Generation and Partial Characterization of Rabbit Monoclonal Antibody to Pyroglutamate Amyloid-β3-42 (pE3-Aβ). - Mehta, Pankaj D; Patrick, Bruce A; Barshatzky, Marc; Mehta, Sangita P; Frackowiak, Janusz; Mazur-Kolecka, Bozena; Wegiel, Jerzy; Wisniewski, Thomas; Miller, David L (J Alzheimers Dis, 2018)
N-terminally truncated pyroglutamate amyloid-β (Aβ) peptide starting at position 3 represents a significant fraction of Aβ peptides (pE3-Aβ) in amyloid plaques of postmortem brains from patients with Alzheimer's disease (AD) and older persons with Down syndrome (DS). Studies in transgenic mouse models of AD also showed that pE3-Aβ is a major component of plaques, and mouse monoclonal antibody to pE3-Aβ appears to be a desirable therapeutic agent for AD. Since small peptides do not typically elicit a good immune response in mice, but do so favorably in rabbits, our aims were to generate and partially characterize a rabbit monoclonal antibody (RabmAb) to pE3-Aβ. The generated RabmAb was found to be specific for pE3-Aβ, since it showed no reactivity with Aβ16, Aβ40, Aβ42, Aβ3-11, and pE11-17 Aβ peptides in an enzyme linked immunosorbent assay (ELISA). The isotype of the antibody was found to be IgG class. The antibody possesses high affinity to pE3-Aβ with dissociation constant (KD) for the antibody of 1 nM. The epitope of the antibody lies within the sequence of pE3-FRHD. In dot blotting, the optimal detection of pE3-Aβ was at an antibody concentration of 0.5 μg/ml. The threshold of pE3-Aβ detection was 2 fmol. The antibody was sensitive enough to detect 10 pg/ml of pE3-Aβ in sandwich ELISA. pE3-Aβ was detected in AD and DS brain extracts in ELISA and immunoblotting. Immunohistological studies showed immunolabeling of plaques and blood vessels in brains from patients with AD, and DS showing AD pathology. Thus, the antibody can be widely applied in AD and DS research, and therapeutic applications.

Genetic Heterogeneity of Alzheimer's Disease: Embracing Research Partnerships. - Nacmias, Benedetta; Bagnoli, Silvia; Piaceri, Irene; Sorbi, Sandro (J Alzheimers Dis, 2018)
Studies on the genetics of Alzheimer's disease (AD) have revealed the complexity and heterogeneity of the disease. All our studies have supported this evidence and contribute to the current understanding of the genetic architecture of AD. This report reviews the success of our investigations, focusing on the implications and importance of the genetics of AD, and demonstrates the relevance of research strategies embracing partnerships.

Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study. - Peloso, Gina M; Beiser, Alexa S; DeStefano, Anita L; Seshadri, Sudha (J Alzheimers Dis, 2018)
Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.

Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort. - Brookes, Keeley J; McConnell, George; Williams, Kirsty; Chaudhury, Sultan; Madhan, Gaganjit; Patel, Tulsi; Turley, Christopher; Guetta-Baranes, Tamar; Bras, Jose; Guerreiro, Rita; Hardy, John; Francis, Paul T; et al. (J Alzheimers Dis, 2018)
The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOEɛ4 allele was identified (p = 3.99×10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.

Geographical Distribution and Diversity of Gut Microbial NADH:Ubiquinone Oxidoreductase Sequence Associated with Alzheimer's Disease. - Paley, Elena L; Merkulova-Rainon, Tatiana; Faynboym, Aleksandr; Shestopalov, Valery I; Aksenoff, Igor (J Alzheimers Dis, 2018)
Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer's disease (AD). Tryptophan is a product of Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough.
Keywords: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Anti-Bacterial Agents; Biological Transport; DNA Primers; Electron Transport Complex I; Feces; Female; Gastrointestinal Microbiome; Geography; Host-Pathogen Interactions; Humans; Male; Middle Aged; Sequence Analysis, DNA; Young Adult

Glucagon-Like Peptide-2 Receptor is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion. - Xie, Yan-Chun; Yao, Zhao-Hui; Yao, Xiao-Li; Pan, Jian-Zhen; Zhang, Shao-Feng; Zhang, Yong; Hu, Ji-Chang (J Alzheimers Dis, 2018)
Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.

Healthy versus Entorhinal Cortical Atrophy Identification in Asymptomatic APOE4 Carriers at Risk for Alzheimer's Disease. - Konishi, Kyoko; Joober, Ridha; Poirier, Judes; MacDonald, Kathleen; Chakravarty, Mallar; Patel, Raihaan; Breitner, John; Bohbot, Véronique D (J Alzheimers Dis, 2018)
Early detection of Alzheimer's disease (AD) has been challenging as current biomarkers are invasive and costly. Strong predictors of future AD diagnosis include lower volume of the hippocampus and entorhinal cortex, as well as the ɛ4 allele of the Apolipoprotein E gene (APOE) gene. Therefore, studying functions that are critically mediated by the hippocampus and entorhinal cortex, such as spatial memory, in APOE ɛ4 allele carriers, may be key to the identification of individuals at risk of AD, prior to the manifestation of cognitive impairments. Using a virtual navigation task developed in-house, specifically designed to assess spatial versus non-spatial strategies, the current study is the first to differentiate functional and structural differences within APOE ɛ4 allele carriers. APOE ɛ4 allele carriers that predominantly use non-spatial strategies have decreased fMRI activity in the hippocampus and increased atrophy in the hippocampus, entorhinal cortex, and fimbria compared to APOE ɛ4 allele carriers who use spatial strategies. In contrast, APOE ɛ4 allele carriers who use spatial strategies have grey matter levels comparable to non-APOE ɛ4 allele carriers. Furthermore, in a leave-one-out analysis, grey matter in the entorhinal cortex could predict navigational strategy with 92% accuracy.
Keywords: Aged; Alleles; Alzheimer Disease; Apolipoprotein E4; Atrophy; Case-Control Studies; Entorhinal Cortex; Female; Heterozygote; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Risk Factors; Spatial Memory

Heme Oxygenase 1 Induces Tau Oligomer Formation and Synapse Aberrations in Hippocampal Neurons. - Si, Zizhen; Wang, Xidi; Zhang, Zhujun; Wang, Jinxin; Li, Jihong; Li, Jing; Li, Ling; Li, Yuanxin; Peng, Yahui; Sun, Chongran; Hui, Yang; Gao, Xu (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by behavioral changes and cognitive decline. Recent evidence suggests that it is the soluble forms of tau oligomers (Tau-O) and Aβ oligomers (oAβ) rather than the well-studied insoluble protein aggregates that possess the neurotoxicity, infectivity, and amplification underlying disease progression. Heme oxygenase 1 (HO-1), an inducible enzyme upregulated in the cortex and hippocampus of AD brains, was reported to damage neural structures and disrupt brain function, suggesting possible contributions to Tau-O-mediated neurodegeneration. In this study, we focused on the effects of HO-1 on Tau-O formation. In hippocampus of HO-1-overexpressing transgenic mice and neural 2a (N2a) cells, Tau-O was co-localized with HO-1 as visualized by immunofluorescence staining. Furthermore, primary cultured hippocampal neurons from HO-1 transgenic mice showed elevated Tau-O and concomitant reductions in spine density and length as well as dendritic length, diameter, and arborization. Blocking Tau-O formation by isoprenaline reversed these HO-1-induced morphological changes. These results indicated that HO-1 contributes to Tau-O formation and ensuing synaptic damage. Thus, HO-1 is a promising target for AD drug development.

Hippocampal Sclerosis in the Oldest Old: A Finnish Population-Based Study. - Kero, Mia; Raunio, Anna; Polvikoski, Tuomo; Tienari, Pentti J; Paetau, Anders; Myllykangas, Liisa (J Alzheimers Dis, 2018)
BACKGROUND: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. OBJECTIVE: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied. METHODS: The population-based Vantaa 85+ study includes all inhabitants of the city of Vantaa, who were >85 years in 1991 (n = 601). Neuropathological assessment was possible in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE- staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. RESULTS: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p < 0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p < 0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. CONCLUSION: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination.

Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse. - Plucińska, Kaja; Crouch, Barry; Yeap, Jie M; Stoppelkamp, Sandra; Riedel, Gernot; Platt, Bettina (J Alzheimers Dis, 2018)
Gene mutations within amyloid precursor protein (APP or AβPP) and/or presenilin 1 (PS1) genes are determinants of familial Alzheimer's disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP) with mutated human APPSwe/Lon and investigated histopathology and behavioral phenotypes. Additionally, PLB2APP mice were cross-bred with a presenilin (PS1A246E) line to assess the impact of this gene combination. Immunohistochemistry determined amyloid-β (Aβ) pathology, astrogliosis (via GFAP labelling), and neuronal densities in hippocampal and cortical brain regions. One-year old PLB2APP mice showed higher levels of intracellular Aβ in CA1, dentate gyrus, and cortical regions compared to PLBWT controls. Co-expression of PS1 reduced hippocampal but elevated cortical Aβ build-up. Amyloid plaques were sparse in aged PLB2APP mice, and co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1 mice. Behaviorally, habituation to a novel environment was delayed in 6-month-old PLB2APP mice, and overall home-cage activity was reduced in both lines at 6 and 12 months, particularly during the dark phase. Spatial learning in the water maze was impaired in PLB2APP mice independent of PS1 expression and associated with reduced spatial navigation strategies. Memory retrieval was compromised in PLB2APP mice only. Our data demonstrate that low expression of APP is sufficient to drive histopathological and cognitive changes in mice without overexpression or excessive plaque deposition. AD-like phenotypes were altered by co-expression of PS1, including a shift from hippocampal to cortical Aβ pathology, alongside reduced deficits in spatial learning.

Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-β Antibodies and ω-3 Not Working in Clinical Trials? - Fiala, Milan; Restrepo, Lucas; Pellegrini, Matteo (J Alzheimers Dis, 2018)
This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1 - 42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients' macrophages in the brain's clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.

Impact of a Virtual Dementia Experience on Medical and Pharmacy Students' Knowledge and Attitudes Toward People with Dementia: A Controlled Study. - Gilmartin-Thomas, Julia F-M; McNeil, John; Powell, Anne; Malone, Daniel T; Wolfe, Rory; Larson, Ian C; O'Reilly, Claire L; Kirkpatrick, Carl M; Kipen, Eva; Petrovich, Tanya; Bell, J Simon (J Alzheimers Dis, 2018)
BACKGROUND: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia. OBJECTIVE: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia. METHODS: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention. RESULTS: A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p < 0.001). CONCLUSION: The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia.
Keywords: Australia; Curriculum; Dementia; Female; Health Knowledge, Attitudes, Practice; Humans; Male; Students, Medical; Students, Pharmacy; Virtual Reality; Young Adult

The Impact of APOE ɛ4 in Alzheimer's Disease Differs According to Age. - Kim, Jaeho; Park, Seongbeom; Yoo, Heejin; Jang, Hyemin; Kim, Yeshin; Kim, Ko Woon; Jang, Young Kyoung; Lee, Jin San; Kim, Sung Tae; Kim, Seonwoo; Lee, Jong Min; Ki, Chang-Seok; et al. (J Alzheimers Dis, 2018)
We evaluated how the impact of apolipoprotein E4 (APOE4) differs according to age in Alzheimer's disease (AD) patients. We recruited 846 AD patients and 815 cognitively normal controls and categorized into three groups with respect to their age (<65, 65-74, and ≥75 years). We evaluated the risk of AD in APOE4 carriers and compared cortical thickness and cognitive function according to APOE4 status in each age group. At the point of this study, in young (<65 years) AD, APOE4 noncarriers had the most severe frontal and perisylvian atrophy, while in old (≥75 years) AD, APOE4 carriers had the most severe medial temporal atrophy. In AD under 75 years, APOE4 noncarriers and heterozygotes showed worse performance in language, visuospatial, and frontal function compared to homozygotes, while, in old (≥75 years) AD, APOE4 homozygotes showed worse performance in memory compared to noncarriers. As the detrimental effects of APOE4 seen in older AD patients were not found in younger AD patients, we suggest that some unrevealed factors are associated with cortical atrophy and non-amnestic cognitive dysfunction in young AD with APOE4 noncarriers.
Keywords: Age Factors; Aged; Alzheimer Disease; Apolipoprotein E4; Atrophy; Brain; Case-Control Studies; Cognition; Female; Heterozygote; Humans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Republic of Korea

The Impact of Creative Arts in Alzheimer's Disease and Dementia Public Health Education. - Burns, Nicole C; Watts, Amber; Perales, Jaime; Montgomery, Robert Neal; Morris, Jill K; Mahnken, Jonathan D; Lowther, Johnna; Vidoni, Eric D (J Alzheimers Dis, 2018)
Previous research involving dramatic performances about Alzheimer's disease and dementia perception have targeted health care workers or caretakers. We examined the influence of a theater performance on the emotional affect of a general audience to determine the utility of this type of theater in large-scale public health education efforts. Our study included 147 participants that attended a self-revelatory theater performance based on the social/relationship experiences of those with dementia and those who care for them. This type of theater engages the audience and actors in a dual transformative process, supporting the emotional growth of all involved. Participants completed pre- and post-performance questionnaires regarding their beliefs and feelings surrounding the topic of dementia and the importance of the Arts for educating on issues surrounding dementia care. We tested for change in emotional affect pre- and post-performance using sensitivity and center of gravity statistical analyses. We found a significant change in emotional affect from an initial strong negative affect to slightly more positive/relaxed view after viewing the performance. Findings support self-revelatory theater as a resource to destigmatize preconceived notions of dementia. Large-scale community health education efforts could benefit from using this style of theater to elicit a change in audience perception of disease realities.

Impact of Mild Cognitive Impairment on Mortality and Cause of Death in the Elderly. - Bae, Jong Bin; Han, Ji Won; Kwak, Kyung Phil; Kim, Bong Jo; Kim, Shin Gyeom; Kim, Jeong Lan; Kim, Tae Hui; Ryu, Seung-Ho; Moon, Seok Woo; Park, Joon Hyuk; Youn, Jong Chul; Lee, Dong Young; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Mild cognitive impairment (MCI) is a cognitive state that lies on the continuum between normal aging and dementia, and the prevalence of MCI is higher than dementia. However, the risk for mortality of people with MCI has been far less studied than that of people with dementia, and the population attributable risk percent (PAR%) of death attributable to MCI has not been estimated yet. OBJECTIVE: To investigate the impact of MCI on mortality and the cause of death in the elderly, and to estimate the PAR% of deaths attributable to MCI. METHODS: Data came from 7,315 elderly subjects aged ≥60 years without dementia from two cohort studies with diagnostic assessments of MCI at baseline. Deaths among participants were confirmed through the nationwide mortality database of Statistics Korea. RESULTS: MCI increased the risk of mortality in a multivariate Cox proportional model adjusting for age, sex, education, smoking, alcohol drinking, chronic illness, depression, vascular components, and cohort (hazard ratio = 1.59, 95% confidence interval 1.30, 1.94). PAR% of death attributable to MCI was 10.7% for age 65-74 years, 16.0% for age 75-84 years, and 24.2% for age ≥85 years. In the elderly with MCI, mortality risks from cerebrovascular disease, respiratory disease, and external causes were higher than in the cognitively normal elderly. CONCLUSIONS: Our results suggest that the mortality risk of MCI in Asian countries may be comparable to that in Western countries, and MCI can contribute to the death of the elderly as much as dementia.

Impact of Total Knee Arthroplasty with General Anesthesia on Brain Networks: Cognitive Efficiency and Ventricular Volume Predict Functional Connectivity Decline in Older Adults. - Huang, Haiqing; Tanner, Jared; Parvataneni, Hari; Rice, Mark; Horgas, Ann; Ding, Mingzhou; Price, Catherine (J Alzheimers Dis, 2018)
Using resting state functional magnetic resonance imaging (RS-fMRI), we explored: 1) pre- to post-operative changes in functional connectivity in default mode, salience, and central executive networks after total knee arthroplasty (TKA) with general anesthesia, and 2) the contribution of cognitive/brain reserve metrics these resting state functional declines. Individuals age 60 and older electing unilateral total knee arthroplasty (TKA; n = 48) and non-surgery peers with osteoarthritis (n = 45) completed baseline cognitive testing and baseline and post-surgery (post-baseline, 48-h post-surgery) brain MRI. We acquired cognitive and brain estimates for premorbid (vocabulary, reading, education, intracranial volume) and current (working memory, processing speed, declarative memory, ventricular volume) reserve. Functional network analyses corrected for pain severity and pain medication. The surgery group declined in every functional network of interest (p < 0.001). Relative to non-surgery peers, 23% of surgery participants declined in at least one network and 15% of the total TKA sample declined across all networks. Larger preoperative ventricular volume and lower scores on preoperative metrics of processing speed and working memory predicted default mode network connectivity decline. Premorbid cognitive and premorbid brain reserve did not predict decline. Within 48 hours after surgery, at least one fourth of the older adult sample showed significant functional network decline. Metrics of current brain status (ventricular volume), working memory, and processing speed predicted the severity of default mode network connectivity decline. These findings demonstrate the relevance of preoperative cognition and brain integrity on acute postoperative functional network change.

Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. - Janssen, Niels; Handels, Ron L; Sköldunger, Anders; Woods, Bob; Jelley, Hannah; Edwards, Rhiannon Tudor; Orrell, Martin; Selbæk, Geir; Røsvik, Janne; Gonçalves-Pereira, Manuel; Marques, Maria J; Zanetti, Orazio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed. OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia. METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items. RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs. CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.

Impaired IL-17 Production in Gut-Residing Immune Cells of 5xFAD Mice with Alzheimer's Disease Pathology. - Saksida, Tamara; Koprivica, Ivan; Vujičić, Milica; Stošić-Grujičić, Stanislava; Perović, Milka; Kanazir, Selma; Stojanović, Ivana (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer's patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; B-Lymphocytes; Disease Models, Animal; Female; Interleukin-17; Lymph Nodes; Male; Mice; Mice, Transgenic; MicroRNAs; Peyer's Patches; Th17 Cells

Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer's Disease Patients. - Di Lorenzo, Francesco; Ponzo, Viviana; Motta, Caterina; Bonní, Sonia; Picazio, Silvia; Caltagirone, Carlo; Bozzali, Marco; Martorana, Alessandro; Koch, Giacomo (J Alzheimers Dis, 2018)
BACKGROUND: Mechanisms of cortical plasticity have been recently investigated in Alzheimer's disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms. OBJECTIVE: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1). METHODS: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS - 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. RESULTS: In healthy subjects, ccPAS - 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols. CONCLUSIONS: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.

Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients. - Costa, Montserrat; Horrillo, Raquel; Ortiz, Ana María; Pérez, Alba; Mestre, Anna; Ruiz, Agustin; Boada, Merce; Grancha, Salvador (J Alzheimers Dis, 2018)
BACKGROUND: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. OBJECTIVE: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. METHODS: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry. RESULTS: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. CONCLUSION: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.

Increased Foxo3a Nuclear Translocation and Activity is an Early Neuronal Response to βγ-Secretase-Mediated Processing of the Amyloid-β Protein Precursor: Utility of an AβPP-GAL4 Reporter Assay. - Law, Bernard M; Guest, Amy L; Pullen, Matthew W J; Perkinton, Michael S; Williams, Robert J (J Alzheimers Dis, 2018)
Sequential cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (β-secretase) followed by theγ-secretase complex, is strongly implicated in Alzheimer's disease (AD) but the initial cellular responses to these cleavage events are not fully defined. β-secretase-mediated AβPP processing yields an extracellular domain (sAβPPβ) and a C-terminal fragment of AβPP of 99 amino acids (C99). Subsequent cleavage by γ-secretase produces amyloid-β (Aβ) and an AβPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AβPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AβPP sequence and linking the assay to Gal4-UAS driven luciferase and GFP expression, to identify responses immediately downstream of AβPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AβPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AβPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by γ-secretase inhibitors, lowered by β-secretase inhibitors, and enhanced by α-secretase inhibitors suggesting that AICD is a product of the βγ-secretase pathway. AβPP-Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AβPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that βγ-secretase-mediated AβPP processing couples to Foxo3a which could be an early neuronal signaling response in AD.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Disease Models, Animal; Forkhead Box Protein O3; Mice; Mutagenesis, Site-Directed; Mutation; Neurons; Phosphorylation; Protein Transport; Signal Transduction

An Inducible Alpha-Synuclein Expressing Neuronal Cell Line Model for Parkinson's Disease1. - Vasquez, Velmarini; Mitra, Joy; Perry, George; Rao, K S; Hegde, Muralidhar L (J Alzheimers Dis, 2018)
Altered expression of α-synuclein is linked to Parkinson's disease (PD). A major challenge to explore how the increased α-synuclein affect neurotoxicity is the lack of a suitable human neuronal cell model that mimics this scenario. Its expression in neural precursors affects their differentiation process, in addition to the neuronal adaptability and variability in maintaining a constant level of expression across passages. Here, we describe an SH-SY5Y line harboring Tet-ON SNCA cDNA cassette that allows for induction of controlled α-synuclein expression after neuronal differentiation, which can be an important tool for PD research.

Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides. - Cam, Morgane; Durieu, Emilie; Bodin, Marion; Manousopoulou, Antigoni; Koslowski, Svenja; Vasylieva, Natalia; Barnych, Bogdan; Hammock, Bruce D; Bohl, Bettina; Koch, Philipp; Omori, Chiori; Yamamoto, Kazuo; et al. (J Alzheimers Dis, 2018)
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. - Gabriel, António José; Almeida, Maria Rosário; Ribeiro, Maria Helena; Carneiro, Diogo; Valério, Daniela; Pinheiro, Ana Cristina; Pascoal, Rui; Santana, Isabel; Baldeiras, Ines (J Alzheimers Dis, 2018)
BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited. OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD. METHODS: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined. RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD. CONCLUSION: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Butyrylcholinesterase; Cognitive Dysfunction; Disease Progression; Female; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Risk Factors; tau Proteins

Influence of Lewy Pathology on Alzheimer's Disease Phenotype: A Retrospective Clinico-Pathological Study. - Roudil, Jennifer; Deramecourt, Vincent; Dufournet, Boris; Dubois, Bruno; Ceccaldi, Mathieu; Duyckaerts, Charles; Pasquier, Florence; Lebouvier, Thibaud (J Alzheimers Dis, 2018)
BACKGROUND: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer's Disease (AD). OBJECTIVE: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD. METHODS: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological data. RESULTS: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with 'classical' (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p < 0.01). There was no significant difference in cognitive profiles. CONCLUSION: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis.

The Influence of the Val66Met Polymorphism of Brain-Derived Neurotrophic Factor on Neurological Function after Traumatic Brain Injury. - Finan, John D; Udani, Shreya V; Patel, Vimal; Bailes, Julian E (J Alzheimers Dis, 2018)
Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.

The In-Hospital Length of Stay after Hip Fracture in Octogenarians: Do Delirium and Dementia Shape a New Care Process? - Monacelli, Fiammetta; Pizzonia, Monica; Signori, Alessio; Nencioni, Alessio; Giannotti, Chiara; Minaglia, Cecilia; Granello di Casaleto, Tommaso; Podestà, Silvia; Santolini, Federico; Odetti, Patrizio (J Alzheimers Dis, 2018)
BACKGROUND: Hip fracture is a major health problem and a patient's biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. OBJECTIVE: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. METHODS: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months' mortality were reported. RESULTS: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. CONCLUSION: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes.

Integrating Sleep and Alzheimer's Disease Pathophysiology: Hints for Sleep Disorders Management. - Proserpio, Paola; Arnaldi, Dario; Nobili, Flavio; Nobili, Lino (J Alzheimers Dis, 2018)
Sleep represents an active phenomenon regulated by a highly integrated network of cortical and subcortical structures. This complex model results in disruptions at various levels during physiological aging and more deeply during neurodegenerative disorders, thus leading to different sleep alterations. In Alzheimer's disease (AD), sleep-wake abnormalities were described to occur even in the preclinical phase, thus suggesting they could be a possible AD biomarker. On the other hand, they also favor the progression of the disease. In this paper, we review current theories regarding sleep regulations and functions to highlight the pathophysiological mechanisms at the basis of the bidirectional relationship between sleep and AD. A better understanding of these complex interactions might also be useful to target both sleep disorder management and AD-related symptoms.

Interactive Effect of Depression and Cognitive Impairment on Olfactory Identification in Elderly People. - Chen, Ben; Zhong, Xiaomei; Mai, Naikeng; Peng, Qi; Zhang, Min; Chen, Xinru; Wu, Zhangying; Zou, Laiquan; Liang, Wanyuan; Ouyang, Cong; Wu, Yujie; Ning, Yuping (J Alzheimers Dis, 2018)
Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p < 0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p < 0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression.

Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples. - Leskelä, Stina; Takalo, Mari; Marttinen, Mikael; Huber, Nadine; Paananen, Jussi; Mitra, Vikram; Rauramaa, Tuomas; Mäkinen, Petra; Leinonen, Ville; Soininen, Hilkka; Pike, Ian; Remes, Anne M; et al. (J Alzheimers Dis, 2018)
A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

Involvement of the Cingulate Cortex in Anosognosia: A Multimodal Neuroimaging Study in Alzheimer's Disease Patients. - Guerrier, Laura; Le Men, Johanne; Gane, Anaıs; Planton, Mélanie; Salabert, Anne-Sophie; Payoux, Pierre; Dumas, Hervé; Bonneville, Fabrice; Péran, Patrice; Pariente, Jérémie (J Alzheimers Dis, 2018)
BACKGROUND: Anosognosia is a frequent symptom of Alzheimer's disease (AD), but its neural substrates remain in question. OBJECTIVE: In this study, we combined neuroimaging with a neuropsychological evaluation to assess neural substrates of anosognosia. METHODS: We prospectively recruited 30 patients with probable early-stage AD and matched healthy controls. Participants underwent MRI, FDG-PET, and a neuropsychological evaluation that includes an assessment of anosognosia. In the AD group, correlations between the anosognosia score, neuroimaging modalities, and neuropsychological performance were performed. RESULTS: Atrophy and hypometabolism were correlated with the anosognosia score in the left dorsal anterior cingulate cortex. The anosognosia score was also correlated with atrophy of the cerebellar vermis, the left postcentral gyrus, and the right fusiform gyrus. No relation was found between anosognosia and the neuropsychological assessment. DISCUSSION: Structural and metabolic alteration in the dorsal anterior cingulate cortex seems to be associated with a diminution of awareness in patients with early-stage AD.

Joint Assessment of Quantitative 18F-Florbetapir and 18F-FDG Regional Uptake Using Baseline Data from the ADNI. - Ben Bouallègue, Fayçal; Mariano-Goulart, Denis; Payoux, Pierre (J Alzheimers Dis, 2018)
Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects was performed using baseline 18F-florbetapir and 18F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37±14 months). Using SVM, the combination of ADAS-cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion.

Leisure-Time Physical Activity and the Risk of Incident Dementia: The Mayo Clinic Study of Aging. - Krell-Roesch, Janina; Feder, Nathanael T; Roberts, Rosebud O; Mielke, Michelle M; Christianson, Teresa J; Knopman, David S; Petersen, Ronald C; Geda, Yonas E (J Alzheimers Dis, 2018)
We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging. We investigated if leisure-time physical activity among individuals with mild cognitive impairment (MCI) was associated with a decreased risk of developing dementia. 280 persons aged≥70 years (median 81 years, 165 males) with MCI and available data from neurologic evaluation, neuropsychological testing, and questionnaire-based physical activity assessment, were followed for a median of 3 years to the outcomes of incident dementia or censoring variables. We conducted Cox proportional hazards regression analyses with age as a time scale and adjusted for sex, education, medical comorbidity, depression, and APOE ɛ4 status. Moderate intensity midlife physical activity among MCI participants was significantly associated with a decreased risk of incident dementia (HR = 0.64; 95% CI, 0.41-0.98). There was a non-significant trend for a decreased risk of dementia for light and vigorous intensity midlife physical activity, as well as light and moderate intensity late-life physical activity. In conclusion, we observed that physical activity may be associated with a reduced risk of dementia among individuals with MCI. Furthermore, intensity and timing of physical activity may be important factors when investigating this association.

Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition. - Ahmed, Rebekah M; Highton-Williamson, Elizabeth; Caga, Jashelle; Thornton, Nicolette; Ramsey, Eleanor; Zoing, Margaret; Kim, Woojin Scott; Halliday, Glenda M; Piguet, Olivier; Hodges, John R; Farooqi, I Sadaf; Kiernan, Matthew C (J Alzheimers Dis, 2018)
BACKGROUND: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels. OBJECTIVE: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival. METHODS: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. RESULTS: There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p < 0.001), total cholesterol/HDL ratio (p < 0.001), and lower HDL levels (p = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration. CONCLUSION: A spectrum of changes in lipid metabolism has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.
Keywords: Adult; Aged; Amyotrophic Lateral Sclerosis; Australia; Body Mass Index; Case-Control Studies; Cholesterol; Cholesterol, HDL; Cognition; Energy Intake; Feeding Behavior; Female; Frontotemporal Dementia; Humans; Lipid Metabolism; Male; Middle Aged; Neuropsychological Tests; Survival Analysis

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. - Cuberas-Borrós, Gemma; Roca, Isabel; Boada, Merce; Tárraga, Lluís; Hernandez, Isabel; Buendia, Mar; Rubio, Lourdes; Torres, Gustavo; Bittini, Ángel; Guzmán-de-Villoria, Juan A; Pujadas, Francesc; Torres, Mireia; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Plasma Exchange; Serum Albumin, Human; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study. - Salloway, Stephen P; Sperling, Reisa; Fox, Nick C; Sabbagh, Marwan N; Honig, Lawrence S; Porsteinsson, Anton P; Rofael, Hany; Ketter, Nzeera; Wang, Daniel; Liu, Enchi; Carr, Stephen; Black, Ronald S; et al. (J Alzheimers Dis, 2018)
BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

Low Accuracy of Brief Cognitive Tests in Tracking Longitudinal Cognitive Decline in an Asian Elderly Cohort. - Phua, April Ka Sin; Hiu, Shaun Kuan Wei; Goh, Win King; Ikram, Mohammad Kamran; Venketasubramanian, Narayanaswamy; Tan, Boon Yeow; Chen, Christopher Li-Hsian; Xu, Xin (J Alzheimers Dis, 2018)
BACKGROUND: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. OBJECTIVE: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. METHODS: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. RESULTS: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). CONCLUSION: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change.

Mediterranean Diet, Its Components, and Amyloid Imaging Biomarkers. - Vassilaki, Maria; Aakre, Jeremiah A; Syrjanen, Jeremy A; Mielke, Michelle M; Geda, Yonas E; Kremers, Walter K; Machulda, Mary M; Alhurani, Rabe E; Staubo, Sara C; Knopman, David S; Petersen, Ronald C; Lowe, Val J; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is accumulating evidence suggesting that diet may play a role in preventing or delaying cognitive decline and dementia, but the underlying biological mechanisms are not well understood. OBJECTIVES: To examine the cross-sectional associations of the Mediterranean diet (MeDi) and its components with 11C-PiB-PET scan measures of amyloid-β (Aβ) deposition. METHODS: The study consisted of 278 Mayo Clinic Study of Aging participants 70+ years old, who were cognitively unimpaired (CU) at the time of completion of the Food Frequency Questionnaire (FFQ) and when they underwent PET imaging. Adherence to the MeDi was assessed by computing the MeDi score for each participant. All scans were performed after the FFQ completion; median [IQR] time between FFQ and Aβ PET was 3.5 (1.4) years. Z-scores were created for component, macro- and micronutrients measured. Linear and logistic regression models were adjusted for age, sex, education, apolipoprotein E (APOE) ɛ4 allele carrier status, time interval between the FFQ completion and PET scan, and total energy intake. RESULTS: Participants' median age at FFQ was 77.7 years (55.8% men; 26.6% with an APOE ɛ4 allele). Higher MeDi score (linear regression slope (beta):-0.035, p = 0.012; per standard deviation increase), vegetable intake (beta:-0.043, p = 0.002), intake of vitamin A (beta:-0.041, p = 0.003) or β-carotene (beta: -0.039, p = 0.005) from food sources and moderate alcohol consumption (beta: -0.074, p = 0.03) were associated with lower 11C-PiB standardized uptake value ratio. CONCLUSION: Findings are consistent with previous studies suggesting that higher adherence to a MeDi pattern and higher vegetable consumption are associated with better neuroimaging biomarker profile. Prospective studies are needed to validate current findings.

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. - Folch, Jaume; Busquets, Oriol; Ettcheto, Miren; Sánchez-López, Elena; Castro-Torres, Ruben Dario; Verdaguer, Ester; Garcia, Maria Luisa; Olloquequi, Jordi; Casadesus, Gemma; Beas-Zarate, Carlos; Pelegri, Carme; Vilaplana, Jordi; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

Mental States in Moving Shapes: Distinct Cortical and Subcortical Contributions to Theory of Mind Impairments in Dementia. - Synn, Artemis; Mothakunnel, Annu; Kumfor, Fiona; Chen, Yu; Piguet, Olivier; Hodges, John R; Irish, Muireann (J Alzheimers Dis, 2018)
Impaired capacity for Theory of Mind (ToM) represents one of the hallmark features of the behavioral variant of frontotemporal dementia (bvFTD) and is suggested to underpin an array of socioemotional disturbances characteristic of this disorder. In contrast, while social processing typically remains intact in Alzheimer's disease (AD), the cognitive loading of socioemotional tasks may adversely impact mentalizing performance in AD. Here, we employed the Frith-Happé animations as a dynamic on-line assessment of mentalizing capacity with reduced incidental task demands in 18 bvFTD, 18 AD, and 25 age-matched Controls. Participants viewed silent animations in which geometric shapes interact in Random, Goal-Directed, and ToM conditions. An exclusive deficit in ToM classification was observed in bvFTD relative to Controls, while AD patients were impaired in the accurate classification of both Random and ToM trials. Correlation analyses revealed robust associations between ToM deficits and carer ratings of affective empathy disruption in bvFTD, and with episodic memory dysfunction in AD. Voxel-based morphometry analyses further identified dissociable neural correlates contingent on patient group. A distributed network of medial prefrontal, frontoinsular, striatal, lateral temporal, and parietal regions were implicated in the bvFTD group, whereas the right hippocampus correlated with task performance in AD. Notably, subregions of the cerebellum, including lobules I-IV and V, bilaterally were implicated in task performance irrespective of patient group. Our findings reveal new insights into the mechanisms potentially mediating ToM disruption in dementia syndromes, and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated.
Keywords: Aged; Alzheimer Disease; Brain; Case-Control Studies; Female; Frontotemporal Dementia; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory, Episodic; Mentalization; Middle Aged; Neuropsychological Tests; Task Performance and Analysis; Theory of Mind

Meta-Analysis of Personality Traits in Alzheimer's Disease: A Comparison with Healthy Subjects. - D'Iorio, Alfonsina; Garramone, Federica; Piscopo, Fausta; Baiano, Chiara; Raimo, Simona; Santangelo, Gabriella (J Alzheimers Dis, 2018)
BACKGROUND: The role of specific personality traits as factor risks of Alzheimer's disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet. OBJECTIVE: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies. METHODS: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges' g unbiased approach. RESULTS: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores. CONCLUSIONS: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD.
Keywords: Alzheimer Disease; Case-Control Studies; Humans; Personality; Personality Inventory

Metabolic Syndrome, Brain Insulin Resistance, and Alzheimer's Disease: Thioredoxin Interacting Protein (TXNIP) and Inflammasome as Core Amplifiers. - Nasoohi, Sanaz; Parveen, Kehkashan; Ishrat, Tauheed (J Alzheimers Dis, 2018)
Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer's disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating "toxic metabolites" emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or "type 3 diabetes". Thioredoxin-interacting protein (TXNIP) as an intracellular amplifier of oxidative stress and inflammasome activation may presumably mediate central insulin resistance. Emerging data including those from our recent studies has demonstrated a sharp TXNIP upregulation in stroke, aging and AD and well underlining the significance of this hypothesis. With the main interest to illustrate TXNIP place in type 3 diabetes, the present review primarily briefs the potential mechanisms contributing to cerebral insulin resistance in a metabolically deranged environment. Then with a particular focus on plausible TXNIP functions to drive and associate with AD pathology, we present the most recent evidence supporting TXNIP as a promising therapeutic target in AD as an age-associated dementia.

microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. - Manzine, Patricia R; Pelucchi, Silvia; Horst, Maria A; Vale, Francisco A C; Pavarini, Sofia C I; Audano, Matteo; Mitro, Nico; Di Luca, Monica; Marcello, Elena; Cominetti, Márcia R (J Alzheimers Dis, 2018)
ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.
Keywords: ADAM10 Protein; Aged; Aged, 80 and over; Alzheimer Disease; Cell Line, Tumor; Cohort Studies; Down-Regulation; Female; Humans; Male; MicroRNAs; Middle Aged; Neuroblastoma; Psychiatric Status Rating Scales; RNA, Messenger; ROC Curve; Transfection

Minor Hallucinations in Alzheimer's Disease. - Ruiz, Maria; Arias, Alfonso; Sánchez-Llanos, Ernesto; Gil, Maria Pilar; López-Ortega, Ricard; Dakterzada, Faridé; Purroy, Francisco; Piñol-Ripoll, Gerard (J Alzheimers Dis, 2018)
BACKGROUND: Hallucinations may have a broad spectrum and include so-called minor hallucinations (MHs). MHs include passage hallucinations (PHs), visual illusions, and presence hallucinations (PrHs). OBJECTIVE: To determine the prevalence and characteristics of MHs in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients, and to describe their potential relationship with cognition, behavioral symptoms, and use of psychoactive drugs. METHODS: We have recruited prospectively and consecutively 268 subjects (90 AD mild-moderate drug-naïve patients, 78 aMCI, and 100 controls). All patients responded to a semi-structured questionnaire in order to rate psychotic phenomena. Clinical, neuropsychological, and demographic data of patients with and without MH were compared with those of age, sex, and education-matched controls. RESULTS: The prevalence of MHs was 21.1% (19) in AD, 12.8% (10) in aMCI, and 3% (3) in controls (p < 0.01). The most frequent MH was PrH (9.3%), followed by PH (4.9%) and illusion (0.7%). Eight (27.8%) patients had more than one MH. After adjusting for age and gender, there was a negative correlation between the presence of MHs and MMSE score (r = -0.261; p < 0.01) and a positive correlation between MHs and Neuropsychiatric Inventory score (r = 0.237; p < 0.01). We did not observe a significant relationship between presence of MHs and the consumption of psychoactive drugs (p > 0.05). CONCLUSION: We have shown that the presence of MHs in patients with newly diagnosed, untreated AD and aMCI is more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MHs as a clinical feature for this population.

miRNA 933 Expression by Endothelial Cells is Increased by 27-Hydroxycholesterol and is More Prevalent in Plasma from Dementia Patients. - Dias, Irundika H K; Brown, Caroline L; Shabir, Kiran; Polidori, M Cristina; Griffiths, Helen R (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (-933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.

MRI-Based Screening of Preclinical Alzheimer's Disease for Prevention Clinical Trials. - Casamitjana, Adrià; Petrone, Paula; Tucholka, Alan; Falcon, Carles; Skouras, Stavros; Molinuevo, José Luis; Vilaplana, Verónica; Gispert, Juan Domingo (J Alzheimers Dis, 2018)
The identification of healthy individuals harboring amyloid pathology represents one important challenge for secondary prevention clinical trials in Alzheimer's disease (AD). Consequently, noninvasive and cost-efficient techniques to detect preclinical AD constitute an unmet need of critical importance. In this manuscript, we apply machine learning to structural MRI (T1 and DTI) of 96 cognitively normal subjects to identify amyloid-positive ones. Models were trained on public ADNI data and validated on an independent local cohort. Used for subject classification in a simulated clinical trial setting, the proposed method is able to save 60% of unnecessary CSF/PET tests and to reduce 47% of the cost of recruitment. This recruitment strategy capitalizes on available MR scans to reduce the overall amount of invasive PET/CSF tests in prevention trials, demonstrating a potential value as a tool for preclinical AD screening. This protocol could foster the development of secondary prevention strategies for AD.

Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease. - Teipel, Stefan J; Metzger, Coraline D; Brosseron, Frederic; Buerger, Katharina; Brueggen, Katharina; Catak, Cihan; Diesing, Dominik; Dobisch, Laura; Fliebach, Klaus; Franke, Christiana; Heneka, Michael T; Kilimann, Ingo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD). OBJECTIVE: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. METHODS: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors. RESULTS: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. CONCLUSION: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

A Multi-Center Study on Human Brain Glutathione Conformation using Magnetic Resonance Spectroscopy. - Shukla, Deepika; Mandal, Pravat K; Ersland, Lars; Grüner, Eli Renate; Tripathi, Manjari; Raghunathan, Partha; Sharma, Ankita; Chaithya, G R; Punjabi, Khushboo; Splaine, Christopher (J Alzheimers Dis, 2018)
Molecular dynamics simulation and in vitro nuclear magnetic resonance (NMR) studies on glutathione (GSH) indicated existence of closed and extended conformations. The present work in a multi-center research setting reports in-depth analysis of GSH conformers in vivo using a common magnetic resonance spectroscopy (MRS) protocol and signal processing scheme. MEGA-PRESS pulse sequence was applied on healthy subjects using 3T Philips MRI scanner (India) and 3T GE MRI scanner (Norway) using the same experimental parameters (echo time, repetition time, and selective 180° refocusing ON-pulse at 4.40 ppm and 4.56 ppm). All MRS data were processed at one site National Brain Research Center (NBRC) using in-house MRS processing toolbox (KALPANA) for consistency. We have found that both the closed and extended GSH conformations are present in human brain and the relative proportion of individual conformer peak depends on the specific selection of refocusing ON-pulse position in MEGA-PRESS pulse sequence. It is important to emphasize that in vivo experiments with different refocusing and inversion pulse positions, echo time, and voxel size, clearly evidence the presence of both the GSH conformations. The GSH conformer peak positions for the closed GSH (Cys-Hβ) peak at ∼2.80 ppm and extended GSH (Cys-Hβ) peak at ∼2.95 ppm remain consistent irrespective of the selective refocusing OFF-pulse positions. This is the first in vivo study where both extended and closed GSH conformers are detected using the MEGA-PRESS sequence employing the parameters derived from the high resolution in vitro NMR studies on GSH.

Multi-Modality Sparse Representation for Alzheimer's Disease Classification. - Kwak, Kichang; Yun, Hyuk Jin; Park, Gilsoon; Lee, Jong-Min (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are age-related neurodegenerative diseases characterized by progressive loss of memory and irreversible cognitive functions. The hippocampus, a brain area critical for learning and memory processes, is especially susceptible to damage at early stages of AD. OBJECTIVE: We aimed to develop prediction model using a multi-modality sparse representation approach. METHODS: We proposed a sparse representation approach to the hippocampus using structural T1-weighted magnetic resonance imaging (MRI) and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) to distinguish AD/MCI from healthy control subjects (HCs). We considered structural and function information for the hippocampus and applied a sparse patch-based approach to effectively reduce the dimensions of neuroimaging biomarkers. RESULTS: In experiments using Alzheimer's Disease Neuroimaging Initiative data, our proposed method demonstrated more reliable than previous classification studies. The effects of different parameters on segmentation accuracy were also evaluated. The mean classification accuracy obtained with our proposed method was 0.94 for AD/HCs, 0.82 for MCI/HCs, and 0.86 for AD/MCI. CONCLUSION: We extracted multi-modal features from automatically defined hippocampal regions of training subjects and found this method to be discriminative and robust for AD and MCI classification. The extraction of features in T1 and FDG-PET images is expected to improve classification performance due to the relationship between brain structure and function.

Multivariate Approach for Alzheimer's Disease Detection Using Stationary Wavelet Entropy and Predator-Prey Particle Swarm Optimization. - Zhang, Yudong; Wang, Shuihua; Sui, Yuxiu; Yang, Ming; Liu, Bin; Cheng, Hong; Sun, Junding; Jia, Wenjuan; Phillips, Preetha; Górriz, Juan Manuel (J Alzheimers Dis, 2018)
BACKGROUND: The number of patients with Alzheimer's disease is increasing rapidly every year. Scholars often use computer vision and machine learning methods to develop an automatic diagnosis system. OBJECTIVE: In this study, we developed a novel machine learning system that can make diagnoses automatically from brain magnetic resonance images. METHODS: First, the brain imaging was processed, including skull stripping and spatial normalization. Second, one axial slice was selected from the volumetric image, and stationary wavelet entropy (SWE) was done to extract the texture features. Third, a single-hidden-layer neural network was used as the classifier. Finally, a predator-prey particle swarm optimization was proposed to train the weights and biases of the classifier. RESULTS: Our method used 4-level decomposition and yielded 13 SWE features. The classification yielded an overall accuracy of 92.73±1.03%, a sensitivity of 92.69±1.29%, and a specificity of 92.78±1.51%. The area under the curve is 0.95±0.02. Additionally, this method only cost 0.88 s to identify a subject in online stage, after its volumetric image is preprocessed. CONCLUSION: In terms of classification performance, our method performs better than 10 state-of-the-art approaches and the performance of human observers. Therefore, this proposed method is effective in the detection of Alzheimer's disease.

Music and Dementia: Individual Differences in Response to Personalized Playlists. - Garrido, Sandra; Stevens, Catherine J; Chang, Esther; Dunne, Laura; Perz, Janette (J Alzheimers Dis, 2018)
Personalized music playlists are increasingly being used in health-care contexts to address the psychological and behavioral symptoms in people with dementia. However, there is little understanding of how people with different mental health histories and symptoms respond differently to music. A factorial experiment was conducted to investigate the influence of depression, anxiety, apathy, and cognitive decline on affective response to music. Ninety-nine people with dementia listened to three music playlists based on personal preferences. Activation of facial action units was measured, and behavioural responses continuously observed. Results demonstrated that people with high levels of depression and with symptoms of Alzheimer's type dementia demonstrated increased levels of sadness when listening to music. People with low depression but high levels of apathy demonstrated the highest behavioral evidence of pleasure during music listening, although behavioral evidence declined with severity of cognitive impairment. It is concluded that as well as accounting for personal preferences, music interventions for people with dementia need to take mental health history and symptoms into account.

Nailfold Capillary Morphology in Alzheimer's Disease Dementia. - Cousins, Clara C; Alosco, Michael L; Cousins, Henry C; Chua, Alicia; Steinberg, Eric G; Chapman, Kimberly R; Bing-Canar, Hanaan; Tripodis, Yorghos; Knepper, Paul A; Stern, Robert A; Pasquale, Louis R (J Alzheimers Dis, 2018)
BACKGROUND: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer's disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail's cuticle and may help to describe further vascular contributions to AD. OBJECTIVE: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC). METHODS: We evaluated nailfold capillary hemorrhages, avascular zones ≥100 microns, and degree of tortuosity in 28 NC, 15 MCI, and 18 AD dementia subjects using NVC. Tortuosity was measured with a semi-quantitative rating scale. To assess the relation between nailfold capillary morphological features and diagnostic grouping, univariate and multivariable logistic regression models were fit to the data. RESULTS: 56% of subjects with AD dementia compared to 14% with NC and 13% with MCI displayed moderate to severe tortuosity. Greater severity of tortuosity was associated with 10.6-fold (95% confidence interval [CI]: 2.4, 46.2; p = 0.0018) and 7.4-fold (95% CI: 1.3, 41.3; p = 0.023) increased odds of AD dementia relative to NC and MCI, respectively, after adjusting for multiple covariates. CONCLUSION: Greater nailfold capillary tortuosity was found in participants with AD dementia compared to those with MCI or NC. These data provide preliminary evidence of a systemic microvasculopathy in AD that may be noninvasively and inexpensively evaluated through NVC.

A Natural Benzofuran from the Patagonic Aleurodiscus vitellinus Fungus has Potent Neuroprotective Properties on a Cellular Model of Amyloid-β Peptide Toxicity. - González-Ramírez, Mariela; Gavilán, Javiera; Silva-Grecchi, Tiare; Cajas-Madriaga, Daniel; Triviño, Sergio; Becerra, José; Saez-Orellana, Francisco; Pérez, Claudia; Fuentealba, Jorge (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus, and evaluate its effect on Aβ peptide. We tested the effect of Fx at a wide concentration range (10-11-10-4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10-6 M. We then measured the effect of Fx (10-7-10-5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10-6 M) was co-incubated with Aβ (5×10-6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Basidiomycota; Benzofurans; Cell Survival; Hippocampus; Neurons; Neuroprotective Agents; PC12 Cells; Plaque, Amyloid; Rats

Naturalistic Driving Study Investigating Self-Regulation Behavior in Early Alzheimer's Disease: A Pilot Study. - Paire-Ficout, Laurence; Lafont, Sylviane; Conte, Fanny; Coquillat, Amandine; Fabrigoule, Colette; Ankri, Joël; Blanc, Frédéric; Gabel, Cécilia; Novella, Jean-Luc; Morrone, Isabella; Mahmoudi, Rachid (J Alzheimers Dis, 2018)
BACKGROUND: Because cognitive processes decline in the earliest stages of Alzheimer's disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants. OBJECTIVE: This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior. METHODS: Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events. RESULTS: Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more "unaware" critical events. CONCLUSION: This pilot study used a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components.

The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features. - Iverson, Grant L; Keene, C Dirk; Perry, George; Castellani, Rudolph J (J Alzheimers Dis, 2018)
There is tremendous recent interest in chronic traumatic encephalopathy (CTE) in former collision sport athletes, civilians, and military veterans. This critical review places important recent research results into a historical context. In 2015, preliminary consensus criteria were developed for defining the neuropathology of CTE, which substantially narrowed the pathology previously reported to be characteristic. There are no agreed upon clinical criteria for diagnosis, although sets of criteria have been proposed for research purposes. A prevailing theory is that CTE is an inexorably progressive neurodegenerative disease within the molecular classification of the tauopathies. However, historical and recent evidence suggests that CTE, as it is presented in the literature, might not be pathologically or clinically progressive in a substantial percentage of people. At present, it is not known whether the emergence, course, or severity of clinical symptoms can be predicted by specific combinations of neuropathologies, thresholds for accumulation of pathology, or regional distributions of pathologies. More research is needed to determine the extent to which the neuropathology ascribed to long-term effects of neurotrauma is static, progressive, or both. Disambiguating the pathology from the broad array of clinical features that have been reported in recent studies might facilitate and accelerate research- and improve understanding of CTE.
Keywords: Chronic Traumatic Encephalopathy; Cognition Disorders; Disease Progression; Gait Disorders, Neurologic; Humans; Neurodegenerative Diseases; Neuropathology; Tremor

NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity. - Garzón, Fernando; Coimbra, Débora; Parcerisas, Antoni; Rodriguez, Yamila; García, Julio Cesar; Soriano, Eduardo; Rama, Ramón (J Alzheimers Dis, 2018)
Many experimental studies show that erythropoietin (EPO) has a neuroprotective action in the brain. EPO in acute and chronic neurological disorders, particularly in stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, has neuroprotective effects. We previously reported the neuroprotective effect of NeuroEPO, a low sialic form of EPO, against oxidative stress induced by glutamate excitotoxicity. In this paper, we analyze the effect of NeuroEPO against apoptosis induced by glutamate excitotoxicity in primary neuronal cultures obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a culture medium containing 100μM glutamate for 15 min. To withdraw glutamate, a new medium containing 100 ng NeuroEPO/mL was added. Apoptosis was analyzed after 24 h. Images obtained by phase contrast microscopy show that neurons treated with glutamate exhibit cell body shrinkage, loss of dendrites that do not make contact with neighboring cells, and that NeuroEPO was able to preserve the morphological characteristics of the control. Immunocytochemistry images show that the culture is essentially pure in neurons; that glutamate causes cell mortality, and that this is partially avoided when the culture medium is supplemented with NeuroEPO. Activation of intrinsic apoptotic pathways was analyzed. The decreases in Bcl-2/Bax ratio, increase in the release of cytochrome c, and in the expression and activity of caspase-3 observed in cells treated with glutamate, were restored by NeuroEPO. The results from this study show that NeuroEPO protects cortical neurons from glutamate-induced apoptosis via upregulation of Bcl-2 and inhibit glutamate-induced activation of caspase-3.

Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease. - Ehrenberg, Alexander J; Suemoto, Claudia K; França Resende, Elisa de Paula; Petersen, Cathrine; Leite, Renata Elaine Paraizo; Rodriguez, Roberta Diehl; Ferretti-Rebustini, Renata Eloah de Lucena; You, Michelle; Oh, Jun; Nitrini, Ricardo; Pasqualucci, Carlos Augusto; Jacob-Filho, Wilson; et al. (J Alzheimers Dis, 2018)
Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer's Disease: A Case Report. - Eikelboom, Willem S; van Rooij, Jeroen G J; van den Berg, Esther; Coesmans, Michiel; Jiskoot, Lize C; Singleton, Ellen; Ossenkoppele, Rik; van Swieten, John C; Seelaar, Harro; Papma, Janne M (J Alzheimers Dis, 2018)
Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the underrecognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy. - Hernández, Félix; Llorens-Martín, María; Bolós, Marta; Pérez, Mar; Cuadros, Raquel; Pallas-Bazarra, Noemí; Zabala, Juan C; Avila, Jesús (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia.

A Nomogram for Predicting Amyloid PET Positivity in Amnestic Mild Cognitive Impairment. - Kim, Si Eun; Woo, Sookyoung; Kim, Seon Woo; Chin, Juhee; Kim, Hee Jin; Lee, Byung In; Park, Jinse; Park, Kyung Won; Kang, Do-Young; Noh, Young; Ye, Byoung Seok; Yoo, Han Soo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Most clinical trials focus on amyloid-β positive (Aβ+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aβ PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aβ biomarker. OBJECTIVE: We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE) genotype between Aβ+ aMCI and Aβ-aMCI and to develop a clinically useful prediction model of Aβ positivity on PET (PET-Aβ+) in aMCI using a nomogram. METHODS: We recruited 523 aMCI patients who underwent Aβ PET imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aβ+ in aMCI patients was constructed using a logistic regression model. RESULTS: PET-Aβ+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOEɛ4 (OR 4.14, p < 0.001) was associated with PET-Aβ+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation. CONCLUSIONS: The nomogram consisting of NP profiles, especially memory domain, and APOEɛ4 genotype may provide a useful predictive model of PET-Aβ+ in patients with aMCI.

The Novel DA-CH3 Dual Incretin Restores Endoplasmic Reticulum Stress and Autophagy Impairments to Attenuate Alzheimer-Like Pathology and Cognitive Decrements in the APPSWE/PS1ΔE9 Mouse Model. - Panagaki, Theodora; Gengler, Simon; Holscher, Christian (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE/PS1ΔE9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE/PS1ΔE9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration. - Piaceri, Irene; Imperiale, Daniele; Ghidoni, Enrico; Atzori, Cristiana; Bagnoli, Silvia; Ferrari, Camilla; Ungari, Silvana; Ambrogio, Luca; Sorbi, Sandro; Nacmias, Benedetta (J Alzheimers Dis, 2018)
BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research. OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). METHODS: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. RESULTS: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature. CONCLUSION: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase. - Lauretti, Elisabetta; Praticò, Domenico (J Alzheimers Dis, 2018)
Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies.

Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. - Popelová, Andrea; Pražienková, Veronika; Neprašová, Barbora; Kasperová, Barbora Judita; Hrubá, Lucie; Holubová, Martina; Zemenová, Jana; Blum, David; Železná, Blanka; Galas, Marie-Christine; Kuneš, Jaroslav; Maletínská, Lenka (J Alzheimers Dis, 2018)
Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.

Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review. - Solfrizzi, Vincenzo; Agosti, Pasquale; Lozupone, Madia; Custodero, Carlo; Schilardi, Andrea; Valiani, Vincenzo; Sardone, Rodolfo; Dibello, Vittorio; Di Lena, Luca; Lamanna, Angela; Stallone, Roberta; Bellomo, Antonello; et al. (J Alzheimers Dis, 2018)
The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014-2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect.

Nutritional Intervention to Prevent Alzheimer's Disease: Potential Benefits of Xanthophyll Carotenoids and Omega-3 Fatty Acids Combined. - Nolan, John M; Mulcahy, Riona; Power, Rebecca; Moran, Rachel; Howard, Alan N (J Alzheimers Dis, 2018)
BACKGROUND: A growing body of scientific evidence suggests that enrichment of certain nutritional compounds in the brain may reduce the risk of Alzheimer's disease (AD). OBJECTIVE: To investigate the impact of supplemental xanthophyll carotenoids plus omega-3 fatty acids on disease progression in patients with AD. METHODS: Three trial experiments were performed. In Trials 1 and 2 (performed on patients with AD over an 18-month period), 12 patients (AD status at baseline: 4 mild and 8 moderate) were supplemented with a xanthophyll carotenoid only formulation (Formulation 1; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day) and 13 patients (AD status at baseline: 2 mild, 10 moderate, and 1 severe) were supplemented with a xanthophyll carotenoid and fish oil combination (Formulation 2; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day plus 1 g/day of fish oil containing 430 mg docohexaenoic acid [DHA] and 90 mg eicopentaenoic acid [EPA]), respectively. In Trial 3, 15 subjects free of AD (the control group) were supplemented for 6 months with Formulation 1. Blood xanthophyll carotenoid response was measured in all trials by HPLC. Omega-3 fatty acids were profiled by direct infusion mass spectrometry. RESULTS: Xanthophyll carotenoid concentration increases were significantly greater for Formulation 2 compared to Formulation 1 (p < 0.05), and progression of AD was less for this group (p = 0.003), with carers reporting functional benefits in memory, sight, and mood. CONCLUSION: This preliminary report suggests positive outcomes for patients with AD who consumed a combination of xanthophyll carotenoids plus fish oil, but further study is required to confirm this important observation.

Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer's Disease. - Choi, Hojin; Yang, YoungSoon; Han, Hyun Jeong; Jeong, Jee Hyang; Park, Mee Young; Kim, Yong Bum; Jo, Kwang Deog; Choi, Jin-Yong; Kang, Kyung-Hun; Kang, Heeyoung; Kwon, Do-Young; Yoo, Bong-Goo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. OBJECTIVE: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. METHODS: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. RESULTS: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. CONCLUSION: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status.

Odor Identification Ability Predicts PET Amyloid Status and Memory Decline in Older Adults. - Kreisl, William Charles; Jin, Peng; Lee, Seonjoo; Dayan, Ezra R; Vallabhajosula, Shankar; Pelton, Gregory; Luchsinger, Jose A; Pradhaban, Gnanavalli; Devanand, D P (J Alzheimers Dis, 2018)
BACKGROUND: Odor identification deficits occur in Alzheimer's disease (AD), as measured by the 40-item University of Pennsylvania Smell Identification Test (UPSIT). OBJECTIVE: To determine if UPSIT scores predict amyloid-β (Aβ) status, determined by 11C-Pittsburgh Compound B PET. We also compared UPSIT scores to Aβ status in predicting future memory decline. METHODS: Subjects were recruited into a longitudinal clinical prediction study. We analyzed data from those who had UPSIT, cognitive testing, PIB PET, and at least 12 months' clinical follow-up. Forty-six amnestic mild cognitive impairment patients and 25 cognitively normal controls were included. Amyloid-positivity was defined as composite PIB standardized uptake value ratio >1.5. Logistic regression and Receiver Operating Characteristic Curve analyses tested the predictive utility of impaired olfaction (defined as UPSIT score <35) and amyloid-positivity for memory decline. RESULTS: High UPSIT scores predicted absence of amyloidosis on PET, with negative predictive value of 100%. Positive predictive value of low UPSIT scores on positive Aβ status was only 41%. Both low UPSIT score (OR = 4.301, 95% CI = 1.248, 14.821, p = 0.021) and positive PET scan (OR = 20.898, 95% CI = 2.222, 196.581, p = 0.008) predicted memory decline. CONCLUSION: Individuals with high UPSIT scores are less likely to have cerebral amyloidosis or experience memory decline. Therefore, UPSIT has potential as a screening tool to determine utility of Aβ PET in clinical practice or enrollment in clinical trials. Low UPSIT score is a non-specific marker of neurodegeneration that could indicate further workup in patients with memory complaints.

Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease. - Wezyk, Michalina; Szybinska, Aleksandra; Wojsiat, Joanna; Szczerba, Marcelina; Day, Kelly; Ronnholm, Harriet; Kele, Malin; Berdynski, Mariusz; Peplonska, Beata; Fichna, Jakub Piotr; Ilkowski, Jan; Styczyńska, Maria; et al. (J Alzheimers Dis, 2018)
The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Oxidative Stress in Elderly with Different Cognitive Status: My Mind Project. - Fattoretti, Patrizia; Malavolta, Marco; Fabbietti, Paolo; Papa, Roberta; Giacconi, Robertina; Costarelli, Laura; Galeazzi, Roberta; Paoloni, Cristina; Postacchini, Demetrio; Lattanzio, Fabrizia; Giuli, Cinzia (J Alzheimers Dis, 2018)
BACKGROUND: Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVE: The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training ("My Mind Project"). METHODS: A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable. RESULTS: We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM. CONCLUSIONS: Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias.

Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. - Robinson, Andrew C; Davidson, Yvonne S; Horan, Michael A; Pendleton, Neil; Mann, David M A (J Alzheimers Dis, 2018)
The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

PCSK9 Concentrations in Cerebrospinal Fluid Are Not Specifically Increased in Alzheimer's Disease. - Courtemanche, Hélène; Bigot, Edith; Pichelin, Matthieu; Guyomarch, Béatrice; Boutoleau-Bretonnière, Claire; Le May, Cédric; Derkinderen, Pascal; Cariou, Bertrand (J Alzheimers Dis, 2018)
The role of PCSK9 in Alzheimer's disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n = 20) compared to patients without neurodegenerative disorders (non-ND, n = 11): 2.80 versus 2.30 (p < 0.005) and 2.83 versus 2.30 ng/mL (p = NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42, T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders rather than specifically in AD.

Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer's Disease. - Laugisch, Oliver; Johnen, Andreas; Maldonado, Alejandra; Ehmke, Benjamin; Bürgin, Walter; Olsen, Ingar; Potempa, Jan; Sculean, Anton; Duning, Thomas; Eick, Sigrun (J Alzheimers Dis, 2018)
BACKGROUND: Recent studies suggest a link between periodontitis and Alzheimer's disease (AD). OBJECTIVE: Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD). METHODS: Clinical periodontal indices were recorded. Cerebrospinal fluid (CSF) was analyzed for total tau protein (T-tau) and amyloid-β (Aβ1-42). In serum and CSF, antibody levels against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Treponema species were quantified. The presence of selected bacteria and inflammatory biomarkers were determined in periodontium, serum, and CSF. RESULTS: In line with diagnoses, CSF-levels of Aβ1-42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis, T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2. CONCLUSION: Periodontal pathogens may enter the brain and stimulate a local immune response. However, in patients with dementia at the age up to 70 years, periodontal pathogens do not act as a trigger for developing AD.

Personality Modulates the Efficacy of Art Intervention on Chronic Pain in a Population of Patients with Alzheimer's Disease. - Rouch, Isabelle; Pongan, Elodie; Leveque, Yohana; Tillmann, Barbara; Trombert, Béatrice; Getenet, Jean Claude; Auguste, Nicolas; Krolak-Salmon, Pierre; Laurent, Bernard; Dorey, Jean-Michel (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) mainly occurs in elderly individuals. Comorbidities and chronic pain are frequent in this population. Previous studies revealed that personality modulates both chronic pain (CP) andADoccurrence and evolution. Moreover, as pain treatments can induce side-effects, non-drugs treatments, such as art interventions, are interesting alternative therapies for decreasing CP in these patients. OBJECTIVE: Our aim was to assess the potential role of personality traits on art intervention efficacy for reducing CP in a population of patients with mild AD. METHODS: Design: multicenter randomized controlled trial. Fifty mild AD patients underwent a 12-week art intervention including singing and painting groups. Personality was assessed with the Big Five Inventory before the sessions. CP was measured with Numeric Rating Scale (NRS) [Usual pain (NRS-U) and most Intense pain (NRS-I)], Simple Visual Scale [Usual pain (SVS-U) and most Intense pain (SVS-I)] and Brief Pain Inventory (BPI) before and after the sessions. The influence of personality traits on CP evolution before and after art intervention was assessed with multiple linear regression models. RESULTS: A positive association was observed between neuroticism and the evolution of three CP measures including NRS-U (B = 0.34, p = 0.01), SVS-U (B = 0.20, p = 0.04), and BPI-U (B = 0.46, p = 0.02) evolution. No significant relationship was observed between neuroticism and NRS-I, SVS-I and BPI-R evolution. CONCLUSIONS: Our findings suggest that neuroticism can decrease the efficacy of group art intervention on pain in patients with mild AD. Individual therapies could be more appropriate for these patients. These results emphasize the interest of taking into account patients' personality before proposing them to participate to a group therapy.

Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People. - Kennedy, Greg; Meyer, Denny; Hardman, Roy J; Macpherson, Helen; Scholey, Andrew B; Pipingas, Andrew (J Alzheimers Dis, 2018)
BACKGROUND: Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. OBJECTIVE: To investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition. METHODS: Residents of independent living facilities, aged 60-90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. RESULTS: Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation. CONCLUSIONS: Greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline.

PICALM Gene Methylation in Blood of Alzheimer's Disease Patients Is Associated with Cognitive Decline. - Mercorio, Roberta; Pergoli, Laura; Galimberti, Daniela; Favero, Chiara; Carugno, Michele; Dalla Valle, Elisabetta; Barretta, Francesco; Cortini, Francesca; Scarpini, Elio; Valentina, Valentina Bollati; Pesatori, Angela Cecilia (J Alzheimers Dis, 2018)
Epigenetic mechanisms might be involved in Alzheimer's disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change - 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development.

Possible Role of Chitin-Like Proteins in the Etiology of Alzheimer's Disease. - Lomiguen, Christine; Vidal, Luis; Kozlowski, Piotr; Prancan, Arthur; Stern, Robert (J Alzheimers Dis, 2018)
Chitin is a β-linked straight chain carbohydrate matrix monopolymer prominent in invertebrates, from fungi to arthropods. Surprisingly, chitin is now documented in vertebrates, including humans, a component of vertebrate physiology that has been neglected until now. Chitin levels are elevated in Alzheimer's disease (AD) patients, not only in the central nervous system but also in the cerebrospinal fluid and plasma. Elevated levels of chitin lectin have been reported in patients with AD. Chitinase activity varies widely in the human population. Chitin levels can increase in individuals with intrinsically low chitinase activity. Elevated amounts of chitin can reflect accumulation of the small chitin fragments that remain wherever rapid hyaluronan synthesis occurs. Another source of chitin may be from remote fungal infections. Chitin can be toxic for neurons, and its accumulation may lead to the development of AD. We present new suggestions for animal models and treatment modalities that could prove useful in future research endeavors. An unexpected connection with Gaucher's disease patients and their heterozygote relatives is also identified. These chitin-related mechanisms are novel approaches to AD whose etiology until now has defied explication.

Potential Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease. - Drummond, Eleanor; Goñi, Fernando; Liu, Shan; Prelli, Frances; Scholtzova, Henrieta; Wisniewski, Thomas (J Alzheimers Dis, 2018)
There is growing genetic and proteomic data highlighting the complexity of Alzheimer's disease (AD) pathogenesis. Greater use of unbiased "omics" approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. We highlight our recent efforts to increase use of human tissue to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity. These therapeutic approaches include the blocking of the Aβ/apoE interaction, stimulation of innate immunity, and the simultaneous blocking of Aβ/tau oligomer toxicity. We believe that future successful therapeutic approaches will need to be combined to better reflect the complexity of the abnormal pathways triggered in AD pathogenesis.

Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers. - Marizzoni, Moira; Ferrari, Clarissa; Jovicich, Jorge; Albani, Diego; Babiloni, Claudio; Cavaliere, Libera; Didic, Mira; Forloni, Gianluigi; Galluzzi, Samantha; Hoffmann, Karl-Titus; Molinuevo, José Luis; Nobili, Flavio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. OBJECTIVE: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. METHODS: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. RESULTS: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). CONCLUSION: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

Prediction of Alzheimer's Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status. - Lange, Catharina; Suppa, Per; Pietrzyk, Uwe; Makowski, Marcus R; Spies, Lothar; Peters, Oliver; Buchert, Ralph (J Alzheimers Dis, 2018)
The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloidosis; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Imaging, Three-Dimensional; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Survival Analysis; tau Proteins

Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. - Sinai, Amanda; Mokrysz, Claire; Bernal, Jane; Bohnen, Ingrid; Bonell, Simon; Courtenay, Ken; Dodd, Karen; Gazizova, Dina; Hassiotis, Angela; Hillier, Richard; McBrien, Judith; McCarthy, Jane; et al. (J Alzheimers Dis, 2018)
BACKGROUND: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer's disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade. OBJECTIVE: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these. METHODS: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated. RESULTS: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment. CONCLUSION: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.
Keywords: Age of Onset; Alzheimer Disease; Down Syndrome; England; Female; Humans; Male; Middle Aged; Risk Factors; Survival Analysis

Preserved Structural Network Organization Mediates Pathology Spread in Alzheimer's Disease Spectrum Despite Loss of White Matter Tract Integrity. - Powell, Fon; Tosun, Duygu; Sadeghi, Roksana; Weiner, Michael; Raj, Ashish (J Alzheimers Dis, 2018)
Models of Alzheimer's disease (AD) hypothesize stereotyped progression via white matter (WM) fiber connections, most likely via trans-synaptic transmission of toxic proteins along neuronal pathways. An important question in the field is whether and how organization of fiber pathways is affected by disease. It remains unknown whether fibers act as conduits of degenerative pathologies, or if they also degenerate with the gray matter network. This work uses graph theoretic modeling in a longitudinal design to investigate the impact of WM network organization on AD pathology spread. We hypothesize if altered WM network organization mediates disease progression, then a previously published network diffusion model will yield higher prediction accuracy using subject-specific connectomes in place of a healthy template connectome. Neuroimaging data in 124 subjects from ADNI were assessed. Graph topology metrics show preserved network organization in patients compared to controls. Using a published diffusion model, we further probe the effect of network alterations on degeneration spread in AD. We show that choice of connectome does not significantly impact the model's predictive ability. These results suggest that, despite measurable changes in integrity of specific fiber tracts, WM network organization in AD is preserved. Further, there is no difference in the mediation of putative pathology spread between healthy and AD-impaired networks. This conclusion is somewhat at variance with previous results, which report global topological disturbances in AD. Our data indicates the combined effect of edge thresholding, binarization, and inclusion of subcortical regions to network graphs may be responsible for previously reported effects.

Prevalence and Determinants of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population-Based DelpHi-Study. - Thyrian, Jochen René; Hertel, Johannes; Schulze, Lara N; Dörr, Marcus; Prüss, Harald; Hempel, Petra; Bimmler, Marion; Kunze, Rudolf; Grabe, Hans Jörgen; Teipel, Stefan; Hoffmann, Wolfgang (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

Prevalence of Delirium in a Population of Elderly Outpatients with Dementia: A Retrospective Study. - Addesi, Desirée; Maio, Raffaele; Smirne, Nicoletta; Laganà, Valentina; Altomari, Natalia; Puccio, Gianfranco; Colao, Rosanna; Cupidi, Chiara; Perticone, Francesco; Bruni, Amalia Cecilia (J Alzheimers Dis, 2018)
BACKGROUND: Delirium is a multifactorial geriatric syndrome and often occurs in patients with cognitive impairment. It also remains under-recognized, specifically in elderly outpatients, because signs of delirium might overlap with symptoms of dementia. OBJECTIVE: The aim of the present study is to retrospectively apply the chart-based delirium instrument on a cohort of elderly outpatients with dementia, to assess prevalence and features of delirium in this population. METHODS: We randomly selected 650 medical records of outpatients referred to the "Neurogenetic Regional Centre" (CRN) of Lamezia Terme. Each evaluation included demographics, medical history, drugs, type and severity of dementia, and cognitive and functional status. Delirium was identified by the application of the chart-based delirium instrument. RESULTS: The prevalence of delirium was 13.3%. The study population was divided, according to the presence of delirium, into two subgroups. Compared to the no delirium group, the delirium group was significantly older and had greater cognitive impairment with lower MMSE scores both at baseline and at the end of the follow up. They also had a significant lower score on the ADL and IADL. In this group, a higher intake of antihypertensive and antipsychotic drugs, together with a lower intake of cholinesterase inhibitors and memantine, was observed. CONCLUSIONS: In this study, the chart-based delirium instrument was applied to an outpatient population affected by dementia and followed for a long time. Our data confirm the importance that age and frailty play on the genesis of delirium and suggest attention should be paid to the pharmacological treatment of these patients.
Keywords: Aged; Aged, 80 and over; Antipsychotic Agents; Cohort Studies; Delirium; Dementia; Female; Geriatric Assessment; Humans; Male; Outpatients; Prevalence; Severity of Illness Index

Prevalence of Dementia and Associated Risk Factors: A Population-Based Study in the Philippines. - Dominguez, Jacqueline; Fe de Guzman, Ma; Reandelar, Macario; Thi Phung, Thien Kieu (J Alzheimers Dis, 2018)
BACKGROUND: The Philippines is experiencing rapid demographic aging and with it, the dementia epidemic. Prevalence of dementia and associated risk factors have not been studied in the Philippines. OBJECTIVES: The study aimed to provide a reliable estimate of dementia prevalence and identify associated risk factors in the Filipino population. METHODS: 1460 participants 60 years and older were randomly selected from the Marikina City's senior registry. A multidisciplinary team (nurse, psychologist, and neurologist) administered a comprehensive assessment to the study population: health history, neurological examination, Geriatric Depression Scale, Neuropsychiatric Inventory, Disability Assessment for Dementia, Alzheimer's Disease 8, and Clinical Dementia Rating Scale. The neurologist analyzed all clinical data to diagnose dementia based on the DSM-IV criteria, Alzheimer's Disease (AD) on the NINCDS-ADRDA criteria, vascular dementia (VaD) on the Hachinski Ischemic Scale, cognitive impairment no dementia (CIND) on a CDR score of 0.5 and not fulfilling DSM-IV criteria for dementia. Risk factors were correlated with dementia prevalence using multivariate binary logistic regression. RESULTS: 1460 persons were randomly selected. 1367 agreed to participate and underwent all assessments. The response rate was 93.6%. Dementia prevalence was found to be 10.6% (95% CI 9.0 to 12.4) with the breakdown 85.5% AD, 11.7% VaD, and 2.7% other dementias. In this population, 82.0% of men and 70.4% of women had at least one cardiovascular risk factor (hypertension, diabetes, dyslipidemia, smoking), which was associated with VaD prevalence but not AD. CONCLUSION: The prevalence of dementia, CIND, and cardiovascular risk factors are high in the Philippines.

Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review. - Hodges, John R; Piguet, Olivier (J Alzheimers Dis, 2018)
The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking.

Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics. - Eldholm, Rannveig Sakshaug; Barca, Maria Lage; Persson, Karin; Knapskog, Anne-Brita; Kersten, Hege; Engedal, Knut; Selbæk, Geir; Brækhus, Anne; Skovlund, Eva; Saltvedt, Ingvild (J Alzheimers Dis, 2018)
BACKGROUND: The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. OBJECTIVE: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). METHODS: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. RESULTS: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. CONCLUSION: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Disease Progression; Female; Humans; Linear Models; Longitudinal Studies; Male; Memory; Neuropsychological Tests; Norway

The Progression of Dementia and Cognitive Decline in a Dutch 2-Year Cohort Study of People with Young-Onset Dementia. - Gerritsen, Adrie A J; Bakker, Christian; Verhey, Frans R J; Bor, Hans; Pijnenburg, Yolande A L; de Vugt, Marjolein E; Koopmans, Raymond T C M (J Alzheimers Dis, 2018)
BACKGROUND: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown. OBJECTIVE: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course. METHODS: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types. RESULTS: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001). CONCLUSION: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function.

Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression. - Scheltens, Nienke M E; Tijms, Betty M; Heymans, Martijn W; Rabinovici, Gil D; Cohn-Sheehy, Brendan I; Miller, Bruce L; Kramer, Joel H; Wolfsgruber, Steffen; Wagner, Michael; Kornhuber, Johannes; Peters, Oliver; Scheltens, Philip; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is a heterogeneous disorder. OBJECTIVE: To investigate whether cognitive AD subtypes are associated with different rates of disease progression. METHODS: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. RESULTS: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05). CONCLUSIONS: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease. - Reddy, P Hemachandra; Manczak, Maria; Yin, XiangLing; Grady, Mary Catherine; Mitchell, Andrew; Tonk, Sahil; Kuruva, Chandra Sekhar; Bhatti, Jasvinder Singh; Kandimalla, Ramesh; Vijayan, Murali; Kumar, Subodh; Wang, Rui; et al. (J Alzheimers Dis, 2018)
The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Curcumin; Disease Models, Animal; Humans; Mice; Neuroprotective Agents; Randomized Controlled Trials as Topic; Spices

Putative Gonadotropin-Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data. - Smith, Mark A; Bowen, Richard L; Nguyen, Richard Q; Perry, George; Atwood, Craig S; Rimm, Alfred A (J Alzheimers Dis, 2018)
BACKGROUND: Estrogen and hormone replacement therapies to reduce Alzheimer's disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population. OBJECTIVE: To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management. METHODS: Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n = 115,789) were compared to three control groups: men of the same demographics undergoing a cholecystectomy (n = 97,267), herniorrhaphy (n = 68,778), or transurethral prostatectomy (n = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group. RESULTS: The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83. CONCLUSION: Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins.

Quality of Life, Care Resource Use, and Costs of Dementia in 8 European Countries in a Cross-Sectional Cohort of the Actifcare Study. - Handels, Ron L H; Sköldunger, Anders; Bieber, Anja; Edwards, Rhiannon Tudor; Gonçalves-Pereira, Manuel; Hopper, Louise; Irving, Kate; Jelley, Hannah; Kerpershoek, Liselot; Marques, Maria J; Meyer, Gabriele; Michelet, Mona; et al. (J Alzheimers Dis, 2018)
BACKGROUND: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care. OBJECTIVE: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs. METHODS: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life (HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver's quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression. RESULTS: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers' utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately € 17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL. CONCLUSION: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care.

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. - Ramos de Matos, Mafalda; Ferreira, Catarina; Herukka, Sanna-Kaisa; Soininen, Hilkka; Janeiro, André; Santana, Isabel; Baldeiras, Ines; Almeida, Maria Rosário; Lleo, Alberto; Dols-Icardo, Oriol; Alcolea, Daniel; Benussi, Luisa; et al. (J Alzheimers Dis, 2018)
Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Quantitative Susceptibility Mapping of Amyloid-β Aggregates in Alzheimer's Disease with 7T MR. - Tiepolt, Solveig; Schäfer, Andreas; Rullmann, Michael; Roggenhofer, Elisabeth; Gertz, Hermann-Josef; Schroeter, Matthias L; Patt, Marianne; Bazin, Pierre-Louis; Jochimsen, Thies H; Turner, Robert; Sabri, Osama; Barthel, Henryk (J Alzheimers Dis, 2018)
BACKGROUND: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution. OBJECTIVE: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging. METHODS: Postmortem human Alzheimer's disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo, 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE. RESULTS: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus - 0.008±0.003 ppm, p < 0.001). In vivo, only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus - 0.009±0.009 ppm; left: 0.293±0.014 versus - 0.007±0.012 ppm, p < 0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r = - 0.69, p = 0.001). CONCLUSION: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology.

Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease. - Yan, Tingxiang; Wang, Luwen; Gao, Ju; Siedlak, Sandra L; Huntley, Mikayla L; Termsarasab, Pichet; Perry, George; Chen, Shu G; Wang, Xinglong (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

Rapidly Progressive Alzheimer's Disease: Contributions to Clinical-Pathological Definition and Diagnosis. - Abu-Rumeileh, Samir; Capellari, Sabina; Parchi, Piero (J Alzheimers Dis, 2018)
Rapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-β aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathologic, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinic-pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathologic data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group.

Rapidly Progressive Alzheimer's Disease in Two Distinct Autopsy Cohorts. - Pillai, Jagan A; Appleby, Brian S; Safar, Jiri; Leverenz, James B (J Alzheimers Dis, 2018)
BACKGROUND: A rapidly progressive phenotype of Alzheimer's disease (AD) has been described in some prion disease cohorts. Limited information regarding rapidly progressive AD (rpAD) is available from longitudinal national cohorts. OBJECTIVE: To compare the clinical characteristics of rpAD in two different national cohorts. METHODS: A retrospective analysis was performed on AD subjects with available neuropathology in the National Alzheimer's Coordinating Center (NACC) database and among neuropathologically characterized AD cases from the National Prion Disease Pathology Surveillance Center (NPDPSC) that were evaluated for suspected prion disease. In the NACC cohort, rpAD was delineated by the lower 10th percentile of follow up duration from pre-dementia to death duration among subjects meeting pathological diagnosis of AD. RESULTS: rpAD from the NPDPSC had a shorter mean symptom duration than the NACC identified rpAD cases (11.6 months versus 62.4 months) and were also younger at the time of their death (60.0 versus 81.8 years). NACC identified rpAD subjects, beginning from a predementia stage, had slower rate of MMSE change per year than NPDPSC cases (2.5 versus 6.0 points). CONCLUSIONS: rpAD constitute an important subset of AD subjects in whom a rapid course of symptomatic clinical decline is noted, as confirmed in both national cohorts. rpAD was best characterized by survival time (≤3 years), as there were clear differences between the rpAD cohorts in terms of symptom duration, age at death, and MMSE change per year, likely due to the strong selection biases. rpAD could shed light on the biology of rate of progression in AD.

The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial. - Kehoe, Patrick G; Blair, Peter S; Howden, Beth; Thomas, David L; Malone, Ian B; Horwood, Jeremy; Clement, Clare; Selman, Lucy E; Baber, Hannah; Lane, Athene; Coulthard, Elizabeth; Passmore, Anthony Peter; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression. OBJECTIVE: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR). METHODS: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables. RESULTS: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits. CONCLUSION: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.
Keywords: Activities of Daily Living; Alzheimer Disease; Antihypertensive Agents; Atrophy; Blood Pressure Monitors; Brain; Clinical Trials, Phase II as Topic; Disease Progression; Double-Blind Method; Female; Humans; Losartan; Magnetic Resonance Imaging; Male; Multivariate Analysis; Quality of Life; Randomized Controlled Trials as Topic; Regression Analysis; Renin-Angiotensin System

Real-World, Multinational, Retrospective Observational Survey of the ADAS-Cog and Associations with Healthcare Resource Utilization in Patients with Alzheimer's Disease. - Ritchie, Craig W; Khandker, Rezaul K; Pike, James; Black, Christopher M; Jones, Eddie; Ambegaonkar, Baishali M (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer's Disease Assessment Scale-Cognition subscale (ADAS-Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials. OBJECTIVE: This study evaluated the relationship between ADAS-Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU)-measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world. METHODS: A retrospective observational survey of physicians and their consulting patients with multiple ADAS-Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS-Cog rate of change, baseline ADAS-Cog, and their interaction included as exposure variables. RESULTS: 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS-Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p < 0.05; joint test) with increasing ADAS-Cog scores (indexing clinical deterioration). CONCLUSION: The results suggest that further understanding the relationship between HCRU and ADAS-Cog changes in real-world clinical practice could potentially provide a baseline upon which the success of disease-modifying, as well as newer symptomatic, dementia therapies can be judged.

Rethinking the Reserve with a Translational Approach: Novel Ideas on the Construct and the Interventions. - Serra, Laura; Gelfo, Francesca; Petrosini, Laura; Di Domenico, Carlotta; Bozzali, Marco; Caltagirone, Carlo (J Alzheimers Dis, 2018)
The concept of brain, cognitive, and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer's disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy.

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER). - Niemantsverdriet, Ellis; Ribbens, Annemie; Bastin, Christine; Benoit, Florence; Bergmans, Bruno; Bier, Jean-Christophe; Bladt, Roxanne; Claes, Lene; De Deyn, Peter Paul; Deryck, Olivier; Hanseeuw, Bernard; Ivanoiu, Adrian; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD). OBJECTIVE: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. METHODS: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. RESULTS: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. CONCLUSION: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

Risk Factors Associated with Cortical Thickness and White Matter Hyperintensities in Dementia Free Okinawan Elderly. - Silbert, Lisa C; Lahna, David; Promjunyakul, Nutta-On; Boespflug, Erin; Ohya, Yusuke; Higashiuesato, Yasushi; Nishihira, Junko; Katsumata, Yuriko; Tokashiki, Takashi; Dodge, Hiroko H (J Alzheimers Dis, 2018)
BACKGROUND: Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear. OBJECTIVE: The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly. METHODS: 96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers. RESULTS: Decreased MCT was associated with SBP 140 + (p = 0.029) and increased serum IL-6 (p = 0.036), HgbA1C (p = 0.002), and Cu (p = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p = 0.004) was associated with greater WMH volume. CONCLUSIONS: Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer's disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals.

Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. - Gulisano, Walter; Maugeri, Daniele; Baltrons, Marian A; Fà, Mauro; Amato, Arianna; Palmeri, Agostino; D'Adamio, Luciano; Grassi, Claudio; Devanand, D P; Honig, Lawrence S; Puzzo, Daniela; Arancio, Ottavio (J Alzheimers Dis, 2018)
The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

The Role of Cognitive Reserve in Alzheimer's Disease and Aging: A Multi-Modal Imaging Review. - Menardi, Arianna; Pascual-Leone, Alvaro; Fried, Peter J; Santarnecchi, Emiliano (J Alzheimers Dis, 2018)
Comforts in modern society have generally been associated with longer survival rates, enabling individuals to reach advanced age as never before in history. With the increase in longevity, however, the incidence of neurodegenerative diseases, especially Alzheimer's disease, has also doubled. Nevertheless, most of the observed variance, in terms of time of clinical diagnosis and progression, often remains striking. Only recently, differences in the social, educational and occupational background of the individual, as proxies of cognitive reserve (CR), have been hypothesized to play a role in accounting for such discrepancies. CR is a well-established concept in literature; lots of studies have been conducted in trying to better understand its underlying neural substrates and associated biomarkers, resulting in an incredible amount of data being produced. Here, we aimed to summarize recent relevant published work addressing the issue, gathering evidence for the existence of a common path across research efforts that might ease future investigations by providing a general perspective on the actual state of the arts. An innovative model is hereby proposed, addressing the role of CR across structural and functional evidences, as well as the potential implementation of non-invasive brain stimulation techniques in the causal validation of such theoretical frame.

The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. - Pasinetti, Giulio Maria; Singh, Risham; Westfall, Susan; Herman, Francis; Faith, Jeremiah; Ho, Lap (J Alzheimers Dis, 2018)
A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.

The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. - Alegret, Montserrat; Peretó, Mar; Pérez, Alba; Valero, Sergi; Espinosa, Ana; Ortega, Gemma; Hernandez, Isabel; Mauleón, Ana; Rosende-Roca, Maitee; Vargas, Liliana; Rodríguez-Gómez, Octavio; Abdelnour, Carla; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Early Diagnosis; Executive Function; Female; Humans; Language Tests; Logistic Models; Longitudinal Studies; Male; Middle Aged; Proportional Hazards Models; Sensitivity and Specificity; Spain

S-[18F]THK-5117-PET and [11C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies. - Leinonen, Ville; Rauramaa, Tuomas; Johansson, Jarkko; Bottelbergs, Astrid; Tesseur, Ina; van der Ark, Peter; Pemberton, Darrel; Koivisto, Anne M; Jääskeläinen, Juha E; Hiltunen, Mikko; Herukka, Sanna-Kaisa; Blennow, Kaj; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. OBJECTIVE: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy. METHODS: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging. RESULTS: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. CONCLUSIONS: S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

A Selection of Important Genes and Their Correlated Behavior in Alzheimer's Disease. - Cruz-Rivera, Yazeli E; Perez-Morales, Jaileene; Santiago, Yaritza M; Gonzalez, Valerie M; Morales, Luisa; Cabrera-Rios, Mauricio; Isaza, Clara E (J Alzheimers Dis, 2018)
In 2017, approximately 5 million Americans were living with Alzheimer's disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected (FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD.

Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. - Brown, Belinda M; Rainey-Smith, Stephanie R; Doré, Vincent; Peiffer, Jeremiah J; Burnham, Samantha C; Laws, Simon M; Taddei, Kevin; Ames, David; Masters, Colin L; Rowe, Christopher C; Martins, Ralph N; Villemagne, Victor L (J Alzheimers Dis, 2018)
Numerous animal studies have reported exercise reduces the accumulation of Alzheimer's disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into low-moderate PA (LMPA; n = 16) or high PA (HPA; n = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: - 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA.

Separating Symptomatic Alzheimer's Disease from Depression based on Structural MRI. - Klöppel, Stefan; Kotschi, Maria; Peter, Jessica; Egger, Karl; Hausner, Lucrezia; Frölich, Lutz; Förster, Alex; Heimbach, Bernhard; Normann, Claus; Vach, Werner; Urbach, Horst; Abdulkadir, Ahmed (J Alzheimers Dis, 2018)
Older patients with depression or Alzheimer's disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n = 28) or moderate and severe depression (n = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of AD versus depression. We found that our algorithm learned discriminative patterns in the subject's grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one-out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments.

Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms. - Brendel, Matthias; Sauerbeck, Julia; Greven, Sonja; Kotz, Sebastian; Scheiwein, Franziska; Blautzik, Janusch; Delker, Andreas; Pogarell, Oliver; Ishii, Kazunari; Bartenstein, Peter; Rominger, Axel (J Alzheimers Dis, 2018)
Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration. - Zanardini, Roberta; Benussi, Luisa; Fostinelli, Silvia; Saraceno, Claudia; Ciani, Miriam; Borroni, Barbara; Padovani, Alessandro; Binetti, Giuliano; Ghidoni, Roberta (J Alzheimers Dis, 2018)
Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.
Keywords: Aged; Biomarkers; C-Peptide; Female; Frontotemporal Lobar Degeneration; Ghrelin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Nicotinamide Phosphoribosyltransferase; Progranulins; Resistin

Serum Non-Ceruloplasmin Non-Albumin Copper Elevation in Mild Cognitive Impairment and Dementia due to Alzheimer's Disease: A Case Control Study. - Rozzini, Luca; Lanfranchi, Francesco; Pilotto, Andrea; Catalani, Simona; Gilberti, Maria Enrica; Paganelli, Matteo; Apostoli, Pietro; Padovani, Alessandro (J Alzheimers Dis, 2018)
Several studies showed high serum copper levels in Alzheimer's disease (AD). The present study applied a newly developed method to detect serum copper free from proteins (free-Cu). Forty-four patients affected by dementia due to AD, thirty-six patients affected by mild cognitive impairment (MCI) due to AD, and twenty-eight healthy controls underwent clinical, cognitive, and MRI assessment. The new method showed higher free-Cu concentrations in MCI and dementia due to AD compared to controls (p < 0.0001). No correlation between copper levels, cognitive or MRI measures were found.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Copper; Female; Humans; Magnetic Resonance Imaging; Male; Psychiatric Status Rating Scales

Severe Agitation in Dementia: An Explorative Secondary Data Analysis on the Prevalence and Associated Factors in Nursing Home Residents. - Palm, Rebecca; Sorg, Christian G G; Ströbel, Armin; Gerritsen, Debby L; Holle, Bernhard (J Alzheimers Dis, 2018)
BACKGROUND: The phenomena of severe agitation is not well understood and often not adequately treated. OBJECTIVE: This article determines the prevalence and associated factors of severe agitation in nursing home residents with dementia. METHODS: Secondary data analysis within an observational study in German nursing homes with n = 1,967 participants. We assessed severity of agitation with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and defined the construct of agitation as a composite score of the NPI-Q items agitation/aggression, disinhibition, and irritability/lability; the dependent variable of severe agitation was considered as being present in residents who scored 'severe' in at least one of these symptoms. A binary logistic regression model was calculated to estimate associations. RESULTS: The prevalence of severe agitation was 6.3% (n = 124). The strongest associations were found for elation/euphoria (OR 7.6, CI 3.1-18.5), delusions (OR 7.3, CI 4.0-13.2), apathy/indifference (OR 2.8, CI 1.7-4.7), anxiety (OR 2.2, CI 1.2-3.8), nighttime behaviors (OR 2.4, CI 1.4-4.2), motor disturbances (OR 2.4, CI 1.4-4.1), and male sex (OR 2.4. CI 1.3-4.2). CONCLUSION: Severe agitation in nursing home residents with dementia is a relevant clinical issue as approximately 70% of residents have a dementia. Residents with elation/euphoria and delusions may have a stronger risk of showing severe agitation. We consider delusions as a possible cause of agitation and therefore a prelude to agitation. Although it might be possible that elation/euphoria follows from agitation, we hypothesize that the residents first experience elation/ euphoria and exhibit agitation afterwards.

Short-Term Effects of Microglia-Specific Mitochondrial Dysfunction on Amyloidosis in Transgenic Models of Alzheimer's Disease. - Steffen, Johannes; Stenzel, Jan; Ibrahim, Saleh; Pahnke, Jens (J Alzheimers Dis, 2018)
Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer's disease. Mitochondrial damage and consequentially enhanced production of reactive oxygen species is particularly occurring in the vicinity of amyloid plaques. Since all cells are affected by mitochondrial damage, analyses of cell type-specific effects are challenging. To study the impact of mitochondrial alterations on microglial activity in a homogeneous genetic background, we generated bone marrow chimeras of irradiated 46-days-old APP-transgenic mice. For reconstitution, bone marrow from CX3CR1-eGFP mice with mitochondria of either non-obese diabetic or C57BL/6J animals was utilized. Successful reconstitution was evident in 100-day-old animals, by the presence of eGFP-positive cells in liver and spleen. In the brain, one-third of IBA1-positive microglia cells were newly recruited eGFP-expressing cells. Although donor-derived microglia were equally located in the proximity of amyloid plaques, no difference was observed in either the amyloid level, total number, or microglial coverage of plaques. These results indicate that during this brief and early phase of amyloid deposition, beneficial mitochondrial alterations in the newly recruited third of microglial cells were not sufficient to affect the amyloidosis in APP-transgenic mice.

Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. - Bouts, Mark J R J; Möller, Christiane; Hafkemeijer, Anne; van Swieten, John C; Dopper, Elise; van der Flier, Wiesje M; Vrenken, Hugo; Wink, Alle Meije; Pijnenburg, Yolande A L; Scheltens, Philip; Barkhof, Frederik; Schouten, Tijn M; et al. (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

Social Dysfunction in Older Age and Relationships with Cognition, Depression, and Apathy: The GreatAGE Study. - Lozupone, Madia; Panza, Francesco; Piccininni, Marco; Copetti, Massimiliano; Sardone, Rodolfo; Imbimbo, Bruno P; Stella, Eleonora; D'Urso, Francesca; Barulli, Maria Rosaria; Battista, Petronilla; Grasso, Alessandra; Tortelli, Rosanna; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects. OBJECTIVE: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation. METHODS: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion. RESULTS: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

SORL1 Variants in Familial Alzheimer's Disease. - Gómez-Tortosa, Estrella; Ruggiero, María; Sainz, Ma José; Villarejo-Galende, Alberto; Prieto-Jurczynska, Cristina; Venegas Pérez, Begoña; Ordás, Carlos; Agüero, Pablo; Guerrero-López, Rosa; Pérez-Pérez, Julián (J Alzheimers Dis, 2018)
The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; LDL-Receptor Related Proteins; Male; Membrane Transport Proteins; Middle Aged; Mutation; Polymorphism, Single Nucleotide; Siblings; Spain

Spatial Navigation in the Elderly with Alzheimer's Disease: A Cross-Sectional Study. - Zanco, Marcos; Plácido, Jessica; Marinho, Valeska; Ferreira, José Vinicius; de Oliveira, Felipe; Monteiro-Junior, Renato; Barca, Maria; Engedal, Knut; Laks, Jerson; Deslandes, Andrea (J Alzheimers Dis, 2018)
BACKGROUND: Spatial navigation is a fundamental cognitive ability that allows an individual to maintain independence by facilitating the safe movement from one place to another. It emerges as one of the first deficits in patients with Alzheimer's disease (AD). OBJECTIVE: To compare spatial navigation performance in the healthy elderly and AD patients through use of the Floor Maze Test (FMT)- an easy-to-apply two-dimensional (2D) maze- and determine which cognitive and functional capacities were associated with performance in this task. METHODS: The FMT was administered to 24 AD patients and 36 healthy controls. Spatial navigation was evaluated through the FMT. Functional capacity was evaluated through the Senior Fitness Test battery of tests. Cognitive functions were evaluated through the Mini-Mental State Examination (MMSE), verbal fluency, digit span test, and the Rey Auditory Verbal Learning Test (RAVLT). RESULTS: The group with AD was significantly slower and presented more errors at all stages of the FMT. Planning Time (PT) performance was associated with cardiorespiratory resistance (Step test) and delayed memory according to the RAVLT (R2 = 0.395, p < 0.001). Performance in the Immediate Maze Time (IMT) and Delayed Maze Time (DMT) was associated with global cognitive status (MMSE) (R2 = 0.509) and delayed memory (R2 = 0.540). CONCLUSION: Patients with AD present significant spatial navigation deficits. Their performance on the FMT is influenced by cardiorespiratory capacity, memory, and global cognitive function. As exercise helps to improve executive function and functional capacity, future intervention studies should be carried out to analyze the possible effects of physical exercise on spatial navigation.

Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat. - Watremez, William; Jackson, Joshua; Almari, Bushra; McLean, Samantha L; Grayson, Ben; Neill, Joanna C; Fischer, Nicolas; Allouche, Ahmad; Koziel, Violette; Pillot, Thierry; Harte, Michael K (J Alzheimers Dis, 2018)
BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. OBJECTIVE: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. METHODS: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). RESULTS: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. CONCLUSION: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. - Ramanan, Vijay K; Przybelski, Scott A; Graff-Radford, Jonathan; Castillo, Anna M; Lowe, Val J; Mielke, Michelle M; Roberts, Rosebud O; Reid, Robert I; Knopman, David S; Jack, Clifford R; Petersen, Ronald C; Vemuri, Prashanthi (J Alzheimers Dis, 2018)
BACKGROUND: Statins have been proposed to reduce the risk of Alzheimer's disease (AD). OBJECTIVE: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia. METHODS: Methods: We analyzed neuroimaging biomarkers in 1,160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging. RESULTS: Statin-treated (5+ years of therapy) individuals had greater burden of mid-and late-life cardiovascular disease (p < 0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated with long-term statin exposure (p < 0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden. CONCLUSIONS: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group.

Stereological Quantification of Plaques and Tangles in Neocortex from Alzheimer's Disease Patients. - Madsen, Jes Buster; Folke, Jonas; Pakkenberg, Bente (J Alzheimers Dis, 2018)
We estimated by stereological methods the neocortical volume occupied by plaques and tangles in females dying with severe Alzheimer's disease (AD), age-matched female subjects with severe vascular dementia (VaD), and normal control brains. Stereological investigations include a uniform sampling of the tissue in the whole of neocortex and its subdivisions. Resultant volume estimates provide information about the overall burden of these two pathological changes and their volume fractions and allow for correlational studies between the pathological changes and factors such as the total neocortical neuronal cell numbers, dementia test scores, and age. We estimated the volume of plaques and tangles in the entire neocortex and frontal-, temporal-, parietal-, and occipital cortex in nine female AD brains, four female patients dying with VaD, and six neurologically normal female control brains using point-counting in uniform samples of neocortex. The volume occupied by plaques comprised approximately 1% of neocortex, while the neocortical tangles made up approximately 0.1% of neocortex of AD patients but were scarcely present in the other study groups. The individual tangle and plaque volumes did not correlate to the ultimate dementia score of the AD subjects, despite correlating with reduced neocortical volume. In neocortex of AD patients, the burden of plaques and tangles is much higher than that in patients with severe vascular dementia or normal older women but only occupy a small fraction of the neocortical volume.

Subtle Cognitive Impairment and Alzheimer's Disease-Type Pathological Changes in Cerebrospinal Fluid are Common Among Neurologically Healthy Subjects. - Haapalinna, Fanni; Kokki, Merja; Jääskeläinen, Olli; Hallikainen, Merja; Helisalmi, Seppo; Koivisto, Anne; Kokki, Hannu; Paajanen, Teemu; Penttinen, Janne; Pikkarainen, Maria; Rautiainen, Minna; Soininen, Hilkka; et al. (J Alzheimers Dis, 2018)
BACKGROUND: The neuropathology of Alzheimer's disease (AD) has previously been shown to be rather common among the elderly. OBJECTIVE: The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEɛ4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. METHODS: This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEɛ4 status were analyzed. RESULTS: Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. CONCLUSION: AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes.

Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. - Power, Rebecca; Coen, Robert F; Beatty, Stephen; Mulcahy, Riona; Moran, Rachel; Stack, Jim; Howard, Alan N; Nolan, John M (J Alzheimers Dis, 2018)
BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties. OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels. METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured. RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009). CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.
Keywords: Adult; Cognition; Dietary Supplements; Double-Blind Method; Executive Function; Female; Healthy Volunteers; Humans; Lutein; Macular Pigment; Male; Memory, Episodic; Middle Aged; Retina; Vision Tests; Zeaxanthins

Targeting Alzheimer's Disease at the Right Time and the Right Place: Validation of a Personalized Approach to Diagnosis and Treatment. - Gauthier, Serge; Ng, Kok Pin; Pascoal, Tharick A; Zhang, Hua; Rosa-Neto, Pedro (J Alzheimers Dis, 2018)
Cautious optimism is appropriate for a near future (five years) time frame for a number of drugs acting on the different pathophysiological components of Alzheimer's disease (amyloid deposition, tau hyperphosphorylation, neuroinflammation, vascular changes, to name the most important known so far). Since the relative weight of these components will be different between individuals and will even change over time for each individual, a 'one drug fit for all' approach is no longer defensible. Precision medicine using biomarkers in the diagnosis and treatment of Alzheimer's disease is the new strategy.

Tau Protein Dysfunction after Brain Ischemia. - Pluta, Ryszard; Ułamek-Kozioł, Marzena; Januszewski, Sławomir; Czuczwar, Stanisław J (J Alzheimers Dis, 2018)
Brain ischemia comprises blood-brain barrier, glial, and neuronal cells. The blood-brain barrier controls permeability of different substances and the composition of the neuronal cells 'milieu', which is required for their physiological functioning. Recent evidence indicates that brain ischemia itself and ischemic blood-brain barrier dysfunction is associated with the accumulation of neurotoxic molecules within brain tissue, e.g., different parts of amyloid-β protein precursor and changed pathologically tau protein. All these changes due to ischemia can initiate and progress neurodegeneration of the Alzheimer's disease-type. This review presents brain ischemia and ischemic blood-brain barrier as a trigger for tau protein alterations. Thus, we hypothesize that the changes in pattern of phosphorylation of tau protein are critical to microtubule function especially in neurons, and contribute to the neurodegeneration following brain ischemia-reperfusion episodes with Alzheimer's disease phenotype.

TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia. - Sahoo, Aradhana; Bejanin, Alexandre; Murray, Melissa E; Tosakulwong, Nirubol; Weigand, Stephen D; Serie, Amanda M; Senjem, Matthew L; Machulda, Mary M; Parisi, Joseph E; Boeve, Bradley F; Knopman, David S; Petersen, Ronald C; et al. (J Alzheimers Dis, 2018)
BACKGROUND: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. OBJECTIVE: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. METHODS: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. RESULTS: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. CONCLUSION: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

Testamentary Capacity Assessment Tool (TCAT): A Brief Instrument for Patients with Dementia. - Papageorgiou, Sokratis G; Voskou, Panagiota; Economou, Alexandra; Beratis, Ion; Douzenis, Athanasios (J Alzheimers Dis, 2018)
BACKGROUND: In current practice, it is common for the medical practitioner to assess a person's testamentary capacity (TC) and give evidence to the Courts about a potential will contest. TC is an advanced cognitive activity that is both situation- and task-specific. OBJECTIVE: The aim of the present study was the development of a brief, specialized instrument for TC assessment in patients with dementia. METHOD: We developed a short tool consisting of four subtests, assessing the person's core functions which are required for TC: memory (orientation, autobiographical memory and realistic perception of beneficiaries), absence of serious psychopathology, knowledge of financial parameters (value of assets, everyday life products, bills), and intention (vignettes, theory of mind). For its validation, we examined 64 outpatients from the Cognitive Disorders/Dementia Unit, 2nd Department of Behavioral Neurology, University of Athens. The decision of the expert served as the gold standard for the evaluation of TC. RESULTS: Of the 64 participants, 39 were judged by the expert as capable of TC and the remaining 25 as incapable. For the total scale (maximum score of 48), the best combination of sensitivity (82.6%) and specificity (100%) was obtained for a cut-off score of 32/33. Cronbach's alpha showed high levels of internal reliability for the scale (α= 0.86) and the point-biserial correlation coefficients showed high levels of criterion-related validity (rbp = 0.797, p < 0.001). CONCLUSION: The new instrument appears to be a reliable screening tool for the evaluation of TC in dementia, which can be used by both the expert and the non-expert. Further research is needed to confirm these promising findings.
Keywords: Adult; Aged; Cognition Disorders; Dementia; Female; Humans; Male; Memory; Mental Competency; Middle Aged; Neuropsychological Tests; Reproducibility of Results; Sensitivity and Specificity; Wills

Testing Hippocampal Memory in Prodromal Dementia with Lewy Bodies. - Bussè, Cinzia; Caffarra, Paolo; Rossi, Alice; Zorzi, Giovanni; Fragiacomo, Federica; Camporese, Giulia; Pompanin, Sara; Di Bernardo, Gian Antonio; Cagnin, Annachiara (J Alzheimers Dis, 2018)
The Free and Cued Selective Reminding test (FCSRT) was used to assess memory in 19 patients with prodromal dementia with Lewy bodies (DLB) and 25 Alzheimer's disease (AD) patients. DLB scored better than AD in selective measures of the FCSRT: immediate total recall (p = 0.01) and index of sensitivity of cueing (p = 0.001), while free delayed and total memory scores were similarly impaired. The index of sensitivity of cueing held a sensitivity of 76% and specificity of 79% in distinguishing DLB. FCSRT could help in disentangling hippocampal memory deficits from memory impairment due to ineffective recall strategies.

Three VCP Mutations in Patients with Frontotemporal Dementia. - Wong, Tsz Hang; Pottier, Cyril; Hondius, David C; Meeter, Lieke H H; van Rooij, Jeroen G J; Melhem, Shami; van Minkelen, Rick; van Duijn, Cornelia M; Rozemuller, Annemieke J M; Seelaar, Harro; Rademakers, Rosa; van Swieten, John C (J Alzheimers Dis, 2018)
Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype.

A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease. - Guzmán-Vélez, Edmarie; Jaimes, Sehily; Aguirre-Acevedo, Daniel C; Norton, Daniel J; Papp, Kathryn V; Amariglio, Rebecca; Rentz, Dorene; Baena, Ana; Henao, Eliana; Tirado, Victoria; Munoz, Claudia; Giraldo, Margarita; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. OBJECTIVE: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. METHODS: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). RESULTS: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. CONCLUSIONS: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

TLR4 Gene Expression and Pro-Inflammatory Cytokines in Alzheimer's Disease and in Response to Hippocampal Deafferentation in Rodents. - Miron, Justin; Picard, Cynthia; Frappier, Josée; Dea, Doris; Théroux, Louise; Poirier, Judes (J Alzheimers Dis, 2018)
One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (p = 0.001 and p = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p = 0.0367 and p = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p = 0.0055 and p = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process.

Trajectories of Physiological Brain Aging and Related Factors in People Aged from 20 to over-80. - Lee, Jin San; Kim, Seonwoo; Yoo, Heejin; Park, Seongbeom; Jang, Young Kyoung; Kim, Hee Jin; Kim, Ko Woon; Kim, Yeshin; Jang, Hyemin; Park, Key-Chung; Yaffe, Kristine; Yang, Jin-Ju; et al. (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: In this study, we investigated a long-term trajectory of brain aging (from the 20 s to over-80) in cognitively normal (CN) individuals. We further determined whether differences in sex, education years, and apolipoprotein E ε 4 status affect age-related cortical thinning. METHODS: A total of 2,944 CN individuals who underwent high-resolution (3.0-Tesla) magnetic resonance imaging were included in this study. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age-related cortical thinning and related factors. RESULTS: Compared to those in their 20 s/30 s, participants in their 40 s showed thinning primarily in the medial and lateral frontal and inferior parietal regions, and cortical thinning occurred across most of the cortices with increasing age. Notably, the precuneus, inferior temporal and lateral occipital regions were relatively spared until later in life. Male and lower education years were associated with greater cortical thinning with distinct regional specificity. CONCLUSION: Our findings provide an important clue to understanding the mechanism of age-related cognitive decline and new strategies for preventing the acceleration of pathological brain aging.

Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease. - Muthukumaran, Krithika; Kanwar, Annie; Vegh, Caleb; Marginean, Alexandra; Elliott, Austin; Guilbeault, Nicholas; Badour, Alexander; Sikorska, Marianna; Cohen, Jerome; Pandey, Siyaram (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Microglia; Mutation; Nerve Tissue Proteins; Peptide Fragments; Presenilin-1; Ubiquinone; Vitamins

Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration. - Santana, Isabel; Baldeiras, Ines; Santiago, Beatriz; Duro, Diana; Freitas, Sandra; Pereira, Miguel Tábuas; Almeida, Maria Rosário; Oliveira, Catarina Resende (J Alzheimers Dis, 2018)
The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer's disease (AD), but this mandatory "amyloid-first pathway" has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1-18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7-9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1-9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative "neurodegeneration-first pathway" for further investigation.

Understanding Epigenetics in the Neurodegeneration of Alzheimer's Disease: SAMP8 Mouse Model. - Griñán-Ferré, Christian; Corpas, Rubén; Puigoriol-Illamola, Dolors; Palomera-Ávalos, Verónica; Sanfeliu, Coral; Pallas, Merce (J Alzheimers Dis, 2018)
Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer's disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD.

Untold New Beginnings: Adult Hippocampal Neurogenesis and Alzheimer's Disease. - Teixeira, Catia M; Pallas-Bazarra, Noemí; Bolós, Marta; Terreros-Roncal, Julia; Avila, Jesús; Llorens-Martín, María (J Alzheimers Dis, 2018)
Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer's disease (AD). Adult hippocampal neurogenesis is a process that continuously gives rise to newborn granule neurons in the dentate gyrus. These cells coexist with developmentally generated granule neurons in this structure, and both cooperative and competition phenomena regulate the communication between these two types of cells. Importantly, it has been revealed that GSK-3β and tau proteins, which are two of the main players driving AD pathology, are cornerstones of adult hippocampal neurogenesis regulation. We have shown that alterations either promoting or impeding the actions of these two proteins have detrimental effects on the structural plasticity of granule neurons. Of note, these impairments occur both under basal conditions and in response to detrimental and neuroprotective stimuli. Thus, in order to achieve the full effectiveness of future therapies for AD, we propose that attention be turned toward identifying the pathological and physiological actions of the proteins involved in the pathogenesis of this condition.

Unusual Clinical Presentations Challenging the Early Clinical Diagnosis of Creutzfeldt-Jakob Disease. - Baiardi, Simone; Capellari, Sabina; Bartoletti Stella, Anna; Parchi, Piero (J Alzheimers Dis, 2018)
The introduction of prion RT-QuIC, an ultrasensitive specific assay for the in vivo detection of the abnormal prion protein, has significantly increased the potential for an early and accurate clinical diagnosis of Creutzfeldt-Jakob disease (CJD). However, in the clinical setting, the early identification of patients with possible CJD is often challenging. Indeed, CJD patients may present with isolated symptoms that remain the only clinical manifestation for some time, or with neurological syndromes atypical for CJD. To enhance awareness of unusual disease presentations and promote earlier diagnosis, we reviewed the entire spectrum of atypical early manifestations of CJD, mainly reported to date as case descriptions or small case series. They included sensory either visual or auditory disturbances, seizures, isolated psychiatric manifestations, atypical parkinsonian syndromes (corticobasal syndrome, progressive supranuclear palsy-like), pseudobulbar syndrome, isolated involuntary movements (dystonia, myoclonus, chorea, blepharospasm), acute or subacute onsets mimicking a stroke, isolated aphasia, and neuropathy. Since CJD is a rare disease and its clinical course rapidly progressive, an in-depth understanding and awareness of early clinical features are mandatory to enhance the overall diagnostic accuracy in its very early stages and to recruit optimal candidates for future therapeutic trials.

Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease. - Wallin, Anders; Román, Gustavo C; Esiri, Margaret; Kettunen, Petronella; Svensson, Johan; Paraskevas, George P; Kapaki, Elisabeth (J Alzheimers Dis, 2018)
Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.
Keywords: Animals; Cerebrovascular Disorders; Dementia; Humans

Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units. - Lage, Carmen; Suarez, Andrea Gonzalez; Pozueta, Ana; Riancho, Javier; Kazimierczak, Martha; Bravo, María; Jimenez Bonilla, Julio; de Arcocha Torres, Marıa; Quirce, Remedios; Banzo, Ignacio; Vázquez-Higuera, José Luis; Rabinovici, Gil D; et al. (J Alzheimers Dis, 2018)
The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study. - Porter, Tenielle; Burnham, Samantha C; Milicic, Lidija; Savage, Greg; Maruff, Paul; Lim, Yen Ying; Li, Qiao-Xin; Ames, David; Masters, Colin L; Rainey-Smith, Stephanie; Rowe, Christopher C; Salvado, Olivier; et al. (J Alzheimers Dis, 2018)
BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. OBJECTIVE: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. METHODS: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC). RESULTS: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Utility of the LIBRA Index in Relation to Cognitive Functioning in a Clinical Health Seeking Sample. - Pons, Anke; LaMonica, Haley M; Mowszowski, Loren; Köhler, Sebastian; Deckers, Kay; Naismith, Sharon L (J Alzheimers Dis, 2018)
BACKGROUND: Dementia prevalence is expected to increase substantially over the next few decades. Since there is currently no cure for dementia available, there is an urgent need for the early identification of individuals at high risk for dementia, so that primary and secondary prevention strategies can be implemented. Recently, the LIfestyle for BRAin health (LIBRA) index was developed as a new dementia risk algorithm. It specifically focuses on modifiable risk and protective factors that can be targeted in midlife. OBJECTIVE: The objective of this study was to evaluate the LIBRA index in relation to markers of cognitive functioning in a clinical, health-seeking sample of community-based older adults. METHODS: 484 participants (mean age 62.7 years) were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney. Participants underwent comprehensive clinical and neuropsychological assessment and completed a self-report survey pack. Participants were rated via consensus as having either subjective cognitive complaints (SCC) or meeting criteria for mild cognitive impairment (MCI). The LIBRA score was calculated based on 11 available risk and protective factors. RESULTS: 65.4% of the sample met criteria for MCI. People with MCI showed a significantly higher LIBRA score compared to people with SCC. Furthermore, multiple cognitive domains, in particular executive functioning, were associated with a higher LIBRA score, with stronger correlations in people with MCI. CONCLUSION: The LIBRA index might be a useful tool to determine lifestyle-attributable risk of cognitive decline in an older health-seeking population, including people with MCI.

Validation of the Spanish Version of the Dementia Knowledge Assessment Tool 2. - Parra-Anguita, Laura; Moreno-Cámara, Sara; López-Franco, María Dolores; Pancorbo-Hidalgo, Pedro L (J Alzheimers Dis, 2018)
BACKGROUND: There are currently no questionnaires to measure the knowledge of nurses about dementia or Alzheimer's disease care in the Spanish language. OBJECTIVE: To validate the Spanish version of the Dementia Knowledge Assessment Tool 2 (DKAT2-Sp). METHODS: The DKAT2 was translated into Spanish and then back-translated. The new Spanish version was validated in a sample of 361 members of the nursing staff from 24 nursing homes and a sample of 297 nursing students in Spain. Psychometric properties were assessed through an item analysis, a Rasch analysis, differential item functioning analysis, construct validity (known groups), and internal consistency (Cronbach's alpha). RESULTS: The 21 items of the DKAT2-Sp fit the model well, showing a wide range of difficulty. Four items have differential items functioning between nursing professionals and students. The DKAT2-Sp shows acceptable internal consistency (Cronbach's alpha = 0.76 for nursing professionals and 0.83 for students). Scores obtained in the known groups test were as hypothesized (Nursing home staff mean = 15.57 versus Nursing student mean = 12.85; p < 0.0001 for mean difference), supporting construct validity. CONCLUSION: The DKAT2-Sp is a reliable and valid questionnaire to measure knowledge about dementia in both nursing professionals and nursing students in Spanish-speaking contexts.

Visual Processing during Short-Term Memory Binding in Mild Alzheimer's Disease. - Fernández, Gerardo; Orozco, David; Agamennoni, Osvaldo; Schumacher, Marcela; Sañudo, Silvana; Biondi, Juan; Parra, Mario A (J Alzheimers Dis, 2018)
Patients with Alzheimer's disease (AD) typically present with attentional and oculomotor abnormalities that can have an impact on visual processing and associated cognitive functions. Over the last few years, we have witnessed a shift toward the analyses of eye movement behaviors as a means to further our understanding of the pathophysiology of common disorders such as AD. However, little work has been done to unveil the link between eye moment abnormalities and poor performance on cognitive tasks known to be markers for AD patients, such as the short-term memory-binding task. We analyzed eye movement fixation behaviors of thirteen healthy older adults (Controls) and thirteen patients with probable mild AD while they performed the visual short-term memory binding task. The short-term memory binding task asks participants to detect changes across two consecutive arrays of two bicolored object whose features (i.e., colors) have to be remembered separately (i.e., Unbound Colors), or combined within integrated objects (i.e., Bound Colors). Patients with mild AD showed the well-known pattern of selective memory binding impairments. This was accompanied by significant impairments in their eye movements only when they processed Bound Colors. Patients with mild AD remarkably decreased their mean gaze duration during the encoding of color-color bindings. These findings open new windows of research into the pathophysiological mechanisms of memory deficits in AD patients and the link between its phenotypic expressions (i.e., oculomotor and cognitive disorders). We discuss these findings considering current trends regarding clinical assessment, neural correlates, and potential avenues for robust biomarkers.

Walnut Supplementation in the Diet Reduces Oxidative Damage and Improves Antioxidant Status in Transgenic Mouse Model of Alzheimer's Disease. - Pandareesh, Mirazkar D; Chauhan, Ved; Chauhan, Abha (J Alzheimers Dis, 2018)
Our previous study has shown beneficial effects of walnuts on memory and learning skills in transgenic mouse model of Alzheimer's disease (AD-tg). To understand underlying mechanism, we studied here whether walnuts can reduce oxidative stress in AD. From 4 months of age, experimental AD-tg mice were fed diets containing 6% (T6) or 9% walnuts (T9) (equivalent to 1 or 1.5 oz, of walnuts per day in humans) for 5, 10, or 15 months. The control groups, i.e., AD-tg (T0) and wild-type (Wt) mice, were fed diets without walnuts. Free radicals, i.e., reactive oxygen species (ROS), lipid peroxidation, protein oxidation, and antioxidant enzymes were assessed in these mice at different ages. AD-tg mice on control diet (T0) showed significant age-dependent increase in ROS levels, lipid peroxidation, and protein oxidation coupled with impaired activities of antioxidant enzymes [superoxide dismutase, catalase, and glutathione peroxidase] compared to Wt mice. Oxidative stress was significantly reduced in AD-tg mice on diets with walnuts (T6, T9), as evidenced by decreased levels of ROS, lipid peroxidation, and protein oxidation, as well as by enhanced activities of antioxidant enzymes compared to T0 mice. Long-term supplementation with walnuts for 10 or 15 months was more effective in reducing oxidative stress in AD-tg mice. Our findings indicate that walnuts can reduce oxidative stress, not only by scavenging free radicals, but also by protecting antioxidant status, thus leading to reduced oxidative damage to lipids and proteins in AD. Therefore, by reducing oxidative stress, a walnut-enriched diet may help reduce the risk or delay the onset and progression of AD.

Word and Picture Version of the Free and Cued Selective Reminding Test (FCSRT): Is There Any Difference? - Arighi, Andrea; Carandini, Tiziana; Mercurio, Matteo; Carpani, Giovanni; Pietroboni, Anna Margherita; Fumagalli, Giorgio; Ghezzi, Laura; Basilico, Paola; Calvi, Alberto; Scarioni, Marta; De Riz, Milena; Fenoglio, Chiara; et al. (J Alzheimers Dis, 2018)
The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results.
Keywords: Aged; Aged, 80 and over; Association Learning; Cognitive Dysfunction; Cues; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Mental Recall; Middle Aged; Neuropsychological Tests; Photic Stimulation; Vocabulary

18F-AV-1451 PET Imaging in Three Patients with Probable Cerebral Amyloid Angiopathy. - Kim, Hee Jin; Cho, Hanna; Werring, David J; Jang, Young Kyoung; Kim, Yeo Jin; Lee, Jin San; Lee, Juyoun; Jun, Soomin; Park, Seongbeom; Ryu, Young Hoon; Choi, Jae Yong; Cho, Young Seok; et al. (J Alzheimers Dis, 2017)
Cerebrovascular deposition of amyloid-β, known as cerebral amyloid angiopathy (CAA), is associated with MRI findings of lobar hemorrhage, cerebral microbleeds, and cortical superficial siderosis. Although pathological studies suggest that tau may co-localize with vascular amyloid, this has not yet been investigated in CAA in vivo. Three patients with probable CAA underwent 11C-Pittsburgh Compound B (PiB) PET or 18F-florbetaben PET to evaluate amyloid burden, and 18F-AV-1451 PET to evaluate paired helical filament tau burden. Regions that had cerebral microbleeds or cortical superficial siderosis largely overlapped with those showing increased 18F-AV-1451. Our preliminary study raised the possibility that lobar cerebral microbleeds, and cortical superficial siderosis, which are characteristic markers of vascular amyloid, may be associated with local production of paired helical filament tau.
Keywords: Aged; Aged, 80 and over; Aniline Compounds; Brain; Carbolines; Cerebral Amyloid Angiopathy; Female; Humans; Image Processing, Computer-Assisted; Male; Positron-Emission Tomography; Thiazoles

A 24-Week Multi-Modality Exercise Program Improves Executive Control in Older Adults with a Self-Reported Cognitive Complaint: Evidence from the Antisaccade Task. - Heath, Matthew; Shellington, Erin; Titheridge, Sam; Gill, Dawn P; Petrella, Robert J (J Alzheimers Dis, 2017)
Exercise programs involving aerobic and resistance training (i.e., multiple-modality) have shown promise in improving cognition and executive control in older adults at risk, or experiencing, cognitive decline. It is, however, unclear whether cognitive training within a multiple-modality program elicits an additive benefit to executive/cognitive processes. This is an important question to resolve in order to identify optimal training programs that delay, or ameliorate, executive deficits in persons at risk for further cognitive decline. In the present study, individuals with a self-reported cognitive complaint (SCC) participated in a 24-week multiple-modality (i.e., the M2 group) exercise intervention program. In addition, a separate group of individuals with a SCC completed the same aerobic and resistance training as the M2 group but also completed a cognitive-based stepping task (i.e., multiple-modality, mind-motor intervention: M4 group). Notably, pre- and post-intervention executive control was examined via the antisaccade task (i.e., eye movement mirror-symmetrical to a target). Antisaccades are an ideal tool for the study of individuals with subtle executive deficits because of its hands- and language-free nature and because the task's neural mechanisms are linked to neuropathology in cognitive decline (i.e., prefrontal cortex). Results showed that M2 and M4 group antisaccade reaction times reliably decreased from pre- to post-intervention and the magnitude of the decrease was consistent across groups. Thus, multi-modality exercise training improved executive performance in persons with a SCC independent of mind-motor training. Accordingly, we propose that multiple-modality training provides a sufficient intervention to improve executive control in persons with a SCC.

A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer's Disease: Preliminary Results from a Neuroimaging Study. - Castellano, Christian-Alexandre; Paquet, Nancy; Dionne, Isabelle J; Imbeault, Hélène; Langlois, Francis; Croteau, Etienne; Tremblay, Sébastien; Fortier, Mélanie; Matte, J Jacques; Lacombe, Guy; Fülöp, Tamás; Bocti, Christian; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits. OBJECTIVE: To determine whether aerobic exercise training modifies brain energy metabolism in mild AD. METHODS: In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program. RESULTS: Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100 g/min; p = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2-3-fold (all p≤0.03). CMRglu was unchanged after Walking (28.0±0.1 μmol/100 g/min; p = 0.96). There was a tendency toward improvement in the Stroop-color naming test (-10% completion time, p = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p≤0.01). CONCLUSION: In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement.

Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study. - Babiloni, Claudio; Del Percio, Claudio; Lizio, Roberta; Noce, Giuseppe; Cordone, Susanna; Lopez, Susanna; Soricelli, Andrea; Ferri, Raffaele; Pascarelli, Maria Teresa; Nobili, Flavio; Arnaldi, Dario; Famá, Francesco; et al. (J Alzheimers Dis, 2017)
The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.

Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer's Disease. - Philippens, Ingrid H; Ormel, Paul R; Baarends, Guus; Johansson, Maja; Remarque, Ed J; Doverskog, Magnus (J Alzheimers Dis, 2017)
BACKGROUND: The immune system is increasingly mentioned as a potential target for Alzheimer's disease (AD) treatment. OBJECTIVE: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. METHODS: Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. RESULTS: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques. CONCLUSION: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD.

Adherence to Clinical Practice Guidelines during Dementia Work-Up in a Real-World Setting: A Study from the Registry of Dementias of Girona. - Turró-Garriga, Oriol; Calvó-Perxas, Laia; Vilalta-Franch, Joan; Hernández-Ferrándiz, Marta; Flaqué, Margarita; Linares, Marta; Cullell, Marta; Gich, Jordi; Casas, Isabel; Perkal, Héctor; Garre-Olmo, Josep (J Alzheimers Dis, 2017)
BACKGROUND: There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia. OBJECTIVE: Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007-2011 and 2012-2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes. METHODS: Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI). RESULTS: The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007-2011 to 8.5 points in 2012-2015 (Cohen's d = 0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases. CONCLUSION: The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases.

Adult-Onset Epilepsy in Presymptomatic Alzheimer's Disease: A Retrospective Study. - DiFrancesco, Jacopo C; Tremolizzo, Lucio; Polonia, Valeria; Giussani, Giorgia; Bianchi, Elisa; Franchi, Carlotta; Nobili, Alessandro; Appollonio, Ildebrando; Beghi, Ettore; Ferrarese, Carlo (J Alzheimers Dis, 2017)
BACKGROUND: The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer's disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. OBJECTIVE: Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. METHODS: We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). RESULTS: In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3-28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD. CONCLUSIONS: Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia.

Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer's Disease. - McClure, Richard; Ong, Henry; Janve, Vaibhab; Barton, Shawn; Zhu, Meiying; Li, Bo; Dawes, Mary; Jerome, W Gray; Anderson, Adam; Massion, Pierre; Gore, John C; Pham, Wellington (J Alzheimers Dis, 2017)
We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

Age and Graphomotor Decision Making Assessed with the Digital Clock Drawing Test: The Framingham Heart Study. - Piers, Ryan J; Devlin, Kathryn N; Ning, Boting; Liu, Yulin; Wasserman, Ben; Massaro, Joseph M; Lamar, Melissa; Price, Catherine C; Swenson, Rod; Davis, Randall; Penney, Dana L; Au, Rhoda; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Digital Clock Drawing Test (dCDT) technology enables the examination of detailed neurocognitive behavior as behavior unfolds in real time; a capability that cannot be obtained using a traditional pen and paper testing format. OBJECTIVE: Parameters obtained from the dCDT were used to investigate neurocognitive constructs related to higher-order neurocognitive decision making and information processing speed. The current research sought to determine the effect of age as related to combined motor and non-motor components of drawing, and higher-order decision making latencies. METHODS: A large group of stroke- and dementia- free Framingham Heart Study participants were administered the dCDT to command and copy with hands set for "10 after 11". Six age groups (age range 28-98) were constructed. RESULTS: Differences between age groups were found for total time to completion, total pen stroke count, and higher-order decision making latencies in both command and copy test conditions. CONCLUSION: Longer age-related decision making latencies may reflect a greater need for working memory and increased self-monitoring in older subjects. These latency measures have potential to serve as neurocognitive biomarkers of Alzheimer's disease and other insidious neurodegenerative disorders.

Algoplus® Scale in Older Patients with Dementia: A Reliable Real-World Pain Assessment Tool. - Monacelli, Fiammetta; Signori, Alessio; Roffredo, Laura; Pace, Katiuscia; Nencioni, Alessio; Pickering, Gisele; Nicolas, Macian; Odetti, Patrizio (J Alzheimers Dis, 2017)
Pain is still a neglected clinical issue in elderly people with dementia and/or communicative disorders, with an unacceptable higher rate of under diagnosis and under treatment. Cognitive deficit and emotional and psychological disturbances entangle pain symptoms, affecting patient self-report. So far, observational pain tools do not have fully adequate clinimetric properties and quality requirements for easy-to-use daily rating. Older patients with dementia represent a clinical challenge. The assessment of pain is important for improving clinical outcomes, such as functional status, frailty trajectories, comorbidity, and quality of life. The PAINAID scale appears to be the most accurate pain tool in people with dementia along with the Algoplus® scale, a recently developed tool to rapidly assess acute pain in hospitals settings. The present study aimed to assess the clinimetric properties of the Algoplus®, as compared to PAINAID, for detecting acute pain in a real-world cohort of hospitalized older patients with dementia.

Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer's Mouse Model. - Brandscheid, Carolin; Schuck, Florian; Reinhardt, Sven; Schäfer, Karl-Herbert; Pietrzik, Claus U; Grimm, Marcus; Hartmann, Tobias; Schwiertz, Andreas; Endres, Kristina (J Alzheimers Dis, 2017)
The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut - the enteric nervous system, or even derive from there. By using a murine Alzheimer's disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer's disease in humans, directly interferes with gut function as shown here for the disease model mice.

Alzheimer's Disease-Related Polymorphisms in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus. - Huovinen, Joel; Helisalmi, Seppo; Paananen, Jussi; Laiterä, Tiina; Kojoukhova, Maria; Sutela, Anna; Vanninen, Ritva; Laitinen, Marjo; Rauramaa, Tuomas; Koivisto, Anne M; Remes, Anne M; Soininen, Hilkka; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH. OBJECTIVE: We aim to evaluate the role of AD-related polymorphisms in iNPH. METHODS: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. RESULTS: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. CONCLUSIONS: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

Amygdala α-Synuclein Pathology in the Population-Based Vantaa 85+ Study. - Raunio, Anna; Myllykangas, Liisa; Kero, Mia; Polvikoski, Tuomo; Paetau, Anders; Oinas, Minna (J Alzheimers Dis, 2017)
We investigated the frequency of Lewy-related pathology (LRP) in the amygdala among the population-based Vantaa 85+ study. Data of amygdala samples (N = 304) immunostained with two α-synuclein antibodies (clone 42 and clone 5G4) was compared with the previously analyzed LRP and AD pathologies from other brain regions. The amygdala LRP was present in one third (33%) of subjects. Only 5% of pure AD subjects, but 85% of pure DLB subjects had LRP in the amygdala. The amygdala LRP was associated with dementia; however, the association was dependent on LRP on other brain regions, and thus was not an independent risk factor. The amygdala-predominant category was a rare (4%) and heterogeneous group.

Angiotensin-III is Increased in Alzheimer's Disease in Association with Amyloid-β and Tau Pathology. - Kehoe, Patrick Gavin; Hibbs, Elliott; Palmer, Laura E; Miners, J Scott (J Alzheimers Dis, 2017)
Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer's disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R), but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and metabolism of Ang-III, respectively) in human postmortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59), for which we had previous measurements of ACE-1 activity, Aβ level, and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aβ load and tau load. Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD.

Anomalous White Matter Structure and the Effect of Age in Down Syndrome Patients. - Fenoll, Raquel; Pujol, Jesus; Esteba-Castillo, Susanna; de Sola, Susana; Ribas-Vidal, Núria; García-Alba, Javier; Sánchez-Benavides, Gonzalo; Martínez-Vilavella, Gerard; Deus, Joan; Dierssen, Mara; Novell-Alsina, Ramón; de la Torre, Rafael (J Alzheimers Dis, 2017)
BACKGROUND: Neural tissue alterations in Down syndrome are fully expressed at relatively late developmental stages. In addition, there is an early presence of neurodegenerative changes in the late life stages. OBJECTIVE: The aims of this study were both to characterize white matter abnormalities in the brain of adult Down syndrome patients using diffusion tensor imaging (DTI) and to investigate whether degenerative alterations in white matter structure are detectable before dementia is clinically evident. METHODS: Forty-five adult non-demented Down syndrome patients showing a wide age range (18-52 years) and a matched 45-subject control group were assessed. DTI fractional anisotropy (FA) brain maps were generated and selected cognitive tests were administered. RESULTS: Compared with healthy controls, non-demented Down syndrome patients showed lower DTI FA in white matter involving the major pathways, but with more severe alterations in the frontal-subcortical circuits. White matter FA decreased with age at a similar rate in both DS and control groups. CONCLUSIONS: Our results contribute to characterizing the expression of white matter structural alterations in adult Down syndrome. However, an accelerated aging effect was not demonstrated, which may suggest that the FA measurements used are not sufficiently sensitive or, alternatively, age-related white matter neurodegeneration is not obvious prior to overt clinical dementia.

The Anti-Amyloid-β and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule. - Maezawa, Izumi; Zou, Bende; Di Lucente, Jacopo; Cao, William S; Pascual, Conrado; Weerasekara, Sahani; Zhang, Man; Xie, Xinmin Simon; Hua, Duy H; Jin, Lee-Way (J Alzheimers Dis, 2017)
There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-Aβ therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral Aβ, including both fibrillary and soluble Aβ species. Interestingly, TP70 enhanced N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the Aβ oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24 h after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents.

APOE ε4 Modulation of Training Outcomes in Several Cognitive Domains in a Sample of Cognitively Intact Older Adults. - López-Higes, Ramón; Rodríguez-Rojo, Inmaculada C; Prados, José M; Montejo, Pedro; Del-Río, David; Delgado-Losada, María Luisa; Montenegro, Mercedes; López-Sanz, David; Barabash, Ana (J Alzheimers Dis, 2017)
BACKGROUND: Most research points to the ɛ4 allele of the apolipoprotein E (APOE) gene as the most recognizable genetic risk factor associated with Alzheimer's disease pathogenesis. It has been also suggested that the APOEɛ4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOEɛ4 interaction with cognitive intervention programs. OBJECTIVE: The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for. METHODS: Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOEɛ4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version. RESULTS: The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POEɛ4 noncarrier group. CONCLUSION: Genetic profile modulates training outcomes in sentence comprehension.

APOEɛ4 Genotype, Amyloid, and Clinical Disease Progression in Cognitively Normal Older Adults. - Hollands, Simone; Lim, Yen Ying; Laws, Simon M; Villemagne, Victor L; Pietrzak, Robert H; Harrington, Karra; Porter, Tenielle; Snyder, Peter; Ames, David; Fowler, Christopher; Rainey-Smith, Stephanie R; Martins, Ralph N; et al. (J Alzheimers Dis, 2017)
BACKGROUND: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) ɛ4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOEɛ4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ. OBJECTIVE: To determine the extent and nature to which APOEɛ4 increases risk for clinical disease progression in CN older adults. METHODS: Data from the total (n = 765) and Aβ-imaged (n = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox proportional hazard models to estimate ɛ4 risk for clinical disease progression over a 72-month follow-up. RESULTS: With Aβ status unknown and risk from demographic characteristics controlled, ɛ4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ4 carriage was no longer predictive of clinical disease progression. CONCLUSION: In CN older adults, the risk of ɛ4 for clinical disease progression occurs through the effect of ɛ4 increasing Aβ levels.

Apolipoprotein E4 Elicits Lysosomal Cathepsin D Release, Decreased Thioredoxin-1 Levels, and Apoptosis. - Persson, Torbjörn; Lattanzio, Francesca; Calvo-Garrido, Javier; Rimondini, Roberto; Rubio-Rodrigo, Marta; Sundström, Erik; Maioli, Silvia; Sandebring-Matton, Anna; Cedazo-Minguez, Angel (J Alzheimers Dis, 2017)
The major genetic risk factor for Alzheimer's disease (AD), apolipoprotein E4 (ApoE4), has been suggested to have detrimental effects on neurons, including direct toxicity via apoptosis. Thioredoxin-1 (Trx1) is an endogenous antioxidant protein important for redox regulation and participates in the regulation of apoptosis through the inhibition of apoptosis signal-regulating kinase-1 (Ask-1). In this study, we have investigated the effects of ApoE on Trx1 in the brain. Our results showed that the protein levels of Trx1 were reduced in the hippocampus of ApoE4 targeted replacement (TR) mice compared to ApoE3 TR mice. The reduction was also seen in vitro after treatment of both human primary cortical neurons and neuroblastoma cells with human recombinant ApoE4 (rApoE4). Furthermore, ApoE4 caused a disruption of lysosomal integrity and a shift in the localization of Cathepsin D, an enzyme known to degrade Trx1. ApoE4 treatment induced in addition apoptosis through translocation of Death-domain associated protein-6 (Daxx) from the nucleus to the cytosol, suggesting an activation of the Ask-1 pathway. This toxicity was prevented by overexpression of Trx1 and other endogenous Ask-1 inhibitors. Our data suggests that down-regulation of Trx1 is involved in the toxicity caused by ApoE4. An activated ASK-1 pathway might indeed make cells more vulnerable to other insults such as amyloid-β, which could partially explain the mechanism behind the strongest genetic risk factor for AD.

Assessment of Driving Safety in Older Adults with Mild Cognitive Impairment. - Anstey, Kaarin J; Eramudugolla, Ranmalee; Chopra, Sidhant; Price, Jasmine; Wood, Joanne M (J Alzheimers Dis, 2017)
BACKGROUND: With population aging, drivers with mild cognitive impairment (MCI) are increasing; however, there is little evidence available regarding their safety. OBJECTIVE: We aimed to evaluate risk of unsafe on-road driving performance among older adults with MCI. METHOD: The study was a cross-sectional observational study, set in Canberra, Australia. Participants were non-demented, current drivers (n = 302) aged 65 to 96 years (M = 75.7, SD = 6.18, 40% female) recruited through the community and primary and tertiary care clinics. Measures included a standardized on-road driving test (ORT), a battery of screening measures designed to evaluate older driver safety (UFOV®, DriveSafe, Multi-D), a neurocognitive test battery, and questionnaires on driving history and behavior. RESULTS: Using Winblad criteria, 57 participants were classified as having MCI and 245 as cognitively normal (CN). While the MCI group had a significantly lower overall safety rating on the ORT (5.61 versus 6.05, p = 0.03), there was a wide range of driving safety scores in the CN and MCI groups. The MCI group performed worse than the CN group on the off-road screening tests. The best fitting model of predictors of ORT performance across the combined sample included age, the Multi-D, and DriveSafe, classifying 90.4% of the sample correctly. CONCLUSION: Adults with MCI exhibit a similar range of driving ability to CN adults, although on average they scored lower on off-road and on-road assessments. Driving specific tests were more strongly associated with safety ratings than traditional neuropsychological tests.

Association Between Later Life Lifestyle Factors and Alzheimer's Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study. - Reijs, Babette L R; Vos, Stephanie J B; Soininen, Hilkka; Lötjönen, Jyrki; Koikkalainen, Juha; Pikkarainen, Maria; Hall, Anette; Vanninen, Ritva; Liu, Yawu; Herukka, Sanna-Kaisa; Freund-Levi, Yvonne; Frisoni, Giovanni B; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear. OBJECTIVE: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1-42 (Aβ42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. METHODS: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. RESULTS: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. CONCLUSIONS: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.

Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer's Disease. - Kim, Min; Nevado-Holgado, Alejo; Whiley, Luke; Snowden, Stuart G; Soininen, Hilkka; Kloszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Thambisetty, Madhav; Dobson, Richard J B; Powell, John F; et al. (J Alzheimers Dis, 2017)
Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer's disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n = 205, Control n = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p < 0.01, Cer18:0 p < 0.01, Cer24:1 p < 0.05). In addition, two PCs in AD plasma (PC36:5 p < 0.05, PC38:6 p < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p < 0.05), while all 3 PCs did so in the older participants (age > 75, p < 0.05). PC36:5 was associated with AD status in the younger group (p < 0.01), while PC38:6 and 40:6 did so in the older group (p < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression.

Association of Central Arterial Stiffness and Pressure Pulsatility with Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities Study-Neurocognitive Study (ARIC-NCS). - Meyer, Michelle L; Palta, Priya; Tanaka, Hirofumi; Deal, Jennifer A; Wright, Jacqueline; Knopman, David S; Griswold, Michael E; Mosley, Thomas H; Heiss, Gerardo (J Alzheimers Dis, 2017)
BACKGROUND: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. OBJECTIVE: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. METHODS: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI and dementia versus no cognitive impairment. RESULTS: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. CONCLUSION: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults.

Associations of CAIDE Dementia Risk Score with MRI, PIB-PET measures, and cognition. - Stephen, Ruth; Liu, Yawu; Ngandu, Tiia; Rinne, Juha O; Kemppainen, Nina; Parkkola, Riitta; Laatikainen, Tiina; Paajanen, Teemu; Hänninen, Tuomo; Strandberg, Timo; Antikainen, Riitta; Tuomilehto, Jaakko; et al. (J Alzheimers Dis, 2017)
BACKGROUND: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile. OBJECTIVES: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures. METHODS: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation. RESULTS: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05-1.43), lower total gray matter (β-coefficient -0.29, p = 0.001) and hippocampal volume (β-coefficient -0.28, p = 0.003), lower cortical thickness (β-coefficient -0.19, p = 0.042), and poorer cognition (β-coefficients -0.31 for total NTB score, -0.25 for executive functioning, -0.33 for processing speed, and -0.20 for memory, all p < 0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15, 95% CI 1.00-1.30). No associations were found with periventricular WML or amyloid accumulation. CONCLUSIONS: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes.

Attitudes toward Potential Participant Registries. - Grill, Joshua D; Holbrook, Andrew; Pierce, Aimee; Hoang, Dan; Gillen, Daniel L (J Alzheimers Dis, 2017)
Difficult participant recruitment is a consistent barrier to successful medical research. Potential participant registries represent an increasingly common intervention to overcome this barrier. A variety of models for registries exist, but few data are available to instruct their design and implementation. To provide such data, we surveyed 110 cognitively normal research participants enrolled in a longitudinal study of aging and dementia. Seventy-four (67%) individuals participated in the study. Most (78%, CI: 0.67, 0.87) participants were likely to enroll in a registry. Willingness to participate was reduced for registries that required enrollment through the Internet using a password (26%, CI: 0.16, 0.36) or through email (38%, CI: 0.27, 0.49). Respondents acknowledged their expectations that researchers share information about their health and risk for disease and their concerns that their data could be shared with for-profit companies. We found no difference in respondent preferences for registries that shared contact information with researchers, compared to honest broker models that take extra precautions to protect registrant confidentiality (28% versus 30%; p = 0.46). Compared to those preferring a shared information model, respondents who preferred the honest broker model or who lacked model preference voiced increased concerns about sharing registrant data, especially with for-profit organizations. These results suggest that the design of potential participant registries may impact the population enrolled, and hence the population that will eventually be enrolled in clinical studies. Investigators operating registries may need to offer particular assurances about data security to maximize registry enrollment but also must carefully manage participant expectations.

Autonomic Nervous System Dysfunctions as a Basis for a Predictive Model of Risk of Neurological Disorders in Subjects with Prior History of Traumatic Brain Injury: Implications in Alzheimer's Disease. - Ho, Lap; Legere, Marc; Li, Tongbin; Levine, Samara; Hao, Ke; Valcarcel, Breanna; Pasinetti, Giulio M (J Alzheimers Dis, 2017)
Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer's disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD.

Baseline Predictors of Antipsychotic Treatment Continuation and Response at Week 8 in Patients with Alzheimer's Disease with Psychosis or Aggressive Symptoms: An Analysis of the CATIE-AD Study. - Nagata, Tomoyuki; Nakajima, Shinichiro; Shinagawa, Shunichiro; Plitman, Eric; Nakayama, Kazuhiko; Graff-Guerrero, Ariel; Mimura, Masaru (J Alzheimers Dis, 2017)
BACKGROUND/OBJECTIVE: The aim of the present study was to investigate predictors of atypical antipsychotic (AAP) treatment continuation and response by week 8 in patients with Alzheimer's disease (AD) who have psychotic/aggressive symptoms using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) dataset. METHODS: Clinical data was utilized from 421 AD outpatients with psychotic/aggressive symptoms who needed interventional treatment. Logistic regression analyses were performed to examine which baseline sociodemographic and clinical characteristics contributed to treatment 'continuation' and 'response', the latter of which was evaluated by the Clinical Global Impression of Change (CGI-C), Neuropsychiatric Inventory (NPI), and Brief Psychiatric Scale (BPRS). RESULTS: The treatment continuation rate was 48.7%, and CGI-C, NPI, and BPRS response rate by the last observation carried forward method were 42.7%, 48.6%, and 37.5%, respectively. No significant predictor was identified for treatment continuation in the Caucasian patients (n = 331), while better treatment response was predicted by a lower Mini-Mental State Examination score, treatment with risperidone (versus olanzapine and quetiapine), history of diabetes mellitus, healthier physical status, and more severe initial psychotic symptoms. CONCLUSIONS: Comparatively high intolerability from AAPs in the short term was confirmed. We found that baseline clinical predictors to treatment response in Caucasian AD patients with psychotic/aggressive symptoms include treatment with risperidone (versus quetiapine and olanzapine), diabetes mellitus, global physical status, cognitive impairment, and psychotic symptoms. Going forward, these findings may help to determine treatment strategies or care plans.

Baseline Telomere Length and Effects of a Multidomain Lifestyle Intervention on Cognition: The FINGER Randomized Controlled Trial. - Sindi, Shireen; Ngandu, Tiia; Hovatta, Iiris; Kåreholt, Ingemar; Antikainen, Riitta; Hänninen, Tuomo; Levälahti, Esko; Laatikainen, Tiina; Lindström, Jaana; Paajanen, Teemu; Peltonen, Markku; Khalsa, Dharma Singh; et al. (J Alzheimers Dis, 2017)
Leukocyte telomere length (LTL) is a biomarker of aging, and it is associated with lifestyle. It is currently unknown whether LTL is associated with the response to lifestyle interventions. The goal is to assess whether baseline LTL modified the cognitive benefits of a 2-year multidomain lifestyle intervention (exploratory analyses). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60-77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL (p-value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals.

Benefits of Occupational Therapy in Dementia Patients: Findings from a Real-World Observational Study. - Pimouguet, Clément; Le Goff, Mélanie; Wittwer, Jérôme; Dartigues, Jean-François; Helmer, Catherine (J Alzheimers Dis, 2017)
BACKGROUND: There is a growing interest in developing non-pharmacological approaches in dementia. Clinical efficacy of occupational therapy (OT) under routine care conditions has not been investigated yet. OBJECTIVE: To analyze the short-term effects of OT in patients with dementia; and to identify factors related to greater benefit. METHODS: Patients referred to OT were evaluated before starting a 3-month intervention and at 3 and 6 months later. Measures included: Mini-Mental State Examination (MMSE), Disability Assessment in Dementia (DAD), Neuropsychiatric Inventory (NPI) Questionnaire, patients' quality of life (EQ 5D-VAS), caregivers' burden (Zarit scale), and amount of informal care. Linear mixed models were used to analyze trajectories of outcomes. Logistic regressions with stepwise descending selection were used to study factors associated with benefits. RESULTS: 421 dementia patients benefited from OT (mean MMSE = 17.3). Patients remained cognitively stable over time. Functional performances also remained stable at 3 months and significantly decreased at 6 months (crude reduction of 2.8 points, p < 0.01). Behavioral troubles were significantly reduced over the intervention period and remained stable after (p < 0.01). Patients' quality of life increased over the 3-month intervention (p = 0.16) and significantly decreased thereafter. Caregivers' burden and informal care significantly decreased over the 3-month intervention and remained stable thereafter. Patients who benefited from OT with regard to function were less educated and had higher cognitive level. CONCLUSION: OT may be an effective intervention to maintain cognition and functionality and to reduce psychiatric symptoms in dementia patients. Mild stages of dementia could gain more benefits from OT with regard to functional decline.

Biomarkers and Functional Decline in Prodromal Alzheimer's Disease. - Robb, Catherine; Udeh-Momoh, Chinedu; Wagenpfeil, Stefan; Schöpe, Jakob; Alexopoulos, Panagiotis; Perneczky, Robert (J Alzheimers Dis, 2017)
BACKGROUND: Little is known of possible associations between Alzheimer's disease (AD) biomarkers and instrumental activities of daily living (IADL) change over time. OBJECTIVE: The present study seeks to identify relationships between baseline imaging and fluid biomarker profiles, and decline in IADL utilizing data collated from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: Generalized estimating equations analysis, adjusted for cognitive deterioration, was applied to a cohort of 509 individuals from all stages of ADNI, including 156 healthy controls, 189 early mild cognitive impairment (MCI) patients and 164 MCI patients. RESULTS: A significant correlation was found between baseline biomarkers, specifically CSF Aβ and FDG PET, and IADL change over a 3-year period in individuals with MCI. Importantly, comparable correlations between presence of pathological biomarker levels and temporal decline in both functional and cognitive performance were also noted. DISCUSSION: We show that distinct baseline biomarkers may predict latent changes in IADL. Our results necessitate a revision of the commonly held view upholding cognitive changes as the predominant endpoint measure associated with presence of abnormal baseline biomarkers.

Biomarkers for Early Diagnosis of Alzheimer's Disease in the Oldest Old: Yes or No? - Paolacci, Lucia; Giannandrea, David; Mecocci, Patrizia; Parnetti, Lucilla (J Alzheimers Dis, 2017)
In recent years, many efforts have been spent to identify sensitive biomarkers able to improve the accuracy of Alzheimer's disease (AD) diagnosis. Two different workgroups (NIA-AA and IWG) included cerebrospinal fluid (CSF) and neuroimaging findings in their sets of criteria in order to improve diagnostic accuracy as well as early diagnosis. The number of subjects with cognitive impairment increases with aging but the oldest old (≥85 years of age), the fastest growing age group, is still the most unknown from a biological point of view. For this reason, the aim of our narrative mini-review is to evaluate the pertinence of the new criteria for AD diagnosis in the oldest old. Moreover, since different subgroups of oldest old have been described in scientific literature (escapers, delayers, survivors), we want to outline the clinical profile of the oldest old who could really benefit from the use of biomarkers for early diagnosis. Reviewing the literature on biomarkers included in the diagnostic criteria, we did not find a high degree of evidence for their use in the oldest old, although CSF biomarkers seem to be still the most useful for excluding AD diagnosis in the "fit" subgroup of oldest old subjects, due to the high negative predictive value maintained in this age group.

Bipolar Disorder and Frontotemporal Dementia: An Intriguing Association. - Papazacharias, Apostolos; Lozupone, Madia; Barulli, Maria Rosaria; Capozzo, Rosa; Imbimbo, Bruno P; Veneziani, Federica; De Blasi, Roberto; Nardini, Marcello; Seripa, Davide; Panza, Francesco; Logroscino, Giancarlo (J Alzheimers Dis, 2017)
Bipolar disorder (BD) could represent a prodromal state of frontotemporal dementia (FTD). Two patients affected by lifelong BD with a progressive decline of cognitive functions, behavioral, and neurological signs, reached the early diagnosis of FTD before the age of 60. They were diagnosed as affected by primary progressive aphasia and FTD with parkinsonism, respectively. A diagnosis of FTD should therefore be taken into account, in case of unexpected cognitive and behavioral decline in patients with a long history of BD. Follow-up studies with genetic, neuropsychological, and neuroimaging markers of these BD/FTD patients could further explore some of the underlying association, opening new viable therapeutic options.

Body Mass Index, Height, and Socioeconomic Position in Adolescence, Their Trajectories into Adulthood, and Cognitive Function in Midlife. - Cohen-Manheim, Irit; Doniger, Glen M; Sinnreich, Ronit; Simon, Ely S; Murad, Havi; Pinchas-Mizrachi, Ronit; Kark, Jeremy D (J Alzheimers Dis, 2017)
BACKGROUND: Whether life course anthropometric indices relate to cognitive function in midlife remains insufficiently explored. Rarely was socioeconomic position (SEP) adequately accounted for. OBJECTIVE: To examine the association of the cumulative life course burden of high-ranked body mass index (BMI), its trajectory, and stature with cognitive function in midlife. METHODS: Weight and height were measured from age 17 across a 33-year follow-up. 507 individuals completed a NeuroTrax computerized cognitive assessment at ages 48-52. Life course SEP was assessed by multiple methods. Using mixed models we calculated the area under the curve (AUC), representing both the life-course burden of BMI (total AUC) and trends in BMI (incremental AUC) from age 17 to midlife. The associations of BMI and height with global cognition and its five component domains were assessed by multiple regression. RESULTS: Higher BMI in late adolescence and total AUC over the life course were associated with poorer global cognition (Standardized beta (Beta) = -0.111, p = 0.005 and Beta = -0.105, p = 0.018, respectively), adjusted for childhood and adulthood SEP, and demographic characteristics. The associations with higher adolescent and midlife BMI were both restricted to those with low childhood SEP (p < 0.05 for interaction). Short adolescent stature was related to poorer cognition (Beta = 0.084, p = 0.044), whereas late final growth in women was associated with better cognition (Beta = 0.213, p = 0.007). CONCLUSION: An adverse association of higher BMI with cognitive function began in adolescence and was restricted to low childhood SEP. Taller stature in both sexes and late growth in women were associated with better midlife cognitive performance.

The Brain's Structural Connectome Mediates the Relationship between Regional Neuroimaging Biomarkers in Alzheimer's Disease. - Pandya, Sneha; Kuceyeski, Amy; Raj, Ashish (J Alzheimers Dis, 2017)
Alzheimer's disease (AD), one of the most common causes of dementia in adults, is a progressive neurodegenerative disorder exhibiting well-defined neuropathological hallmarks. It is known that disease pathology involves misfolded amyloid-β (Aβ) and tau proteins, and exhibits a relatively stereotyped progression over decades. The relationship between AD neuropathological hallmarks (Aβ, hypometabolism, and tau proteins) and imaging biomarkers (MRI, AV-45/FDG-PET) is not fully understood. In addition, biomarker pathologies are oftentimes discordant, wherein it may show varying levels of abnormality across brain regions. Evidence based on recent elucidation of trans-neuronal "prion-like" transmission and other available data already suggests that disease spread follows the brain's fiber connectivity network. Thereby, the brain's connectome information can be used to predict the process of disease spread in AD. A recently established mathematical model of AD pathology spread using a connectome-based network diffusion model was successful in encapsulating neurodegenerative progression. Motivated by these network-based findings, the current study explores whether and how network connectivity mediates the interactions between various AD biomarkers. We hypothesized that the structural connectivity matrix will mediate the cross-sectional association between regional AD-associated hypometabolism and Aβ deposition. Given recent reports of inherent or lifetime activity of brain regions as strong predictors of Aβ deposition in patients, we also tested whether healthy metabolism exerts a network-mediated effect on Aβ deposition and hypometabolism in AD patients. We found that regional Aβ deposition is best predicted by a linear combination of both regional healthy local metabolism and connectome-mediated regional healthy metabolism.

Can Musical or Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with Mild Alzheimer's Disease? Evidence from a Randomized Controlled Trial. - Pongan, Elodie; Tillmann, Barbara; Leveque, Yohana; Trombert, Béatrice; Getenet, Jean Claude; Auguste, Nicolas; Dauphinot, Virginie; El Haouari, Hanane; Navez, Malou; Dorey, Jean-Michel; Krolak-Salmon, Pierre; Laurent, Bernard; et al. (J Alzheimers Dis, 2017)
BACKGROUND: Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer's disease (AD) and patients presenting chronic pain. However, their efficacy is still under debate. OBJECTIVE: Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients. METHODS: In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n = 31) or painting group (PG; n = 28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a 'per protocol' approach. RESULTS: Both singing and painting interventions led to significant pain reduction (Time effect: F = 4.71; p = 0.01), reduced anxiety (Time effect: F = 10.74; p < 0.0001), improved Quality of Life (Time effect: F = 6.79; p = 0.002), improved digit span (F = 12.93; p = 0.001), and inhibitory processes (Time effect: F = 4.93; p = 0.03). Depression was reduced over time in PG only (Time x Group effect: F = 4.53; p = 0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F = 9.29; p = 0.004). CONCLUSION: Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance.

CD44 Splice Variants as Potential Players in Alzheimer's Disease Pathology. - Pinner, Elhanan; Gruper, Yaron; Ben Zimra, Micha; Kristt, Don; Laudon, Moshe; Naor, David; Zisapel, Nava (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles, and neuronal cell death. Neuroinflammation is commonly believed to participate in AD pathogenesis. CD44 is an inflammation-related gene encoding a widely-distributed family of alternatively spliced cell surface glycoproteins that have been implicated in inflammation, metastases, and inflammation-linked neuronal injuries. Here we investigated the expression patterns of CD44S (which does not contain any alternative exon) and CD44 splice variants in postmortem hippocampal samples from AD patients and matched non-AD controls. The expression of CD44S and CD44 splice variants CD44V3, CD44V6, and CD44V10 was significantly higher in AD patients compared to non-AD controls. Immunohistochemistry of human hippocampal sections revealed that CD44S differentially localized to neuritic plaques and astrocytes, whereas CD44V3, CD44V6, and CD44V10 expression was mostly neuronal. Consistent with these findings, we found that the expression of CD44V6 and CD44V10 was induced by Aβ peptide in neuroblastoma cells and primary neurons. Furthermore, in loss of function studies we found that both CD44V10-specific siRNA and CD44V10 antibody protected neuronal cells from Aβ-induced toxicity, suggesting a causal relationship between CD44V10 and neuronal cell death. These data indicate that certain CD44 splice variants contribute to AD pathology and that CD44V10 inhibition may serve as a new neuroprotective treatment strategy for this disease.

Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients. - Ketter, Nzeera; Brashear, H Robert; Bogert, Jennifer; Di, Jianing; Miaux, Yves; Gass, Achim; Purcell, Derk D; Barkhof, Frederik; Arrighi, H Michael (J Alzheimers Dis, 2017)
BACKGROUND: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). OBJECTIVES: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers). METHODS: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. RESULTS: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. CONCLUSION: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

Cerebral Hemodynamics in Mild Cognitive Impairment: A Systematic Review. - Beishon, Lucy; Haunton, Victoria J; Panerai, Ronney B; Robinson, Thompson G (J Alzheimers Dis, 2017)
BACKGROUND: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target. OBJECTIVE: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS). METHODS: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity. RESULTS: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies. CONCLUSION: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia.

Cerebrospinal Fluid Amyloid-β 42, Total Tau and Phosphorylated Tau are Low in Patients with Normal Pressure Hydrocephalus: Analogies and Differences with Alzheimer's Disease. - Santangelo, Roberto; Cecchetti, Giordano; Bernasconi, Maria Paola; Cardamone, Rosalinda; Barbieri, Alessandra; Pinto, Patrizia; Passerini, Gabriella; Scomazzoni, Francesco; Comi, Giancarlo; Magnani, Giuseppe (J Alzheimers Dis, 2017)
Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer's Disease. - Lewczuk, Piotr; Matzen, Anja; Blennow, Kaj; Parnetti, Lucilla; Molinuevo, José Luis; Eusebi, Paolo; Kornhuber, Johannes; Morris, John C; Fagan, Anne M (J Alzheimers Dis, 2017)
BACKGROUND: Decreased concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer's disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone. OBJECTIVE: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results. METHODS: CSF obtained from a mixed cohort (n = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n = 150 PET-negative, n = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar's test for paired proportions. RESULTS: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases. CONCLUSION: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ.

Cerebrospinal Fluid Biomarkers and Clinical Progression in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment. - Wolfsgruber, Steffen; Polcher, Alexandra; Koppara, Alexander; Kleineidam, Luca; Frölich, Lutz; Peters, Oliver; Hüll, Michael; Rüther, Eckart; Wiltfang, Jens; Maier, Wolfgang; Kornhuber, Johannes; Lewczuk, Piotr; et al. (J Alzheimers Dis, 2017)
BACKGROUND: There is very limited data on the prevalence of abnormal cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and their predictive value for clinical progression in memory clinic patients with subjective cognitive decline (SCD). OBJECTIVE: To assess the frequency of abnormal CSF biomarkers of AD and their predictive value for clinical progression in memory clinic patients with SCD in comparison to patients with mild cognitive impairment (MCI) from the same cohort. METHODS: We analyzed prospective data from memory clinic patients of the German Competence Network Dementia cohort with a baseline diagnosis of SCD (n = 82) or MCI (n = 134), distinguished by actuarial neuropsychological MCI criteria ("Jak-Bondi criteria"). Risk of clinical progression during 3-year follow-up was evaluated with Cox-Proportional-Hazard models. RESULTS: Prevalence of abnormal values in CSF markers of tau-mediated neurodegeneration (67.8% versus 46.3%) but not of amyloid deposition (40.3% versus 35.4%) was significantly higher in MCI compared to SCD. The rate of incident AD dementia (26.1% versus 12.2%) was also significantly higher in MCI. In SCD, additional 22% progressed to MCI during follow-up. Combined amyloid/tau abnormality was the strongest predictor of clinical progression in both groups. CONCLUSION: High prevalence of biomarker abnormality and clinical progression, together with the predictive value of CSF biomarkers, in memory clinic patients with SCD support the validity and usefulness of this condition as a "pre-MCI" at risk stage of AD.

Cerebrospinal Fluid Biomarkers as a Diagnostic Tool of the Underlying Pathology of Primary Progressive Aphasia. - Paraskevas, George P; Kasselimis, Dimitrios; Kourtidou, Evie; Constantinides, Vasilios; Bougea, Anastasia; Potagas, Costas; Evdokimidis, Ioannis; Kapaki, Elisabeth (J Alzheimers Dis, 2017)
BACKGROUND: Primary progressive aphasia (PPA) may present with three main clinical variants, namely nonfluent agrammatic (nfaPPA), semantic (sPPA), and logopenic (lPPA) subtypes. Frontotemporal lobar degenerations (FTLD) or Alzheimer's disease (AD) are the most common etiologies. OBJECTIVE: To study the potential of cerebrospinal fluid (CSF) biomarkers for identifying the underlying pathology in patients with PPA. METHODS: CSF levels of total tau protein (τT), amyloid-β peptide (Aβ42), and tau phosphorylated at threonine-181 (τP - 181) were measured by double sandwich, enzyme-linked immunosorbent assay (ELISA) in 43 patients with PPA, 26 patients with AD, and 17 healthy controls. RESULTS: All patients could be classified as compatible with the AD or non-AD biomarker profile, either with the three biomarkers (90.7%) or their ratios, especially the τP - 181/Aβ42 ratio (9.3%). An AD-compatible biomarker profile was present in 39.5% of all PPA patients, specifically 22.2%, 35.7%, and 75% of nfaPPA, sPPA, and lPPA, respectively. In PPA patients with a non-AD profile (presumably FTLD), two different clusters could be identified according to the τP - 181/τT ratio, possibly corresponding to the two major FTLD pathologies (tau and TDP-43). CONCLUSION: CSF biomarkers may be a valuable tool for the discrimination between PPA patients with AD and non-AD pathophysiology and possibly between FTLD patients with tau and TDP-43 pathology.

Cerebrospinal Fluid Biomarkers for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Lobar Degeneration: Systematic Review, HSROC Analysis, and Confounding Factors. - Rivero-Santana, Amado; Ferreira, Daniel; Perestelo-Pérez, Lilisbeth; Westman, Eric; Wahlund, Lars-Olof; Sarría, Antonio; Serrano-Aguilar, Pedro (J Alzheimers Dis, 2017)
BACKGROUND: Differential diagnosis in dementia is at present one of the main challenges both in clinical practice and research. Cerebrospinal fluid (CSF) biomarkers are included in the current diagnostic criteria of Alzheimer's disease (AD) but their clinical utility is still unclear. OBJECTIVE: We performed a systematic review of studies analyzing the diagnostic performance of CSF Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in the discrimination between AD and frontotemporal lobar degeneration (FTLD) dementias. METHODS: The following electronic databases were consulted until May 2016: Medline and PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. For the first-time in the field, a Hierarchical Summary Receiver Operating Characteristic (HRSOC) model was applied, which avoids methodological problems of meta-analyses based on summary points of sensitivity and specificity values. We also investigated relevant confounders of CSF biomarkers' diagnostic performance such as age, disease duration, and global cognitive impairment. RESULTS: The p-tau/Aβ42 ratio showed the best diagnostic performance. No statistically significant effects of the confounders were observed. Nonetheless, the p-tau/Aβ42 ratio may be especially indicated for younger patients. P-tau may be preferable for less cognitively impaired patients (high MMSE scores) and the t-tau/Aβ42 ratio for more cognitively impaired patients (low MMSE scores). CONCLUSION: The p-tau/Aβ42 ratio has potential for being implemented in the clinical routine for the differential diagnosis between AD and FTLD. It is of utmost importance that future studies report information on confounders such as age, disease duration, and cognitive impairment, which should also stimulate understanding of the role of these factors in disease mechanisms and pathophysiology.

Challenges in Screening and Recruitment for a Neuroimaging Study in Cognitively Impaired Geriatric Inpatients. - Apostolova, Ivayla; Lange, Catharina; Roberts, Anna; Igel, Hans Joachim; Mäurer, Anja; Liese, Stephanie; Estrella, Melanie; Prasad, Vikas; Stechl, Elisabeth; Lämmler, Gernot; Steinhagen-Thiessen, Elisabeth; Buchert, Ralph (J Alzheimers Dis, 2017)
BACKGROUND: Neuroimaging-based biomarkers have the potential to improve etiological diagnosis of cognitive impairment in elderly inpatients. However, there is a relative lack of studies on neuroimaging-based biomarkers in hospitalized geriatric patients, as the vast majority of neuroimaging studies in dementia have focused on memory clinic outpatients. An important aspect of study planning is a priori estimation of the rate of screen failures. OBJECTIVE: To report on the rate and causes of screen failures in a prospective study on the utility of neuroimaging (PET, MRI) for the etiological diagnosis of newly manifested cognitive impairment in acutely hospitalized geriatric patients. METHODS: Ten acute care geriatrics clinics with 802 beds participated in the study. The potential recruitment rate had been estimated to 5 patients/100 beds/week. RESULTS: Seventeen months of pre-screening resulted in 322 potential participants. 109 of these patients were enrolled, i.e., the screen failure rate was 66%. 58% of the screen failures were due to refusal of participation by the patient, most often due to lack of interest in clarifying the cause of the cognitive impairment or due to reluctance to engage in additional diagnostic procedures associated with physical stress. 42% of pre-screened patients were excluded because of violation of the eligibility criteria. CONCLUSION: Enrollment for neuroimaging studies presents considerable additional challenges in acutely hospitalized geriatric patients compared to outpatient settings. Low rate of approaching potential candidates by attending geriatricians and a high rate of screen failures have to be anticipated in the study design.

Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment. - Devanand, D P; Lentz, Cody; Chunga, Richard E; Ciarleglio, Adam; Scodes, Jennifer M; Andrews, Howard; Schofield, Peter W; Stern, Yaakov; Huey, Edward D; Bell, Karen; Pelton, Gregory H (J Alzheimers Dis, 2017)
BACKGROUND: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology. OBJECTIVE: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). METHODS: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks. RESULTS: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07). CONCLUSIONS: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

Changes in Plasma β-NGF and Its Receptors Expression on Peripheral Blood Monocytes During Alzheimer's Disease Progression. - Crispoltoni, Lucia; Stabile, Anna Maria; Pistilli, Alessandra; Venturelli, Massimo; Cerulli, Giuliano; Fonte, Cristina; Smania, Nicola; Schena, Federico; Rende, Mario (J Alzheimers Dis, 2017)
Alzheimer's disease (AD), the most common cause of dementia, is characterized by the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, and by neuroinflammation. During the pathogenesis of AD, monocyte-macrophage lineage cells become increasingly ineffective in clearing Aβ deposits, less able to differentiate, and shift toward pro-inflammatory processes. Beta-nerve growth factor (β-NGF) and its receptors, TrKA and p75NTR, produce several biological responses, including cell apoptosis and survival, and inflammation. In the central nervous system, the involvement of these receptors in several critical hallmarks of AD is well known, but their role in circulating monocytes during the progression of dementia is unclear. We investigated the relationship between plasma β-NGF concentration and TrkA/p75NTR receptor expression in monocytes of patients with mild cognitive impairment (MCI), mild AD, and severe AD. We observed that plasma β-NGF concentration was increased with a higher expression of TrKA, but not of p75NTR, in monocytes from patients with MCI and mild AD, whereas β-NGF concentration and TrKA expression were decreased and p75NTR expression was increased, associated with caspase 3-mediated apoptosis, in patients with severe AD. In our study, we show evidence of variation in plasmatic β-NGF and monocytic TrkA/p75NTR receptor expression during the progression of dementia. These novel findings add evidence to support the hypothesis for the involvement of β-NGF and its receptors on monocytes during AD progression.

Chinese Calligraphy Writing for Augmenting Attentional Control and Working Memory of Older Adults at Risk of Mild Cognitive Impairment: A Randomized Controlled Trial. - Chan, Sam C C; Chan, Chetwyn C H; Derbie, Abiot Y; Hui, Irene; Tan, Davynn G H; Pang, Marco Y C; Lau, Stephen C L; Fong, Kenneth N K (J Alzheimers Dis, 2017)
BACKGROUND: Nonpharmacological intervention for individuals with mild cognitive impairment (MCI) needs further investigation. OBJECTIVE: Test efficacy of an eight-week Chinese calligraphy writing training course in improving attentional control and working memory. METHODS: Ninety-nine participants with MCI were randomized into the eight-week calligraphy writing (n = 48) or control (tablet computer) training (n = 51). Outcomes of the interventions were attentional control, working memory, visual scan and processing speed. They were measured at baseline, post-training, and six-month follow-up. RESULTS: Calligraphy writing, when compared with control, significantly improved working memory as reflected from DST-Backward sequence (p = 0.009) and span scores (p = 0.002), and divided attention as reflected from CTT2 (p < 0.001), and at the post-training. The unique improvement in working memory (span: p < 0.001; sequence: p = 0.008) of the intervention group was also found at follow-up when comparing with those at baseline. Changes in the other outcome measures were not statistically significant. CONCLUSION: The findings provide support that Chinese calligraphy writing training for eight weeks using a cognitive approach would improve working memory and to a lesser extent attentional control functions of patients with early MCI. They also demonstrate the usefulness of using mind-and-body practice for improving specific cognitive functions.

Cholinesterase Inhibitor Therapy in Alzheimer's Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates. - Moss, Donald E; Perez, Ruth G; Kobayashi, Haruo (J Alzheimers Dis, 2017)
Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer's disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.
Keywords: Acetylcholinesterase; Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Erythrocytes; Injections, Intramuscular; Macaca fascicularis; Male; Nootropic Agents; Time Factors

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson's Disease. - Vasquez, Velmarini; Mitra, Joy; Hegde, Pavana M; Pandey, Arvind; Sengupta, Shiladitya; Mitra, Sankar; Rao, K S; Hegde, Muralidhar L (J Alzheimers Dis, 2017)
Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (∼2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.

Chronic Lithium Treatment in a Rat Model of Basal Forebrain Cholinergic Depletion: Effects on Memory Impairment and Neurodegeneration. - Gelfo, Francesca; Cutuli, Debora; Nobili, Annalisa; De Bartolo, Paola; D'Amelio, Marcello; Petrosini, Laura; Caltagirone, Carlo (J Alzheimers Dis, 2017)
Alzheimer's disease (AD) is an age-related neurodegenerative disorder with multifactorial etiopathogenesis, characterized by progressive loss of memory and other cognitive functions. A fundamental neuropathological feature of AD is the early and severe brain cholinergic neurodegeneration. Lithium is a monovalent cation classically utilized in the treatment of mood disorders, but recent evidence also advances a beneficial potentiality of this compound in neurodegeneration. Interestingly, lithium acts on several processes whose alterations characterize the brain cholinergic impairment at short and long term. On this basis, the aim of the present research was to evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes, by investigating memory functions and neurodegeneration correlates. Adult male rats were lesioned by bilateral injections of the immunotoxin 192 IgG-Saporin into the basal forebrain. Starting 7 days before the surgery, the animals were exposed to a 30-day lithium treatment, consisting of a 0.24% Li2CO3 diet. Memory functions were investigated by the open field test with objects, the sociability and preference for social novelty test, and the Morris water maze. Hippocampal and neocortical choline acetyltransferase (ChAT) levels and caspase-3 activity were determined. Cholinergic depletion significantly impaired spatial and social recognition memory, decreased hippocampal and neocortical ChAT levels and increased caspase-3 activity. The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.

Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage. - Villarreal, Stephanie; Zhao, Fuqiang; Hyde, Lynn A; Holder, Daniel; Forest, Thomas; Sondey, Marie; Chen, Xia; Sur, Cyrille; Parker, Eric M; Kennedy, Matthew E (J Alzheimers Dis, 2017)
Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AβPPswe mice. Animals were treated with verubecestat or controls including the anti-Aβ antibody analog of bapineuzumab (3D6) as a positive control for ARIA induction. ARIA-H was measured using in-life longitudinal T2*-MRI and Prussian blue histochemistry at study end. Verubecestat reduced plasma and cerebrospinal fluid Aβ40 and Aβ42 by >90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-Aβ treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Aβ antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain Aβ40 and Aβ42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Aβ immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls. The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aβ peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials.

The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer's Disease Study. - Gareri, Pietro; Castagna, Alberto; Cotroneo, Antonino Maria; Putignano, Daria; Conforti, Raffaele; Santamaria, Francesco; Marino, Saverio; Putignano, Salvatore (J Alzheimers Dis, 2017)
BACKGROUND: Citicoline can have beneficial effects both in degenerative and in vascular cognitive decline in a variety of ways (apoptosis inhibition, neuroplasticity potentiation, phospholipid, and acetylcholine (ACh) synthesis). Acetylcholinesterase inhibitors (AChEIs) have been used for treatment of Alzheimer's disease (AD). When co-administered with cholinergic precursors, they are able to increase the intrasynaptic levels of ACh more than when the single drugs given alone. OBJECTIVE: The aim of the present study was to show the effectiveness of oral citicoline plus AChEIs in patients affected with AD. METHODS: This was a retrospective multi-centric case-control study, involving seven Centers for Cognitive Impairment and Dementia in Italy, on 448 consecutive patients aged 65 years old or older affected with AD. 197 patients were treated with an AChEI while 251 were treated with an AchEI + citicoline 1000 mg/day given orally. Cognitive functions were assessed by MMSE, daily life functions by ADL and IADL, behavioral symptoms by NPI, comorbidities by CIRS, and mood by GDS-short form. Tests were administered at baseline (T0), after 3 (T1), and 9 months (T2). The primary outcomes were effects of combined administration versus AChEIs given alone on cognitive functions assessed by MMSE. The secondary outcomes were possible side effects or adverse events of combination therapy versus AChEIs alone. RESULTS: Patients treated with citicoline plus an AChEI showed a statistically significant increase in MMSE between T0 and T1 (16.88±3.38 versus 17.62±3.64; p = 0.000) and between T1 and T2 (17.62±3.64 versus 17.89±3.54; p = 0.000). CONCLUSION: The present study encourages the role of combined administration in disease management by slowing disease progression.

Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms. - Miranda, Luís F J R; Gomes, Karina B; Tito, Pedro A L; Silveira, Josianne N; Pianetti, Gerson A; Byrro, Ricardo M D; Peles, Patrícia R H; Pereira, Fernando H; Santos, Thiago R; Assini, Arthur G; Ribeiro, Valéria V; Moraes, Edgar N; et al. (J Alzheimers Dis, 2017)
The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer's disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥-1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms.

The Clinical Use of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease Diagnosis: The Italian Selfie. - Sancesario, Giulia M; Toniolo, Sofia; Chiasserini, Davide; Di Santo, Simona G; Zegeer, Josh; Bernardi, Gaetano; Musicco, Massimo; Caltagirone, Carlo; Parnetti, Lucilla; Bernardini, Sergio (J Alzheimers Dis, 2017)
Although the use of cerebrospinal fluid (CSF) amyloid β1-42 (Aβ42), tau (T-tau), and phosphorylated tau (p-tau181) gives added diagnostic and prognostic values, the diffusion is still limited in clinical practice and only a restricted number of patients receive an integrated clinico-biological diagnosis. By a survey, we aimed to do a "selfie" of the use and diffusion of CSF biomarkers of dementia in Italy, the standardization of pre-analytical procedures, the harmonization of ranges, and the participation to Quality Control programs. An online questionnaire was sent to the members of SIBioC and SINdem-ITALPLANED and to main neurological clinics all over Italy. In Italy, 25 laboratories provide biomarkers analysis in addition to a network of 15 neighboring hospitals. In sum, 40 neurological centers require CSF analyses. 7/20 regions (35%) lack CSF laboratories. Standardization of pre-analytical procedures is present in 62.02% of the laboratories; only 56.00% of the laboratories participate in International Quality Control. There is no harmonization of cut-offs. In Italy, the use of CSF biomarkers is still limited in clinical practice. Standardization and harmonization of normal ranges are needed. To optimize and expand the use of CSF biomarkers, a cost-benefit analysis should be promoted by scientific societies and national health services.