Paul; Laforce, Robert (J Alzheimers Dis, 2016)
Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer's disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers' outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones.

The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests. - Rattanabannakit, Chatchawan; Risacher, Shannon L; Gao, Sujuan; Lane, Kathleen A; Brown, Steven A; McDonald, Brenna C; Unverzagt, Frederick W; Apostolova, Liana G; Saykin, Andrew J; Farlow, Martin R (J Alzheimers Dis, 2016)
BACKGROUND: The perception of cognitive decline by individuals and those who know them well ("informants") has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms. OBJECTIVE: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms. METHODS: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models. RESULTS: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant. CONCLUSION: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.
Keywords: Adult; Aged; Aged, 80 and over; Analysis of Variance; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Perception; Self Report

Cognitive Impairment after Mild Stroke: Development and Validation of the SIGNAL2 Risk Score. - Kandiah, Nagaendran; Chander, Russell Jude; Lin, Xuling; Ng, Aloysius; Poh, Yen Yeong; Cheong, Chin Yee; Cenina, Alvin Rae; Assam, Pryseley Nkouibert (J Alzheimers Dis, 2016)
BACKGROUND: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3-6 months after mild stroke will be useful for clinicians. OBJECTIVE: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI. METHODS: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients. RESULTS: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months. CONCLUSION: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI.
Keywords: Aged; Aging; Area Under Curve; Brain; Brain Ischemia; Cognition Disorders; Constriction, Pathologic; Educational Status; Female; Follow-Up Studies; Humans; Logistic Models; Male; Middle Aged; Prospective Studies; Retrospective Studies; Risk; Severity of Illness Index; Stroke; White Matter

Combination of Structural MRI and FDG-PET of the Brain Improves Diagnostic Accuracy in Newly Manifested Cognitive Impairment in Geriatric Inpatients. - Ritter, Kerstin; Lange, Catharina; Weygandt, Martin; Mäurer, Anja; Roberts, Anna; Estrella, Melanie; Suppa, Per; Spies, Lothar; Prasad, Vikas; Steffen, Ingo; Apostolova, Ivayla; Bittner, Daniel; et al. (J Alzheimers Dis, 2016)
BACKGROUND: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease. OBJECTIVE: To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients. METHODS: Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimer's disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), which remained uncertain after standard diagnostic workup. Additional procedures performed after enrollment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis. RESULTS: Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p = 0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p≤0.001). Integration of all modalities resulted in 76% accuracy (p≤0.001). CONCLUSION: These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process.

Comparing Longitudinal Behavior Changes in the Primary Progressive Aphasias. - Van Langenhove, Tim; Leyton, Cristian E; Piguet, Olivier; Hodges, John R (J Alzheimers Dis, 2016)
BACKGROUND: Differentiating between primary progressive aphasia (PPA) variants based on the profile of language deficits can be difficult in a proportion of patients. Further, little is presently know about the pattern of longitudinal changes in behavior in PPA variants. OBJECTIVE: To determine the presence of behavioral changes in the main variants of PPA: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA), and logopenic (lv-PPA), and establish the course of these changes over time. METHODS: We measured behavioral changes in 73 prospectively recruited PPA (30 sv-PPA, 22 nfv-PPA, and 21 lv-PPA), as well as 33 behavioral variant frontotemporal dementia (bv-FTD) and 31 Alzheimer's disease (AD) patients, at baseline and after 1 year, using the Cambridge Behavioural Inventory Revised. All included patients had mild dementia severity at baseline. RESULTS: Both at baseline and follow-up, sv-PPA exhibited significantly more behavioral disturbances of the type characteristic of bv-FTD compared with other PPA variants. 74% of sv-PPA patients with mild dementia severity exhibited at least one behavior disturbance at baseline, which increased to 84% during follow-up. Behavioral symptoms did not differ between nfv-PPA and lv-PPA groups at baseline. At follow-up, however, empathy loss was significantly more pronounced in nfv-PPA. The prevalence and course of behavioral symptoms in lv-PPA was similar to that found in AD. CONCLUSIONS: sv-PPA show more prominent FTD-like behavioral disturbances compared with other PPA variants which typically emerge already early in the disease course. Empathy loss may be an important factor that helps differentiating nfv-PPA from lv-PPA. Our results may allow improved prediction of likely progression in behavioral symptoms across the PPA variants.

Comparing the Effects of Multisensory Stimulation and Individualized Music Sessions on Elderly People with Severe Dementia: A Randomized Controlled Trial. - Sánchez, Alba; Maseda, Ana; Marante-Moar, M Pilar; de Labra, Carmen; Lorenzo-López, Laura; Millán-Calenti, José Carlos (J Alzheimers Dis, 2016)
The objective of this study was to compare the effects of a multisensory stimulation environment (MSSE) and individualized music sessions on agitation, emotional and cognitive status, and dementia severity in a sample of institutionalized patients with severe dementia. Twenty-two participants with a diagnosis of severe or very severe dementia were randomly assigned to two groups: MSSE and individualized music sessions. Both groups participated in two 30-min weekly sessions over 16 weeks. Outcomes were agitation (Cohen-Mansfield Agitation Inventory, CMAI), mood (Cornell Scale for Depression in Dementia, CSDD), anxiety (Rating Anxiety in Dementia, RAID), cognitive function (Severe Mini-Mental State Examination, SMMSE), and the overall severity of dementia (Bedford Alzheimer Nursing Severity Scale, BANS-S). They were assessed at baseline (pre-trial), in the middle (mid-trial), at the end of the intervention (post-trial), and 8 weeks after the intervention (follow-up). Patients in the MSSE group showed significant improvement in their RAID and BANS-S scores compared with the individualized music group post- versus pre-trial. With regard to agitation, there was improvement during the intervention in both the MSSE and individualized music groups in the CMAI total score after 16 weeks of intervention, with no significant differences between the groups. The results suggest that MSSE could have better effects on anxiety symptoms and dementia severity in comparison with individualized music sessions in elderly patients with severe dementia.
Keywords: Affect; Aged; Aged, 80 and over; Anxiety; Cognition; Dementia; Environment; Female; Follow-Up Studies; Humans; Male; Mental Status Schedule; Music Therapy; Precision Medicine; Sensory Art Therapies; Severity of Illness Index; Treatment Outcome

Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics. - Lelental, Natalia; Brandner, Sebastian; Kofanova, Olga; Blennow, Kaj; Zetterberg, Henrik; Andreasson, Ulf; Engelborghs, Sebastiaan; Mroczko, Barbara; Gabryelewicz, Tomasz; Teunissen, Charlotte; Mollenhauer, Brit; Parnetti, Lucilla; et al. (J Alzheimers Dis, 2016)
BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples. OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers. METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study. RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects. CONCLUSION: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.
Keywords: Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Biomarkers; Cattle; Clinical Chemistry Tests; Dementia; Humans; Peptide Fragments; Quality Control; Reference Standards; Serum Albumin, Bovine; Sodium Azide; tau Proteins; Time Factors; Tissue Preservation

Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease. - Hakobyan, Svetlana; Harding, Katharine; Aiyaz, Mohammed; Hye, Abdul; Dobson, Richard; Baird, Alison; Liu, Benjamine; Harris, Claire Louise; Lovestone, Simon; Morgan, Bryan Paul (J Alzheimers Dis, 2016)
There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p < 10- 5). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

Concanavalin agglutinin levels are decreased in peripheral blood of Alzheimer's disease patients. - Sun, Xuying; Ma, Ronghong; Yao, Xiuqing; Shang, Xiaoling; Wang, Qun; Wang, Jian-Zhi; Liu, Gongping (J Alzheimers Dis, 2016)
Alzheimer's disease (AD) seriously threatens patients' lives and causes severe burden to the families. Early prevention and treatment can alleviate the development of the disease; therefore it is important to find new effective and non-traumatic biomarkers for early diagnosis. In this study, peripheral blood samples were collected from 24 AD patients and the same number of age- and gender-matched control subjects. Lectin reactive glycosylation levels including beta-D-galactosyl ricinus communis agglutinin 120 (RCA), peanut agglutinin (PNA), concanavalin agglutinin (Con A), alpha-L-fucosyl ulex europeus agglutinin (UEA), dolichos biflorus agglutinin (DBA), and galanthus nivalis (GNL), in the red blood cells of peripheral blood were examined by western blotting. We found that lectin levels were altered with aging and gender; some lectin levels were different between AD patients and the control subjects. Only Con A levels were significantly decreased in AD patients compared to age-matched control subjects. These results suggest that Con A levels in peripheral blood may be a potent diagnostic marker for AD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Case-Control Studies; Concanavalin A; Female; Humans; Lectins; Male; Plant Lectins

Connected Language in Late Middle-Aged Adults at Risk for Alzheimer's Disease. - Mueller, Kimberly Diggle; Koscik, Rebecca L; Turkstra, Lyn S; Riedeman, Sarah K; LaRue, Asenath; Clark, Lindsay R; Hermann, Bruce; Sager, Mark A; Johnson, Sterling C (J Alzheimers Dis, 2016)
Connected language is often impaired among people with Alzheimer's disease (AD), yet little is known about when language difficulties first emerge on the path to a clinical diagnosis. The objective of this study was to determine whether individuals with psychometric (preclinical) evidence of amnestic mild cognitive impairment (pMCI) showed deficits in connected language measures. Participants were 39 pMCI and 39 cognitively healthy (CH) adults drawn from the Wisconsin Registry for Alzheimer's Prevention, who were matched for age, literacy, and sex. Participants completed a connected language task in which they described the Cookie Theft picture from the Boston Diagnostic Aphasia Examination. Language samples were analyzed across three language domains: content, syntactic complexity, and speech fluency. Paired t-tests were used to compare CH and pMCI groups on all variables, and Cohen's d effect sizes were calculated for each comparison. The CH and pMCI groups differed significantly on measures of content (e.g., CH group produced more semantic units, more unique words and had larger idea density, on average, than the pMCI group). The picture description findings are consistent with previous retrospective studies showing semantic language differences in adults with autopsy-confirmed AD. Given that these comparisons are between cognitively healthy and pMCI individuals (before a clinical MCI diagnosis), these findings may represent subtle language difficulty in spontaneous speech, and may be predictive of larger language changes over time.

Contribution of the Cholinergic System to Verbal Memory Performance in Mild Cognitive Impairment. - Peter, Jessica; Lahr, Jacob; Minkova, Lora; Lauer, Eliza; Grothe, Michel J; Teipel, Stefan; Köstering, Lena; Kaller, Christoph P; Heimbach, Bernhard; Hüll, Michael; Normann, Claus; Nissen, Christoph; et al. (J Alzheimers Dis, 2016)
Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.

Copeptin, a Marker of Vasopressin, Predicts Vascular Dementia but not Alzheimer's Disease. - Nilsson, Erik D; Melander, Olle; Elmståhl, Sölve; Lethagen, Eva; Minthon, Lennart; Pihlsgård, Mats; Nägga, Katarina (J Alzheimers Dis, 2016)
BACKGROUND: Copeptin is a reliable surrogate marker for the neurohypophyseal hormone vasopressin. Elevated plasma level of copeptin has been associated with cardiovascular and metabolic disease risk. OBJECTIVE: To investigate the association between copeptin and risk of dementia. METHODS: In all, 18,240 individuals from Malmö, Sweden, were examined between 2002 and 2006 (mean age 69.3 years, 69.8% men). Incident cases of dementia until 31 December 2009 were identified by linkage with the Swedish National Patient Register. To validate the dementia diagnoses, medical records as well as laboratory and neuroimaging data were carefully reviewed. Baseline level of copeptin was measured in frozen plasma in: (1) all participants who were diagnosed with dementia during follow-up, (2) a random sample of 5100 individuals of the cohort. RESULTS: During a median follow-up of 4.2 years, there were 374 incident dementia cases (age range 60-83 years at baseline): 120 were classified as Alzheimer's disease (AD), 84 as vascular dementia (VaD), and 102 as mixed dementia. In logistic regressions adjusted for cardiovascular risk factors, baseline level of copeptin predicted incident VaD (Odds ratio (OR) 1.30 per 1 SD increase in log copeptin, 95% CI 1.03-1.64). Copeptin did not predict incidence of all-cause dementia (OR 1.05, 95% CI 0.94-1.18), AD (OR 0.97, 95% CI 0.79-1.18), or mixed dementia (OR 0.85, 95% CI 0.68-1.05). CONCLUSION: Elevated plasma level of copeptin is a risk marker for incident VaD, but not for incident AD. This suggests that the vasopressin hormonal system might be involved in the development of VaD.

Cortical Amyloid Burden Differences Across Empirically-Derived Mild Cognitive Impairment Subtypes and Interaction with APOE ɛ4 Genotype. - Bangen, Katherine J; Clark, Alexandra L; Werhane, Madeline; Edmonds, Emily C; Nation, Daniel A; Evangelista, Nicole; Libon, David J; Bondi, Mark W; Delano-Wood, Lisa (J Alzheimers Dis, 2016)
We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

Cost Related to Dementia in the Young and the Impact of Etiological Subtype on Cost. - Kandiah, Nagaendran; Wang, Vivian; Lin, Xuling; Nyu, Mei Mei; Lim, Linda; Ng, Adeline; Hameed, Shahul; Wee, Hwee Lin (J Alzheimers Dis, 2016)
BACKGROUND: Young onset dementia (YOD) presents in individuals who are economically productive and socially active. While the cost related to dementia in the elderly has been widely studied, the cost related to YOD is largely unknown. OBJECTIVE: To study the economic burden of community dwelling YOD in relation to late onset dementia (LOD) and cost of YOD based on etiology. METHODS: In this prospective cross-sectional study of 255 patients attending a tertiary neurology center, data on economic burden, clinical features, and caregiver burden were collected using structured financial questionnaire, standard cognitive and neuropsychiatric measures, and Zarit caregiver burden scale. Cost components were grouped into those relating to direct medical costs, direct non-medical costs, and those related to indirect costs. Cost was also categorized based on etiology of YOD. RESULTS: The mean age at symptom onset in the YOD and LOD cohort was 57.0 (SD 5.1) and 75.0 (SD 5.9) years, respectively. The median annual cost for patients with YOD was almost twice that of LOD (USD 15,815 versus USD 8,396). Indirect cost contributed heavily to cost related to YOD. Even when grouped by dementia etiology, YOD patients with Alzheimer's disease, frontotemporal dementia (FTD), and vascular dementia had higher cost compared to their elderly counterparts. Young onset FTD had the highest cost. 43.2% of YOD reported loss of employment due to dementia, which was significantly higher than that in LOD (2.4%). CONCLUSION: Patients with YOD have a high economic burden. Young patients with FTD have the highest cost followed by vascular dementia and Alzheimer's disease.
Keywords: Age of Onset; Aged; Cohort Studies; Costs and Cost Analysis; Cross-Sectional Studies; Dementia; Female; Humans; Independent Living; Male; Mental Disorders; Middle Aged; Perceptual Disorders; Prospective Studies; Psychiatric Status Rating Scales; Severity of Illness Index; Surveys and Questionnaires; Young Adult

Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. - Geng, Junhua; Xia, Lu; Li, Wanjie; Zhao, Changqi; Dou, Fei (J Alzheimers Dis, 2016)
Neurofibrillary tangles are the main pathological feature of Alzheimer's disease. Insoluble tau protein is the major component of neurofibrillary tangles. Defects in the tau protein degradation pathway in neurons can lead to the accumulation of tau and its subsequent aggregation. Currently, contradictory results on the tau degradation pathway have been reported by different groups. This discrepancy is most likely due to different cell lines and methods used in those studies. In this study, we found that cycloheximide treatment induced mild activation of a ZVAD-sensitive protease in Drosophila Kc cells, resulting in cleavage of tau at its C-terminus; this cleavage could generate misleading tau protein degradation pattern results depending on the antibodies used in the assay. Because cycloheximide is a broadly used chemical reagent for the study of protein degradation, the unexpected artificial effect we observed here indicates that cycloheximide is not suitable for the study of tau degradation. Other methods, such as inducible expression systems and pulse-chase assays, may be more appropriate for studying tau degradation under physiological conditions.
Keywords: Animals; Apoptosis; Caspase 3; Cell Line; Cycloheximide; Drosophila; Drosophila Proteins; Drug Evaluation, Preclinical; Humans; Oligopeptides; Peptide Hydrolases; Protease Inhibitors; Protein Synthesis Inhibitors; tau Proteins; Time