Volume 50, Number 1, 2016

Pages 1-7
Short Communication

María Carmona- Iragui, Ana Fernández-Arcos, Daniel Alcolea, Fabrizio Piazza, Estrella Morenas, Sofía Antón-Aguirre, Isabel Sala, Jordi Clarimon, Oriol Dols-Icardo, Valle Camacho, Frederic Sampedro, Josep Munuera, Fidel Nuñez-Marin, Alberto Lleó, Juan Fortea, Beatriz Gómez-Ansón, Rafael Blesa (Handling Associate Editor: Giorgio Giaccone)
Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation
Abstract: We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ40 and Aβ42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOE ε4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis, potentially avoiding brain biopsy.

Pages 9-11
Commentary

Andreas Charidimou
Cerebral Amyloid Angiopathy–Related Inflammation Biomarkers: Where Are We Now?
Abstract: Cerebral amyloid angiopathy–related inflammation (CAA-ri) is an aggressive disease subtype of CAA with characteristic clinical and radiological findings. CAA-ri is an important diagnosis to reach in clinical practice, as patients typically respond to prompt immunosuppressive treatment. A definitive diagnosis of CAA-ri still requires a brain biopsy, and hence developing non-invasive diagnostic criteria and biomarkers for this syndrome are key priorities in the field. CAA-ri has gained additional interest for its notable similarities to amyloid-related imaging abnormalities, a complication of immunotherapy treatments in Alzheimer’s disease patients. In this commentary, the current state of biomarkers research for CAA-ri and recently suggested diagnostic criteria are put into context.

Pages 13-17
Short Communication

Lei Gao*, Zhen Cui*, Liang Shen, Hong-Fang Ji *These authors contributed equally to the work.
Shared Genetic Etiology between Type 2 Diabetes and Alzheimer’s Disease Identified by Bioinformatics Analysis
Abstract: Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are two major health issues, and increasing evidence in recent years supports the close connection between these two diseases. The present study aimed to explore the shared genetic etiology underlying T2D and AD based on the available genome wide association studies (GWAS) data collected through August 2014. We performed bioinformatics analyses based on GWAS data of T2D and AD on single nucleotide polymorphisms (SNPs) level, gene level, and pathway level, respectively. Six SNPs (rs111789331, rs12721046, rs12721051, rs4420638, rs56131196, and rs66626994) were identified for the first time to be shared genetic factors between T2D and AD. Further functional enrichment analysis found lipid metabolism related pathways to be common between these two disorders. The findings may have important implications for future mechanistic and interventional studies for T2D and AD.

Pages 19-25
Guillaume Sacco, Corinne Caillaud, Gregory Ben Sadoun, Philippe Robert, Renaud David, Jeanick Brisswalter
Exercise Plus Cognitive Performance Over and Above Exercise Alone in Subjects with Mild Cognitive Impairment
Abstract: Background: Epidemiological studies highlight the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments. Objectives: The aim of this study was to ascertain the effect of aerobic exercise associated with cognitive enrichment on cognitive performance in subjects with mild cognitive impairment (MCI). Method: Eight participants with MCI (72 ± 2 years) were enrolled in a 9-month study that consisted of two 3-months experimental interventions separated by a training cessation period of 3 months. The interventions included either aerobic exercise alone or aerobic exercise combined with cognitive enrichment. The exercise program involved two 20-min cycling exercise bouts per week at an intensity corresponding to 60% of the heart rate reserve. Cognitive performance was assessed using a task of single reaction time (SRT) and an inhibition task (Go-no-Go) before, immediately after, and 1 month after each intervention. Results: The exercise intervention improved the speed of responses during the Go-no-Go task without any increase in errors. This improvement was enhanced by cognitive enrichment (6 ± 1%; p > 0.05), when compared with exercise alone (4 ± 0.5%,). Following exercise cessation, this positive effect disappeared. No effect was observed on SRT performance. Conclusion: Regular aerobic exercise improved cognitive performance in MCI subjects and the addition of cognitive tasks during exercise potentiated this effect. However, the influence of aerobic exercise on cognitive performance did not persist after cessation of training. Studies involving a larger number of subjects are necessary to confirm these results.

Pages 27-40
Shir Lynn Lim, Qi Gao, Ma Shwe Zin Nyunt, Lingli Gong, Josephine B. Lunaria, May Li Lim, Audrey Ling, Carolyn Su-Ping Lam, Arthur Mark Richards, Lieng Hsi Ling, Tze Pin Ng (Handling Associate Editor: Francesco Panza)
Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies
Abstract: Background: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease. Objective: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases. Methods: Cognition was assessed by Mini-Mental State Examination (MMSE) (n=308) and detailed neuropsychological tests (n=155). Vascular measures included measures of carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (β), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors. Results: The participants’ mean age was 63.0±6.1 years. Inverse associations with MMSE were found for AC (β=0.128, p=0.019), Ep (β=-0.151, p=0.008), β index (β=-0.122, p=0.029), carotid stiffness z-score (β=-0.154, p=0.007); with executive function for CFPWV (β=-0.209, p=0.026), AC (β=0.214, p=0.005), Ep ( β=-0.160, p=0.050), β index (β=-0.165, p=0.041), and both aortic (β=-0.229, p=0.010) and carotid (β=-0.208, p=0.010) stiffness z-scores; with verbal memory for AI (β=-0.229, p=0.004) and aortic (β=-0.263, p=0.004) stiffness z-score; with language for AI (β=-0.155, p=0.025), aortic stiffness z-score (β=-0.196, p=0.011). RHI positively correlated with visuospatial ability (β=0.195, p=0.013) and executive function (β=0.151, p=0.045). Conclusion: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment.

Pages 41-45
Brian K. Lebowitz, Cheryl Weinstein, Alexa Beiser, Sudha Seshadri, Philip A. Wolf, Sandford Auerbach, Rhoda Au
Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis
Abstract: Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.

Pages 47-59
Bernhard Michalowsky, Jochen René Thyrian, Tilly Eichler, Johannes Hertel, Diana Wucherer, Steffen Flessa, Wolfgang Hoffmann (Handling Associate Editor: Tae-Jin Lee)
Economic Analysis of Formal Care, Informal Care, and Productivity Losses in Primary Care Patients who Screened Positive for Dementia in Germany
Abstract: Background: The majority of people with dementia (PwD) live at home and require professional formal care and informal care that is generally provided by close relatives. Objective: To determine the utilization and costs of formal and informal care for PwD, indirect costs because of productivity losses of caregivers, and the associations between cost, socio-demographic and clinical variables. Methods: The analysis includes the data of 262 community-dwelling PwD and their caregivers. Socio-demographics, clinical variables, and the utilization of formal care were assessed within the baseline assessment. To evaluate informal care costs, the Resource Utilization in Dementia (RUD) questionnaire was used. Costs were calculated from a social perspective. Associations were evaluated using multiple linear and logistic regression models. Results: Formal care services were utilized less (26.3%) than informal care (85.1%), resulting in a cost ratio of one to ten (1,646 €; 16,473 €, respectively). In total, 29% of caregivers were employed, and every seventh (14.3%) experienced productivity losses, which corresponded to 1,258 € annually. Whereas increasing deficits in daily living activities were associated with higher formal and higher informal costs, living alone was significantly associated with higher formal care costs and the employment of a caregiver was associated with lower informal care costs. Conclusion: Informal care contributes the most to total care costs. Living alone is a major cost driver for formal costs because of the lower availability of potential informal care. The availability of informal care is limited and productivity losses are increased when a caregiver is employed.

Pages 61-70
Camillo Marra, Guido Gainotti, Lucia Fadda, Roberta Perri, Giordano Lacidogna, Eugenia Scaricamazza, Chiara Piccininni, Davide Quaranta
Usefulness of an Integrated Analysis of Different Memory Tasks to Predict the Progression from Mild Cognitive Impairment to Alzheimer’s Disease: The Episodic Memory Score (EMS)
Abstract: Taking into the account both the severity and the consistency of performances obtained on memory test by patients with amnestic mild cognitive impairment (aMCI) could improve the power to predict their progression to Alzheimer’s disease. For this purpose, we constructed the Episodic Memory Score (EMS), which is obtained by subdividing in tertiles performances obtained at baseline in verbal (RAVLT) and visual episodic memory (Rey-Osterrieth Figure-delayed recall) and giving a score ranging from 1 (worst result) to 3 (best result) to results falling within each tertile. The EMS was computed for each patient by summing the tertile score obtained on each memory task, so that the total score ranged from 4 (worst performance) to 12 (best performance). The aMCI sample consisted of 198 subjects who completed the two-year follow-up, at the end of which 55 subjects had converted to dementia. The mean EMS score obtained by aMCI converters was significantly lower than that of aMCI-stable patients. In detecting conversion to dementia, the comparison between EMS and individual memory scores obtained at baseline was made by computing ROC curves, and estimating the respective area under the curve (AUC). The EMS had a larger AUC than the individual memory scores. At baseline aMCI converters performed worse than non-converters not only on memory tasks, but also on executive functions tasks. However, in a multiple variables logistic regression analysis in which all scores showing statistically significant differences between aMCI-converters and aMCI-stable were entered, the EMS was the only reliable predictor of progression from aMCI to dementia.

Pages 71-76
Kyle Steenland, Felicia C. Goldstein, Allan Levey, Whitney Wharton
A Meta-Analysis of Alzheimer’s Disease Incidence and Prevalence Comparing African-Americans and Caucasians
Abstract: Background: Several studies have shown higher Alzheimer’s disease (AD) incidence rates are in African-Americans (AAs) than Caucasians (CCs). If this finding is consistent across studies, it raises important etiologic questions regarding factors responsible for this discrepancy. It also affects the likely public health burden of AD in the US in the future, as the non-Caucasian population becomes the majority. Objective: Estimate the AA/CC rate ratio for AD incidence across all available studies. Methods: We conducted a meta-analysis of population-based studies for the rate ratio (RR) of AD incidence for AAs versus CCs, after identifying six relevant studies from the literature. We calculated an AA/CC rate ratio across all studies using inverse-variance weighting, and assessed inter-study heterogeneity. Using these incidence data, as well as data on survival after diagnosis, and on all-cause mortality, we also estimated the US prevalence of AD among AAs and CCs. Results: There were six population-based studies with data comparing AD incidence between AAs and CCs, with an estimated 370 AA and 640 CC incident cases. The meta-analysis RR showed that the AD rate for AAs was 64% higher than for CCs (RR=1.64 (95% CI 1.35-2.00)). We estimated the current US AD prevalence for ages 65-90 to be 5.5% for CCs, and 8.6% for AAs (prevalence ratio 1.56). Conclusion: AAs have an increased risk of incident and prevalent AD compared to CCs for reasons which are unknown, but are hypothesized to reflect biological, psychological, and socioeconomic factors.

Pages 77-87
Marta Bolós*, María Llorens-Martín*, Jerónimo Jurado-Arjona, Félix Hernández, Alberto Rábano, Jesús Avila *These authors contributed equally to this work.
Direct Evidence of Internalization of Tau by Microglia in vitro and in vivo
Abstract: The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons—a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer’s disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.

Pages 89-99
Emilie Avondino, Pascal Antoine
Heterogeneity of Cognitive Anosognosia and its Variation with the Severity of Dementia in Patients with Alzheimer’s Disease
Abstract: Currently, the lack of awareness of deficits, i.e., anosognosia, is a major obstacle in the healthcare circuit that delays the diagnosis of Alzheimer’s disease (AD). However, a clear framework is lacking in the literature related to this phenomenon in terms of its definition, mechanisms, and objects. The aim of this study is to assess the different levels of cognitive anosognosia using a prediction-performance procedure and to identify the potential correlates of these levels. A sample of patients with probable AD was divided into three groups according to the severity of dementia (mild (MiD), moderate (MoD), and moderately severe (MSD) dementia), ranked according to the results of the Mini-Mental State Examination. We observed the following three scores: the real score, the prediction score, and the anosognosia score. These scores were calculated based on the prediction-performance task MISAwareness from the Dementia Rating Scale for cognitive processes (i.e., Attention, Initiation, Conceptualization, Construction, and Memory). We obtained a strong plateau effect between the MiD and MoD groups for anosognosia scores for actual performance or prediction for both the level of overall functioning and for specific processes. The sole exception was the result for memory processes. Moreover, the profiles of the patients’ responses on the Memory subscale were substantially different and, indeed, opposite from those for the other processes. The main results confirm the multidimensionality of anosognosia and its variability with the stage of dementia and specifically implicate memory processes that indicate a cleavage between memory and other cognitive functions.

Pages 101-110
Julie Vallortigara, David Whitfield, William Quelch, Amani Alghamdi, David Howlett, Tibor Hortobágyi, Mary Johnson, Johannes Attems, John T. O’Brien, Alan Thomas, Clive G. Ballard, Dag Aarsland, Paul T. Francis
Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia
Abstract: Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), but are also frequently present in Alzheimer’s disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key ‘SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor’ (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n=130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p<0.001). This correlated to the final MMSE score before death (p=0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p=0.0004) and monomeric α-syn (p=0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

Pages 111-126
Martin Kleinschmidt, Robby Schoenfeld, Claudia Göttlich, Daniel Bittner, Jürgen Erich Metzner, Bernd Leplow, Hans-Ulrich Demuth
Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology
Abstract: Background. Current treatment in Alzheimer’s disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. Objective. The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. Methods. In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively. Results. Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ε4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ. Conclusion. Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.

Pages 127-131
Cláudia Yang Santos, Yen Ying Lim, Wen-Chih Wu, Jason Timothy Machan, Shahena Polynice, Rachel Schindler, Paul Maruff, Peter Jeffrey Snyder (Handling Associate Editor: Mark Bondi)
Resting-State Cardiac Workload is Related to Both Increased Neocortical Aggregation of Amyloid-β and Relative Impairments in Spatial Working Memory in Pre-Clinical Alzheimer’s Disease
Abstract: We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage=62.8 years; range=55 to 75 years) at risk for Alzheimer’s disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2=0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands.

Pages 133-148
Rosa Yu, Chetram Deochand, Alexander Krotow, Raiane Leão, Ming Tong, Amit R. Agarwal, Enrique Cadenas, Suzanne M. de la Monte (Handling Associate Editor: Deborah Gustafson)
Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration
Abstract: Background: Meta-analysis studies showed that smokers have increased risk for developing Alzheimer’s disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity. Objective: The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions. Methods: Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). The frontal lobes were used for histology and qRT-PCR analysis. Results: Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated. Conclusion: CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.

Pages 149-159
Tatsuhiro Hisatsune, Jun Kaneko, Hiroki Kurashige, Yuan Cao, Hideo Satsu, Mamoru Totsuka, Yoshinori Katakura, Etsuko Imabayashi, Hiroshi Matsuda (Handling Associate Editor: Takashi Asada)
Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People
Abstract: Our goal in this study was to determine whether or not anserine/carnosine supplementation (ACS) is capable of preserving cognitive function of elderly people. In a double-blind randomized controlled trial, volunteers were randomly assigned to an ACS or placebo group at a 1:1 ratio. The ACS group took 1.0 g of an anserine/carnosine (3:1) formula daily for 3 months. Participants were evaluated by psychological tests before and after the 3-month supplementation period. Thirty-nine healthy elderly volunteers (60-78 years old) completed the follow-up tests. Among the tests, delayed recall verbal memory assessed by the Wechsler Memory Scale-Logical Memory showed significant preservation in the ACS group, compared to the placebo group (p=0.0128). Blood analysis revealed a decreased secretion of inflammatory cytokines, including CCL-2 and IL-8, in the ACS group. MRI analysis using arterial spin labeling showed a suppression in the age-related decline in brain blood flow in the posterior cingulate cortex area in the ACS group, compared to the placebo group (p=0.0248). In another randomized controlled trial, delayed recall verbal memory showed significant preservation in the ACS group, compared to the placebo group (p=0.0202). These results collectively suggest that ACS may preserve verbal episodic memory and brain perfusion in elderly people, although further study is needed.

Pages 161-174
Aki Mishima*, Takashi Nihashi*, Yoshio Ando, Hisashi Kawai, Takashi Kato, Kengo Ito, Teruhiko Terasawa *These authors contributed equally to the study and manuscript.
Biomarkers Differentiating Dementia with Lewy Bodies from Other Dementias: A Meta-Analysis
Abstract: Background: Several nuclear imaging and cerebrospinal fluid (CSF) biomarkers are under investigation, aimed at facilitating the differential diagnosis of dementias. Objective: To quantitatively synthesize data on test performance in differentiating dementia with Lewy bodies (DLB) from other dementias. Methods: We searched PubMed (January 2000–March 2015) for English-language publications that assessed a selected set of five imaging and three CSF biomarkers for this purpose. We meta-analyzed measures of agreement between biomarker results and clinical diagnosis. Results: Forty-five publications were eligible. The majority of evidence was based on studies that enrolled representative disease populations. For differentiating between DLB and Alzheimer’s disease (AD) or other dementias, metaiodobenzylguanidine scintigraphy and dopamine transporter (DAT) single photon emission computed tomography (SPECT) showed, respectively, excellent (summary kappa=0.85; 95% confidence interval [95%CI], 0.74–0.96) and good (summary kappa=0.71; 95%CI, 0.43–0.99) agreement. Metaiodobenzylguanidine scintigraphy appeared superior to fluorodeoxyglucose–positron emission tomography (summary kappa=0.53; 95%CI, 0.36–0.69) and cerebral blood flow SPECT (summary kappa=0.40; 95%CI, 0.33–0.47). For differentiating DLB from AD, CSF t-tau levels (summary kappa=0.68; 95%CI, 0.55–0.82) performed comparably to metaiodobenzylguanidine scintigraphy and DAT SPECT. Sparse direct comparative evidence failed to corroborate these indirect comparisons. Conclusion: Metaiodobenzylguanidine scintigraphy and DAT SPECT are highly concordant with clinical diagnosis in differentiating DLB from other dementias. However, given the limitations in the study design, the applicability of these results to real-world differential diagnosis remains unclear. Prospective studies targeting patients with atypical presentations that adopt gold standard tests would reliably estimate the true test performance of these promising biomarkers.

Pages 175-188
Assaf Ezra, Inna Rabinovich- Nikitin, Polina Rabinovich-Toidman, Beka Solomon (Handling Associate Editor: Debomoy Lahiri)
Multifunctional Effect of Human Serum Albumin Reduces Alzheimer’s Disease Related Pathologies in the 3xTg Mouse Model
Abstract: Alzheimer’s disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifests simultaneously, eventually leading to cognitive impairment and death. No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies underlying AD. This study provides insight into the mechanism for HSA's therapeutic effect. In vivo, a myriad of beneficial effects were observed by pumps infusing HSA intracerebroventricularly, for the first time in an AD 3xTg mice model. A significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42, soluble oligomers, and total plaque area were reduced. Neuroblastoma SHSY5Y cell line confirmed that the reduction in Aβ1-42 toxicity was due direct binding rather than other properties of HSA. Total and hyperphosphorylated tau were reduced along with an increase in tubulin, suggesting increased microtubule stability. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. These multidimensional beneficial effects of intracranial administrated HSA, together or individually, contributed to an improvement in cognitive tests, suggesting a non-immune or Aβ efflux dependent means for treating AD.

Pages 189-200
Soonmin Lim, Jin Gyu Choi, Minho Moon, Hyo Geun Kim, Wonil Lee, Hyoung-rok Bak, Hachang Sung, Chi Hye Park, Sun Yeou Kim, Myung Sook Oh
An Optimized Combination of Ginger and Peony Root Effectively Inhibits Amyloid-β Accumulation and Amyloid-β-Mediated Pathology in AβPP/PS1 Double-Transgenic Mice
Abstract: The progressive aggregation of amyloid-β protein (Aβ) into senile plaques is a major pathological factor of Alzheimer’s disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aβ accumulation and memory impairment in amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 μg/ml OCGP inhibited Aβ accumulation to the same extent as did 10 μM curcumin. Furthermore, AβPP/PS1 double-transgenic mice treated with OCGP (50 or 100 mg/kg/day given orally for 14 weeks) exhibited reduced Aβ plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aβ accumulation and inflammation in the brain.

Pages 201-215
Carola Stockburger, Davide Miano, Marion Baeumlisberger, Thea Pallas, Tabiwang N. Arrey, Michael Karas, Kristina Friedland, Walter E. Müller (Handling Associate Editor: P. Hemachandra Reddy)
A Mitochondrial Role of SV2a Protein in Aging and Alzheimer’s Disease: Studies with Levetiracetam
Abstract: Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer’s disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, we hypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.

Pages 217-232
Domingo J. Quintana-Hernández, María T. Miró-Barrachina, Ignacio J. Ibáñez-Fernández, Angelo Santana-del Pino, María P. Quintana-Montesdeoca, Bienvenida Rodríguez-de Vera¸ David Morales-Casanova, María del Carmen Pérez-Vieitezf, Javier Rodríguez-García, Noelia Bravo-Caraduje
Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer’s Disease: A Randomized Clinical Trial
Abstract: Background: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer’s disease (AD). However, no specific data on the maintenance of cognitive capacities were presented. Objective: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD. Methods: Design: Longitudinal, non-inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group. Participants: Patients with AD who voluntarily attended the Lidia García Foundation (n=502). Only those who were treated with donepezil and MMSE ≥18 were included (n=120). Intervention: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation. Measures: Cognitive assessment CAMDEX-R (MMSE and CAMCOG). Statistical analysis: Repeated-measures ANOVA (p<0.05) and the effect size Cohen’s d was performed. Results: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p<0.05), while mindfulness and cognitive stimulation therapy were equivalent (p≥0.05). Group cognitive stimulation evolved better than the control (p<0.05) group but not better than the muscle relaxation group (p≥0.05). The effect size compared over two years was large for the mindfulness group (p≥0.80), moderate for the relaxation group (p≥0.50), and low for the cognitive stimulation group (p≥0.20). Conclusion: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD.

Pages 233-248
Shuihua Wang*, Yudong Zhang*, Ge Liu, Preetha Phillips, Ti-Fei Yuan *These authors contributed equally to this work.
Detection of Alzheimer’s Disease by Three-Dimensional Displacement Field Estimation in Structural Magnetic Resonance Imaging
Abstract: Background: Within the past decade, computer scientists have developed many methods using computer vision and machine learning techniques to detect Alzheimer’s disease (AD) in its early stages. Objective: However, some of these methods are unable to achieve excellent detection accuracy, and several other methods are unable to locate AD-related regions. Hence, our goal was to develop a novel AD brain detection method. Methods: In this study, our method was based on the three-dimensional (3D) displacement-field (DF) estimation between subjects in the healthy elder control group and AD group. The 3D-DF was treated with AD-related features. The three feature selection measures were used in the Bhattacharyya distance, Student’s t-test, and Welch’s t-test (WTT). Two non-parallel support vector machines, i.e., generalized eigenvalue proximal support vector machine and twin support vector machine (TSVM), were then used for classification. A 50 x 10-fold cross validation was implemented for statistical analysis. Results: The results showed that “3D-DF + WTT + TSVM” achieved the best performance, with an accuracy of 93.05±2.18, a sensitivity of 92.57±3.80, a specificity of 93.18±3.35, and a precision of 79.51±2.86. This method also exceled in 13 state-of-the-art approaches. Additionally, we were able to detect 17 regions related to AD by using the pure computer-vision technique. These regions include sub-gyral, inferior parietal lobule, precuneus, angular gyrus, lingual gyrus, supramarginal gyrus, postcentral gyrus, third ventricle, superior parietal lobule, thalamus, middle temporal gyrus, precentral gyrus, superior temporal gyrus, superior occipital gyrus, cingulate gyrus, culmen, and insula. These regions were reported in recent publications. Conclusions: The 3D-DF is effective in AD subject and related region detection.

Pages 249-260
Anna Malishkevich, Gad A. Marshall, Aaron P. Schultz, Reisa A. Sperling, Judith Aharon-Peretz, Illana Gozes
Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer’s Disease Biomarkers
Abstract: Biomarkers for Alzheimer’s disease (AD) are vital for disease detection in the clinical setting. Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) is essential for brain formation and linked to cognitive functions. Here, we revealed that blood borne expression of ADNP and its paralog ADNP2 is correlated with premorbid intelligence, AD pathology, and clinical stage. Age adjustment showed significant associations between: 1) higher premorbid intelligence and greater serum ADNP, and 2) greater cortical amyloid and lower ADNP and ADNP2 mRNAs. Significant increases in ADNP mRNA levels were observed in patients ranging from mild cognitive impairment (MCI) to AD dementia. ADNP2 transcripts showed high correlation with ADNP transcripts, especially in AD dementia lymphocytes. ADNP plasma/serum and lymphocyte mRNA levels discriminated well between cognitively normal elderly, MCI, and AD dementia participants. Measuring ADNP blood-borne levels could bring us a step closer to effectively screening and tracking AD.

Pages 261-270
Hanneke F.M. Rhodius-Meester, Juha Koikkalainen, Jussi Mattila, Charlotte E. Teunissen, Frederik Barkhof, Afina W. Lemstra, Philip Scheltens, Jyrki Lötjönen, Wiesje M. van der Flier (Handling Associate Editor: Sebastiaan Engelborghs)
Integrating Biomarkers for Underlying Alzheimer’s Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers
Abstract: Background: Recent criteria allow biomarkers to provide evidence of Alzheimer’s disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients. Objective: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis. Methods: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure. Results: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86). Conclusion: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice.

Pages 271-282
Helen Hochstetler, Paula T. Trzepacz, Shufang Wang, Peng Yu, Michael Case, David B. Henley, Elisabeth Degenhardt, Jeannie-Marie Leoutsakos, Constantine G. Lyketsos for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Maheen Mausoof Adamson)
Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline
Abstract: Background: Alzheimer’s disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. Objective: This exploratory study aimed to define latent classes from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. Methods: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer’s Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. Results: GMM identified three trajectory classes (C): C1 (n=162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n=819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n=211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ε4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. Conclusions: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class.

Pages 283-295
Corinne E. Fischer, Winnie Qian, Tom A. Schweizer, Colleen P. Millikin, Zahinoor Ismail, Eric E. Smith, Lisa M. Lix, Paul Shelton, David G. Munoz (Handling Associate Editor: Giorgio Giaccone)
Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer’s Disease
Abstract: Background: The neuropathological correlates of psychosis in Alzheimer’s disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association. Objective: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD. Method: We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately. Results: 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis. Conclusions: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.