Volume 42, Number 3, 2014

Pages 707-722
Review
Alcibiades E. Villarreal, Rachel Barron, K.S. Rao, Gabrielle B. Britton
The Effects of Impaired Cerebral Circulation on Alzheimer’s Disease Pathology: Evidence from Animal Studies
Abstract: Persistent systemic hypoxia, a direct consequence of alterations in vascular function, can compromise the brain by increasing the risk of developing dementias such as Alzheimer’s disease (AD). Vascular contributions to cognitive impairment and AD in aged individuals are common, and several vascular risk factors for AD are linked to hypoxia. Clinical evidence confirms that structural and functional changes characteristic of AD pathology also occur following hypoxic-ischemic events such as stroke and traumatic brain injury. Studies with transgenic and non-transgenic mouse models reliably show that hypoxia increases the levels of amyloid-β peptides that form the characteristic plaques in AD brains. Moreover, some studies suggest that vascular lesions also promote tau phosphorylation, modulate apolipoprotein E expression, and have more profound in effects in aged animals, but additional evidence is needed to establish these findings. Although the mechanisms underlying hypoxia-related effects remain unclear, controlled animal studies continue to reveal mechanistic aspects of the relationship between hypoxia and AD pathology that are necessary for therapeutic developments. The present review summarizes evidence from rodent studies regarding the effects of hypoxia on AD-related pathology and evaluates its impact on understanding human disease.

Pages 723-737
Review
Sim K. Singhrao, Alice Harding, Tal Simmons, Sarita Robinson, Lakshmyya Kesavalu*, StJohn Crean* *These authors contributed equally to this work.
Oral Inflammation, Tooth Loss, Risk Factors, and Association with Progression of Alzheimer’s Disease
Abstract: Periodontitis is a polymicrobial chronic inflammatory disease of tooth-supporting tissues with bacterial etiology affecting all age groups, becoming chronic in a subgroup of older individuals. Periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola are implicated in the development of a number of inflammatory pathologies at remote organ sites, including Alzheimer’s disease (AD). The initial inflammatory hypothesis proposed that AD hallmark proteins were the main contributors of central nervous system (CNS) inflammation. This hypothesis is expanding to include the role of infections, lifestyle, and genetic and environmental factors in the pathogenesis of AD. Periodontal disease (PD) typifies a condition that encompasses all of the above factors including pathogenic bacteria. These bacteria not only are the source of low-grade, chronic infection and inflammation that follow daily episodes of bacteremia arising from everyday tasks such as brushing, flossing teeth, chewing food, and during dental procedures, but they also disseminate into the brain from closely related anatomical pathways. The long-term effect of inflammatory mediators, pathogens, and/or their virulence factors, reaching the brain systemically or otherwise would, over time, prime the brain’s own microglia in individuals who have inherent susceptibility traits. Such susceptibilities contribute to inadequate neutralization of invading agents, upon reaching the brain. This has the capacity to create a vicious cycle of sustained local inflammatory milieu resulting in the loss of cytoarchitectural integrity and vital neurons with subsequent loss of function (deterioration in memory). The possible pathways between PD and AD development are considered here, as well as environmental factors that may modulate/exacerbate AD symptoms.

Pages 739-755
Review
Song Chi, Jin-Tai Yu, Meng-Shan Tan, Lan Tan
Depression in Alzheimer’s Disease: Epidemiology, Mechanisms, and Management
Abstract: Depression occurs with a high prevalence of up to 50% in patients with Alzheimer’s disease (AD) and increases the caregivers’ burden. Depression symptoms can precede clinical diagnosis of AD for years or occurs around the onset of AD, although the etiology and pathologic mechanism of depression in AD pathogenesis remain unclear. Here, we provide an overview on recent studies, indicating that genetic factors, neuroanatomic changes, vascular risk factors, and the imbalance of neurotransmitters might contribute to depressive symptoms in AD. Tau pathology and amyloid-β accumulation also correlate with depression in AD. In addition, the alteration of hypothalamic-pituitary-adrenal axis, inflammatory pathway, and neurotrophin deficiency are the possible biological mechanisms linking depression and AD, and might become the potential targets for AD treatment. Current data support that antidepressants are promising to alleviate the symptom, though the efficacy is controversial. Moreover, antidementia medication and non-pharmacological interventions can be potential choices. In this review, we describe the prevalence and clinical course of depression in AD, analyze the underlying mechanisms, and discuss the possible management strategies for depression in patients with AD.

Pages 757-760
Short Communication
Roger Delabio, Lucas Rasmussen, Igor Mizumoto, Gustavo-Arruda Viani, Elizabeth Chen, João Villares, Isabela-Bazzo Costa, Gustavo Turecki, Sandra Aparecido Linde, Marilia Cardoso Smith, Spencer-Luiz Payão
PSEN1 and PSEN2 Gene Expression in Alzheimer’s Disease Brain: A New Approach
Abstract: Presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes encode the major component of y–secretase, which is responsible for sequential proteolytic cleavages of amyloid precursor proteins and the subsequent formation of amyloid-β peptides. 150 RNA samples from the entorhinal cortex, auditory cortex and hippocampal regions of individuals with Alzheimer’s disease (AD) and controls elderly subjects were analyzed with using real-time rtPCR. There were no differences between groups for PSEN1 expression. PSEN2 was significantly downregulated in the auditory cortex of AD patients when compared to controls and when compared to other brain regions of the patients. Alteration in PSEN2 expression may be a risk factor for AD.

Pages 761-766
Short Communication
Iván Manuel, Estíbaliz González de San Román, M. Teresa Giralt, Isidro Ferrer, Rafael Rodríguez-Puertasa (Handling Associate Editor: Mauro Maccarrone)
Type-1 Cannabinoid Receptor Activity During Alzheimer’s Disease Progression
Abstract: The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer’s disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack of classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance.

Pages 767-775
Sarah B. Martin, Amy L.S. Dowling, Joann Lianekhammy, Ira T. Lott, Eric Doran, M. Paul Murphy, Tina L. Beckett, Frederick A. Schmitt, Elizabeth Head
Synaptophysin and Synaptojanin-1 in Down Syndrome are Differentially Affected by Alzheimer’s Disease
Abstract: Adults with Down syndrome (DS) develop Alzheimer’s disease (AD) neuropathology by 40 years of age. Synaptophysin (SYN) consistently declines with age and is further reduced with sporadic AD. Thus, we hypothesized that SYN would be reduced in DS with AD. The gene for synaptojanin-1 (SYNJ1), involved in synaptic vesicle recycling, is on chromosome 21. We measured SYN and SYNJ1 in an autopsy series of 39 cases with DS and 28 without DS, along with 7 sporadic AD cases were examined. SYN was significantly lower in DSAD compared with DS alone and similar to sporadic AD. Reduced SYN is associated with AD neuropathology and with Aβ levels in DS, as is seen in sporadic AD. SYNJ1 was significantly higher in DS and correlated with several measures of Aβ. SYNJ1 was higher in DSAD and significantly higher than SYNJ1 in sporadic AD. Although significantly higher in DS, SYNJ1 is further increased with AD neuropathology suggesting interesting differences in a synapse-associated protein that is overexpressed in trisomy 21.

Pages 777-788
Cristina Valcárcel Nazco, Lilisbeth Perestelo Pérez, José Luis Molinuevo, Javier Mar, Iván Castilla, Pedro Serrano Aguilar (Handling Associate Editor: Ramon Luengo-Fernandez)
Cost-Effectiveness of the Use of Biomarkers in Cerebrospinal Fluid for Alzheimer’s Disease
Abstract: Background: The use of cerebrospinal fluid (CSF) biomarkers could facilitate early detection of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI) and the differential diagnosis between AD and non-AD dementias. The aim of this study is to assess the clinical and economic value of CSF biomarkers to diagnose AD. Objective: To determine the cost-effectiveness of the use of amyloid-β peptide (Aβ42), total tau, and phosphorylated tau proteins in CSF to diagnose AD in MCI and dementia patients. Methods: An economic evaluation was performed by means of cost-effectiveness analysis comparing two AD diagnostic alternatives: the combined determination of Aβ42 proteins, total tau, and phosphorylated tau in CSF as biomarkers of AD, and the standard clinical diagnosis based on the Related Disorders Association (NINDS-ADRDA) criteria. A decision analytic model was developed to synthesize the identified evidence and to compare the costs and effectiveness associated with each diagnostic strategy. A probabilistic sensitivity analysis using 2nd order Monte Carlo simulations was performed. Subsequently, acceptability curves were calculated and ANCOVA models were applied to the results of the Monte Carlo simulations in order to identify the parameters that led greater variability in the model outcomes. Results: The use of CSF biomarkers as an early diagnostic strategy of AD in MCI patients is a dominant alternative (less costly and more effective strategy than diagnostic criteria). In dementia patients, although there is a higher uncertainty, biomarkers in CSF seem a more cost-effective alternative than diagnostic criteria. Conclusions: Detecting AD in MCI patients by determining Aβ42, total tau, and phosphorylated tau proteins biomarkers in CSF is a cost-effective diagnostic alternative. No conclusive results were obtained on dementia patients.

Pages 789-799
Marie-France Nissou*, Audrey Guttin*, Cyril Zenga, François Berger, Jean-Paul Issartel*, Didier Wion* (Handling Associate Editor: William Grant) *These authors contributed equally to this work.
Additional Clues for a Protective Role of Vitamin D in Neurodegenerative Diseases: 1,25-Dihydroxyvitamin D3 Triggers an Anti-Inflammatory Response in Brain Pericyte
Abstract: Epidemiological and experimental studies suggest that 1,25-dihydroxyvitamin D3 (1,25D) plays a neuroprotective role in neurodegenerative diseases including Alzheimer’s disease. Most of the experimental data regarding the genes regulated by this hormone in brain cells have been obtained with neuron and glial cells. Pericytes play a critical role in brain function that encompasses their classical function in blood-brain barrier control and maintenance. However, the gene response of brain pericyte to 1,25D remains to be investigated. Analyses of the transcriptomic response of human brain pericytes to 1,25D demonstrate that human brain pericytes in culture respond to 1,25D by regulating genes involved in the control of neuroinflammation. In addition, pericytes respond to the pro-inflammatory cytokines tumor necrosis factor-α and Interferon-γ by inducing the expression of the CYP27B1 gene which is involved in 1,25D synthesis. Taken together, these results suggest that neuroinflammation could trigger the synthesis of 1,25D by brain pericytes, which in turn respond to the hormone by a global anti-inflammatory response. These findings identify brain pericyte as a novel 1,25D-responsive cell type and provide additional evidence for the potential value of vitamin D in the prevention or therapy of Alzheimer’s disease and other neurodegenerative/neuropsychiatric diseases associated with an inflammatory component.

Pages 801-811
Virginia Mato Abad, Alicia Quirós, Roberto García-Álvarez, Javier Pereira Loureiro, Juan Álvarez-Linera, Ana Frank, Juan Antonio Hernández-Tamames
The Partial Volume Effect in the Quantification of 1H Magnetic Resonance Spectroscopy in Alzheimer’s Disease and Aging
Abstract: 1H-MRS variability increases due to normal aging and also as a result of atrophy in grey and white matter caused by neurodegeneration. In this work, an automatic process was developed to integrate data from spectra and high-resolution anatomical images to quantify metabolites, taking into account tissue partial volumes within the voxel of interest avoiding additional spectra acquisitions required for partial volume correction. To evaluate this method, we use a cohort of 135 subjects (47 male and 88 female, aged between 57 and 99 years) classified into 4 groups: 38 healthy participants, 20 amnesic mild cognitive impairment patients, 22 multi-domain mild cognitive impairment patients, and 55 Alzheimer’s disease patients. Our findings suggest that knowing the voxel composition of white and grey matter and cerebrospinal fluid is necessary to avoid partial volume variations in a single-voxel study and to decrease part of the variability found in metabolites quantification, particularly in those studies involving elder patients and neurodegenerative diseases. The proposed method facilitates the use of 1H-MRS techniques in statistical studies in Alzheimer’s disease, because it provides more accurate quantitative measurements, reduces the inter-subject variability, and improves statistical results when performing group comparisons.

Pages 813-821
Geidy E. Serrano, Marwan N. Sabbagh, Lucia I. Sue, Jose A. Hidalgo, Julie A. Schneider, Barry J. Bedell, Vivianna M. Van Deerlin, Eunran Suh, Haruhiko Akiyama, Abhinay D. Joshi, Michael J. Pontecorvo, Mark A. Mintun, Thomas G. Beach
Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions
Abstract: Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia and amyotrophic lateral sclerosis, and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer’s disease pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation, and dysphasia. Positron emission tomography imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus, and striatum, Braak stage II neurofibrillary degeneration, and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that Alzheimer’s disease is the sole cause.

Pages 823-831
Yvonne Freund-Levi*, Inger Vedin*, Erik Hjorth, Hans Basun, Gerd Faxén Irving, Marianne Schultzberg, Maria Eriksdotter, Jan Palmblad, Bengt Vessby, Lars-Olof Wahlund, Tommy Cederholm,**, Samar Basu,** (Handling Associate Editor: Robert Friedland) *,**These authors contributed equally to this work.
Effects of Supplementation with Omega-3 Fatty Acids on Oxidative Stress and Inflammation in Patients with Alzheimer’s Disease: The OmegAD Study
Abstract: Background: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer’s disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. Objective: The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA. Methods: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured. Results: F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid. Conclusion: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.

Pages 833-839
Brian S. Appleby, Tonya D. Rincon-Beardsley, Kristin K. Appleby, Barbara J. Crain, Mitchell T. Wallin (Handling Associate Editor: Inga Zerr)
Initial Diagnoses of Patients Ultimately Diagnosed with Prion Disease
Abstract: Background: Prion diseases are rapidly progressive neurodegenerative diseases that frequently mimic other forms of dementia making them difficult to diagnose. Objective: To explore factors associated with the initial diagnoses of cases later determined to be caused by prion disease in an attempt to recognize key clinical variables that impact the timely diagnosis of prion disease. Methods: A retrospective chart review performed at Johns Hopkins Medicine and the Department of Veterans Affairs Health Care System (1995-2008) was conducted. Ninety-two subjects with definite or probable prion disease were included in the analyses. Demographic, clinical, diagnostic test results, neuropathologic, molecular, and genetic data were collected using a standardized instrument and compared between initial diagnosis groups. Results: Cases were separated into five broad categories pertaining to their initial diagnoses: prion disease, non-prion-related dementia, psychiatric disorder, stroke, and other. The majority of cases did not receive an initial diagnosis of prion disease (n=76, 83%). The plurality of subjects received an initial diagnosis of a non-prion disease related dementia (n=33, 36%). Mean survival times varied between initial diagnosis groups (p=0.042). Times to cerebrospinal fluid 14-3-3 analysis and electroencephalogram also differed between initial diagnosis groups. Conclusions: Most patients with prion disease are initially diagnosed with a non-prion disease related dementia. Several clinical features were associated with initial diagnoses including survival time, onset of specific symptoms, and times to 14-3-3 analyses and electroencephalogram. Expanding our knowledge of the various clinical presentations of prion disease, especially dementia, may aid in the earlier diagnoses of these rapidly progressive diseases.

Pages 841-850
Yaojing Chen*, Jun Wang*, Junying Zhang, Ting Zhang, Kewei Chen, Adam Fleisher, Yongyan Wang, Zhanjun Zhang (Handling Associate Editor: Xinqing Zhang) *These authors contributed equally to this work.
Aberrant Functional Networks Connectivity and Structural Atrophy in Silent Lacunar Infarcts: Relationship with Cognitive Impairments
Abstract: Silent or asymptomatic lacunar infarcts (LACI) are common in elderly individuals, but it remains largely unclear how these often neglected silent brain infarcts lead to multiple domain cognitive deficits and even Alzheimer’s disease (AD). In this study, we investigated the difference between patients with silent LACI in basal ganglia region and healthy controls for the structural and functional changes in the aspects of alterations of gray matter (GM) volume and intra-/inter-default mode network (DMN) and salience network (SN) connectivity. Thirty patients with silent LACI in the basal ganglia region and thirty healthy controls participated in the study. Voxel-based morphometry analysis was employed to measure the GM volume. We further investigated the intra/inter-network connectivity of DMN and SN using resting-state functional magnetic resonance imaging. Compared with healthy controls, patients performed worse in cognitive function in the aspects of general mental status, attention, and memory. The LACIs showed more severe GM atrophy in insula, anterior cingulate cortex, caudate, and superior temporal pole than controls. The connectivity within and between two networks was also reduced in patients. Importantly, the disrupted connectivity correlated with the patients’ cognitive performance. Our findings support the hypothesis that silent lacunar infarcts result in cognitive decline, GM, and functional connectivity loss.

Pages 851-864
Letizia Polito, Armando Chierchia, Marta Tunesi, Patrick Gavin Kehoe, Diego Albani, Gianluigi Forloni (Handling Associate Editor: Alessandro Serretti)
Environmental Enrichment Lessens Cognitive Decline in APP23 Mice Without Affecting Brain Sirtuin Expression
Abstract: Environmental enrichment (EE) is a non-pharmacological intervention reported to counteract pathological signs in models of Alzheimer’s disease (AD). We developed EE protocols in APP23 mice and evaluated how they influenced cognitive decline and brain amyloid-β (Aβ) burden. We also investigated the involvement of sirtuins (SIRTs) as a possible molecular mediator of EE, by assessing hippocampal and cortical mRNA and protein levels of the SIRT family members (SIRT1 to SIRT7). APP23 transgenic mice were moved to EE cages (TG-EEs) starting from 3 months of age. TG-EEs were compared to transgenic mice housed in standard cages (TG-SHs) and to wild-type littermates in the two housing conditions (WT-EEs and WT-SHs). At 7 months of age, all mice were tested for behavioral performance with Morris Water Maze (MWM) and visual Object Recognition Test (vORT). After a month, a group underwent biochemical analyses, while another group continued in the EE environment till 18 months of age, when Aβ plaque load was assessed. At 7 months, TG-SHs had impaired behavioral performance in MWM and vORT. In contrast, TG-EE mice had restored behavioral performance. At 8 months, EE did not affect AβPP expression or processing, Aβ40/42, pGlu-Aβ3-40/3-42, or Aβ oligomer level. The expression of two Aβ degrading enzymes (insulin degrading enzyme and neprilysin) was not modulated by EE. Brain sirtuin mRNA and protein levels were unchanged, while brain-derived neurotrophic factor expression increased after EE. Aβ deposition was attenuated in 18-month-old TG-EE mice, without apparent reduction of neuroinflammatory signs. We suggest that EE had a beneficial effect on cognitive performance and lessened long-term Aβ accumulation, but brain sirtuin expression was not modulated when cognitive impairment was restored.

Pages 865-878
Yawei Tong*, Huan Yang*, Xiaosheng Tian, Hecheng Wang, Ting Zhou, Shouzi Zhang, Jia Yu, Tao Zhang, Dongshen Fan, Xiangyang Guo, Takeshi Tabira, Fanjun Kong, Zheng Chen, Weizhong Xiao, Dehua Chui *These authors contributed equally to this paper.
High Manganese, A Risk for Alzheimer’s Disease: High Manganese Induces Amyloid-β Related Cognitive Impairment
Abstract: Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimer’s disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-β (Aβ) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aβ peptides increased with elevated Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aβ by Mn treatment, which was probably caused by disrupted Aβ degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor.

Pages 879-884
Claudia Lanza, Oliver Knörzer, Michael Weber, Matthias W. Riepe (Handling Associate Editor: Richard Dodel)
Autonomous Spatial Orientation in Patients with Mild to Moderate Alzheimer’s Disease by using Mobile Assistive Devices: A Pilot Study
Abstract: Background/Objective: Spatial orientation declines early in patients with Alzheimer’s disease (AD) and is a major cause for institutionalization of patients. Methods: Use of either an aerial map or an assistive device to get from start to goal zone, both located on the campus of the hospital (distance between start and goal zone 300 m to 500 m). Use of the assistive device was trained for 15 minutes prior to the task. Results: We assessed 14 patients with mild to moderate AD (DSM-IV and NINCDS-ADRDA criteria; 9 female patients, 5 male patients; age 71.9 ± 7.4 years; MMSE 21.7 ± 2.9 (mean ± SD), range 16–26). Each patient had to find the way for three different routes with different start and goal zones. None of the patients found their way to the goal zone for any of the routes when using an aerial map in which the way was highlighted. With use of the assistive device, patients found their way from start to goal zones autonomously for 20 of 42 routes (3 routes each for 14 patients). For 22 of 42 routes intermediate re-assurance was necessary, but herewith routes were completed. Conclusion: This study lays ground for the use of mobile technical devices in patients with mild to moderate AD. Mobile assistive devices may enable patients with mild to moderate AD to maintain autonomous spatial orientation in unfamiliar environments. Improvement of the familiarization of patients with the device and further sophistication of assistive cues is likely to further improve autonomous use of navigational devices in patients with mild to moderate AD.

Pages 885-892
Alby Elias, Michael Woodward, Christopher C. Rowe
Management Impact of FDG-PET in Dementia: Results from a Tertiary Center Memory Clinic
Abstract: Background. 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) may assist the diagnosis of dementia but it is an expensive investigation. Objective. To obtain management impact data for FDG-PET in dementia. Methods. This was a prospective study of 194 consecutive patients referred from a memory clinic for FDG-PET at the discretion of the dementia specialists. Diagnosis and management plans formulated at a multidisciplinary patient review meeting were compared before and after the release of PET findings. Results. FDG-PET had moderate to high impact on the diagnosis and management in 85 (44%) participants. Diagnosis changed from probable neurodegenerative disease in 27 patients to a non-degenerative diagnosis and vice versa in 12 patients. PET changed the type of dementia in another 29 (15%) participants and prescription of cholinesterase inhibitors in 33 patients (17%). Number of uncertain diagnoses reduced from 58 to 35 (p<0.001, χ2=15.12), differential diagnoses reduced from 127 to 55 (p=0.003) and very probable diagnoses increased from 5 to 42 (p≤0.001, χ2=1.01). Mini-Mental State Examination score was higher in those where PET had high diagnostic impact (26.3±3.1 versus 23.9±5.1, p≤0.05). The degree of impact correlated with the pre-scan level of diagnostic uncertainty (ρ=-0.258, p<0.001). Discussion. The management impact was higher in those with greater diagnostic uncertainty and in those with less severe cognitive impairment. The findings suggest that FDG-PET is a useful adjunct for the management of suspected dementing disorders in appropriately selected patients.

Pages 893-900
Xiao-Li Shen, Jian-Han Yu, Dong-Feng Zhang, Jun-Xia Xie, Hong Jiang (Handling Associate Editor: Kevin Barnham)
Positive Relationship Between Mortality from Alzheimer’s Disease and Soil Metal Concentration in Mainland China
Abstract: An imbalance of metal ions is involved in the development of Alzheimer’s disease (AD). We investigated the relationship between the annual mortality of AD and ionic concentration (iron, zinc, copper, and aluminum) in the soil in mainland China. The AD annual mortality data were from 26 provinces and 3 municipal districts within mainland China between the years 1991 and 2000 and were provided by the National Death Cause Surveillance Database of China. The ionic concentration in soil was provided by the China State Environmental Protection Bureau, which was published in 1990. The results showed that the relative risk of mortality in the regions with the highest copper concentrations (60-80 mg/kg) reached 2.634 (95% CI: 2.626-2.642) compared with the regions that had the lowest copper concentrations. The relative risk was 1.292 (95% CI: 1.290-1.294) and 1.248 (95% CI: 1.245-1.251) when the soil iron concentrations exceeded 3 mg/kg and 4 mg/kg, respectively. When the soil zinc concentration was over 100 mg/kg and 200 mg/kg, the relative risk was 1.870 (95% CI: 1.859-1.881) and 2.289 (95% CI: 2.275-2.303), respectively. However, the relative risk was 0.560 (95% CI: 0.559-0.561), 0.604 (95% CI: 0.603-0.605), and 0.267 (95% CI: 0.265-0.268) when the soil aluminum concentration was over 6 mg/kg, 7 mg/kg, and 8 mg/kg, respectively. This study suggests that high concentrations of iron and copper in the soil might be associated with the high AD annual mortality in this region in China, while aluminum had no association with AD mortality.

Pages 901-908
Anna Antonell, Alicia Mansilla, Lorena Rami, Albert Lladó, Alex Iranzo, Jaume Olives, Mircea Balasa, Raquel Sánchez-Valle, José Luis Molinuevo (Handling Associate Editor: Piotr Lewczuk)
Cerebrospinal Fluid Level of YKL-40 Protein in Preclinical and Prodromal Alzheimer’s Disease
Abstract: Background: An increase in YKL-40 levels seems to correlate with disease severity and poor prognosis in many diseases, including several neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease (AD). Specifically, YKL-40 protein is increased in mild AD with respect to controls, both in cerebrospinal fluid (CSF) and plasma. Objective: We hypothesize that subjects in the preclinical (Pre-AD) and prodromal (Prod-AD) stage of AD could already present an increase in CSF YKL-40 levels with respect to healthy controls and idiopathic REM sleep behavior disorder (iRBD) subjects, included as a control group of a distinct neurological disease. Methods: We measured CSF YKL-40 levels using a commercial ELISA kit in a cohort of 95 subjects, consisting of controls (n=43), Pre-AD (n=18), Prod-AD (n=22), and iRBD (n=12) subjects. We explored for possible correlations of YKL-40 levels with demographic characteristics, a wide battery of neuropsychological tests, and the AD CSF biomarkers: amyloid-β42 (Aβ42), total-tau protein (t-tau), and phosphorylated-tau protein (p-tau). Results: We detected statistically significant differences between Prod-AD patients and controls. YKL-40 levels showed a significant correlation with t-tau and p-tau levels in the predementia AD continuum and the Pre-AD group. We also observed significant correlations with the MMSE, FCSRT, and M@T tests within the AD continuum, but not in iRBD subjects. Conclusion: Our data suggest that CSF YKL-40 levels, although not useful as a diagnostic marker for Prod-AD, may be a valuable marker to detect early physiopathological changes potentially linked with the neurodegenerative process.

Pages 909-914
Michael A. Williams, Vittorio Silvestri, David Craig, A. Peter Passmore, Giuliana Silvestri
The Prevalence of Age-Related Macular Degeneration in Alzheimer’s Disease
Abstract: Background: Age-related macular degeneration (AMD) and Alzheimer's disease (AD) share several features, including the presence of extracellular abnormal deposits associated with neuronal degeneration, drusen, and plaques, respectively. Investigation of any association of AMD and specifically AD is worthwhile but has rarely been done. Objectives: The aim of this study was to determine the prevalence of AMD in subjects with AD in comparison with an age-matched cognitively normal cohort. Methods: Cases were defined as those diagnosed with AD using standardized criteria as part of their clinical care, while controls were cognitively intact individuals aged 65 years or more. Dilated retinal photographs were taken, and a range of potentially confounding factors measured including APOE genotype. AMD features were recorded and AMD grades given. Results: Data was collected on 322 controls and 258 cases. While AMD was associated with AD, and the proportion of cases of advanced AMD in AD cases was twice that of controls, when corrected the association was lost. AD was associated with age, the presence of an APOE allele, and smoking, while being 'generally unwell recently' was associated with a reduced risk of AD. Conclusion: AD and AMD are both associated with age, but our study does not find evidence they are associated with each other. However the retina offers an opportunity to non-invasively image neuronal tissue, and more sophisticated imaging techniques may shed light on ocular biomarkers of AD.

Pages 915-937
Hui Ma, Yinglin Huang, Zhengtu Cong, Yuan Wang, Wenhai Jiang, Shuhe Gao, Gang Zhu
The Efficacy and Safety of Atypical Antipsychotics for the Treatment of Dementia: A Meta-Analysis of Randomized Placebo-Controlled Trials
Abstract: Background: The application of atypical antipsychotics (SGAs) for treatment of psychiatric and behavioral symptoms of dementia is controversial since their efficacy might be offset by their adverse events (AEs). Objective: To assess the efficacy, safety, and tolerability of SGAs for treatment of psychological and behavioral symptoms of dementia. Methods: Two researchers searched MEDLINE, PsychINFO, and the Cochrane Central Register of Controlled Trials independently for double-blind, placebo-controlled, randomized controlled trials (DB-PC-RCTs) as of June 2013, written in English. Efficacy was measured using the Brief Psychiatric Rating Scale (BPRS), Cohen-Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory (NPI), Clinical Global Impression of Change (CGI-C), and (or) Clinical Global Impression of Severity (CGI-S). Safety and tolerability were measured by frequencies of drop-outs, adverse events (AEs), and death. In total, 19 treatment comparisons drawn from 16 DB-PC-RCTs were included, and 3,343 patients randomized to the antipsychotic group and 1,707 to the placebo group were assessed. Results: This meta-analysis demonstrated a significant efficacy of atypical antipsychotics on BPRS (MD=-1.58, 95% CI=-2.52 – -0.65), CMAI (-1.84, -3.01 – -0.61), NPI (-2.81, -4.35 – -1.28), CGI-C (-0.32, -0.44 – -0.20), and CGI-S (-0.19, -0.30 – -0.09), compared to placebo (p<0.01 for all). Patients receiving atypical antipsychotics showed no difference in risk for discontinuation (p>0.05), significantly higher risks (p<0.05 for all) for somnolence (OR=2.95), extrapyramidal symptoms (1.74), cerebrovascular AEs (2.50), urinary tract infection (1.35), edema (1.80), gait abnormality (3.35), and death (1.52), and a lower risk for agitation (OR=0.80, p=0.03). Conclusions: The higher risks for AEs and mortality may offset the efficacy of atypical antipsychotics for treatment of dementia. Efficacy, safety, and tolerability thus should be carefully considered against clinical need.

Pages 939-947
Gianfranco Puoti, Maria Cristina Lerza , Maria Giulia Ferretti, Orso Bugiani, Fabrizio Tagliavini, Giacomina Rossi
A Mutation in the 5'-UTR of GRN Gene Associated with Frontotemporal Lobar Degeneration: Phenotypic Variability and Possible Pathogenetic Mechanisms
Abstract: Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5-10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level detected, we sequenced GRN and found the new mutation EX0-5’ splice site A>G in the 5’-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5’ splice site A>G mutation widens the GRN regions affected by null mutations, including the 5’-UTR, and confirms once more the large phenotypic variability linked to GRN mutations.

Pages 949-958
Bernhard Michalowsky, Tilly Eichler, Jochen René Thyrian, Johannes Hertel, Diana Wucherer, Sebastian Laufs, Steffen Fleßa, Wolfgang Hoffmann
Medication Cost of Persons with Dementia in Primary Care in Germany
Abstract: Background: Results of cost-of-illness studies in dementia have shown a considerable divergence in costs of medication for persons with dementia. However, detailed economic analyses of medication costs for community dwelling persons with dementia are currently still missing, especially on the basis of primary data. Objective: To determine medication cost, cost per drug, and number of drugs taken of community-dwelling persons with dementia and analyze their associated factors; to estimate the current price reduction of anti-dementia drugs due to implementation of low-priced generics. Method: The present analysis included 205 patients screened positive for dementia. Medication data were assessed within a medication review. To estimate the cost effect of implementing generics, the most favorable equivalent generic was assigned to each anti-dementia drug. Factors associated with medication cost, cost per drug, and number of drugs taken were evaluated using multiple regression models. Results: Medication cost and cost per drug were higher and the number of taken drugs lower in advanced stages of cognitive impairment. Prescription of anti-dementia generics could decrease overall medication cost by 28%. Medication cost was associated with number of diagnoses, deficits in activities of daily living, and age. Dementia severity was related to cost per drug and number of drugs taken. Conclusion: Medication cost increases with the number of diagnoses and growing deficits in activities of daily living and decreases with age. Severely cognitively impaired persons are treated with a small number of high-priced drugs, which could suggest inadequate medication of multimorbid persons.

Pages 959-971
George M. Haig, Yili Pritchett, Andreas Meier, Ahmed A. Othman, Coleen Hall, Laura M. Gault, Robert A. Lenz
A Randomized Study of H3 Antagonist ABT-288 in Mild-To-Moderate Alzheimer’s Dementia
Abstract: Background: ABT 288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers. Objective: Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimer’s dementia. Methods: The study used a randomized, double-blind, placebo- and active-controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT 288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score. Results: The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT-288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting. Conclusion: ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimer’s dementia.

Pages 973-984
Chuanhai Cao, Yaqiong Li, Hui Liu, Ge Bai, Jonathan Mayl, Xiaoyang Lin, Kyle Sutherland, Neel Nabar, Jianfeng Cai
The Potential Therapeutic Effects of THC on Alzheimer’s Disease
Abstract: The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer’s disease. N¬2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin’s enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.

Pages 985-998
Seiko Goto, Naveed Kamal*, Helene Puzio*, Fred Kobylarz, Karl Herrup *These authors contributed equally to this work.
Differential Responses of Individuals with Late-Stage Dementia to Two Novel Environments: A Multimedia Room and an Interior Garden
Abstract: The purpose of this study was to determine the responses of individuals with advanced dementia to two novel sensory environments in a nursing home facility. The first was a multisensory Snoezelen room; the second was a temporary Japanese garden. Subjects viewed each environment twice a week for 15 minutes during the study. Stress was measured using heart rate and informant-based behavioral changes. By these criteria, the garden-viewing group showed positive behavioral changes while the responses of the subjects in the Snoezelen group were more negative. The response of the subjects’ pulse rate was most dramatic. During the 15 minutes in the garden, the average rate (all subjects/all visits) was significantly less than in their residential room. In the Snoezelen room, we detected little or no change. The impact of the garden could also be seen in the negative behavioral signs elicited upon returning the subjects to the garden room after the installation had been replaced with plants and furniture arranged with no formal design. We propose that exposure to a small interior Japanese garden could be an effective intervention for individuals suffering from late stage Alzheimer’s disease.

Pages 999-1014
David J. Libon, Deborah A.G. Drabick, Tania Giovannetti, Catherine C. Price, Mark W. Bondi, Joel Eppig, Kathryn Devlin, Christine Nieves, Melissa Lamar, Lisa Delano-Wood, Daniel A. Nation, Laura Brennan, Rhoda Au, Rod Swenson
Neuropsychological Syndromes Associated with Alzheimer’s/Vascular Dementia: A Latent Class Analysis
Abstract: Background: Epidemiologic autopsy studies show mixed Alzheimer’s disease (AD)/vascular pathology in many patients. Moreover, clinical research shows that it is not uncommon for AD and vascular dementia (VaD) patients to be equally impaired on memory, executive, or other neurocognitive tests. However, this clinical heterogeneity has not been incorporated into the new diagnostic criteria for AD (Dubois et al., 2010; McKhann et al., 2011). Objective: The current research applied Latent Class Analysis (LCA) to a protocol of six neuropsychological parameters to identify phenotypic subtypes from a large group of AD/VaD participants. Follow-up analyses examined difference between groups on neuroradiological parameters and neuropsychological measures of process and errors. Methods: 223 AD/VaD patients were administered a comprehensive neuropsychological protocol. Measures of whole brain and hippocampal volume were available for a portion of the sample (n=76). Results: LCA identified four distinct groups: moderate/mixed dementia (n=54; 24.21%), mild/mixed dementia (n=91; 40.80%); dysexecutive (n=49, 21.97%), and amnestic (n=29, 13.00%). Follow-up analyses comparing the groups on neuropsychological process and error scores showed that the dysexecutive group exhibited difficulty sustaining mental set. The moderate/mixed group evidenced pronounced impairment on tests of lexical retrieval/naming along with significant amnesia. Amnestic patients also presented with gross amnesia, but showed relative sparing on other neuropsychological measures. Mild/mixed patients exhibited milder memory deficits that were intermediary between the amnestic and moderate/mixed groups. Conclusions: There are distinct neuropsychological profiles in patients independent of clinical diagnosis, suggesting that the two are not wholly separate and that this information should be integrated into new AD diagnostic paradigms.

Pages 1015-1028
Franca Rosa Guerini, Cristina Agliardi, Manuela Sironi, Beatrice Arosio, Elena Calabrese, Milena Zanzottera, Elisabetta Bolognesi, Cristian Ricci, Andrea Saul Costa, Daniela Galimberti, Ludovica Griffanti, Anna Bianchi, Federica Savazzi, Daniela Mari, Elio Scarpini, Francesca Baglio, Raffaello Nemni, Mario Clerici (Handling Associate Editor: Marco Bozzali)
Possible Association between SNAP-25 Single Nucleotide Polymorphisms and Alterations of Categorical Fluency and Functional MRI Parameters in Alzheimer’s Disease
Abstract: Synaptosomal-associated protein of 25kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer’s disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD, we analyzed five gene polymorphisms in patients with AD (n=607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI) (n=148) and in two groups of age-matched healthy controls (HC1: n=615 and HC2: n=310). Results showed that the intronic rs363050(A) and rs363043(T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo- parietal (angular gyrus) area. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD.

Pages 1029-1039
Yiyuan Xia, Rong Liu, Rong Chen, Qing Tian, Kuan Zeng, Jichang Hu, Xinghua Liu, Qun Wang, Peng Wang, Xiao-Chuan Wang, Jian-Zhi Wang (Handling Associate Editor: Xuemin Xu)
Novel Multipotent AChEI-CCB Attenuates Hyperhomocysteinemia-Induced Memory Deficits and Neuropathologies in Rats
Abstract: Alzheimer’s disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.

Pages 1041-1046
Walter Struhal, Andrija Javor, Cornelia Brunner, Thomas Benesch, Verena Schmidt, Milan R. Vosko, Gerhard Ransmayr
The Phoenix from the Ashes: Cardiovascular Autonomic Dysfunction in Behavioral Variant of Frontotemporal Dementia
Abstract: Background: Patients with autonomic failure may experience postural dizziness, syncope, and falls. Identifying symptomatic dysautonomia in dementia is of importance to ensure appropriate management and reduce risk of falls. Objective: The aim of this prospective study is to identify cardiovascular autonomic dysfunction in patients suffering from behavioral variant of frontotemporal dementia (bvFTD), compared to Alzheimer’s disease (AD). Methods: Patients were prospectively recruited from 2009 until 2013. Clinical autonomic function tests were carried out in an Autonomic Unit according to Ewing’s cardiovascular battery. Parasympathetic tests included resting heart rate variability, deep breathing, and Valsalva. Sympathetic function tests compromised blood pressure regulation on valsalva, cutaneous cold stimulation, and 70° head up tilt including of plasma noradrenaline. Results: 26 patients (17 female) with bvFTD and 18 patients (10 female) with AD were examined. Mean age of bvFTD was 69 ± 11 years, AD 74 ± 9 years. History taking was often not conclusive and did not correlate with autonomic signs. In 42% bvFTD patients and 44% AD patients, autonomic dysfunction was demonstrated. Manifest orthostatic hypotension (OH) was present in 19% of bvFTD and 33% AD patients. Frequency of autonomic dysfunction and orthostatic hypotension did not differ between bvFTD and AD, but were significantly higher than in healthy controls. Autonomic dysfunction was associated with an increased risk of falling (assessed with Tinetti Score). Conclusion: This is the first prospective study to elucidate autonomic dysfunction in bvFTD patients. There is a considerable high frequency of cardiovascular dysfunction and OH in bvFTD. History taking may be not conclusive thus cannot exclude cardiovascular dysautonomia.