Volume 64, Number 2, 2018

Pages 337-347

Sotirios Posporelis, Anthony S. David, Keyoumars Ashkan*, Paul Shotbolt* *These authors contributed equally to this work.
Deep Brain Stimulation of the Memory Circuit: Improving Cognition in Alzheimer’s Disease
Abstract: Deep brain stimulation (DBS) is an effective invasive treatment for a wide range of neurological and psychiatric disorders. Neurosurgically implanted electrodes deliver stimulation of pre-programmed amplitude, frequency, and pulse width within deep brain structures; those settings can be adjusted at a later stage according to individual needs for optimal response. This results in variable effects dependent on the targeted region. An established treatment for movement disorders, the effectiveness of DBS in dementia remains under investigation. Translational studies have uncovered a pro-cognitive effect mediated by changes on cellular as well as network level. Several groups have attempted to examine the benefits of DBS in Alzheimer's disease; differences in inclusion criteria and methodology make generalization of results difficult. This review aims to summarize all completed and ongoing human studies of DBS in Alzheimer’s disease. The results are classified by targeted anatomical structure. Future directions, as well as economical and ethical arguments, are explored in the final section.

Pages 349-353
Short Communication

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

Paages 355-362
Short Communication

Keeley J. Brookes, George McConnell, Kirsty Williams, Sultan Chaudhury, Gaganjit Madhan, Tulsi Patel, Christopher Turley, Tamar Guetta-Baranes, Jose Bras, Rita Guerreiro, John Hardy, Paul T. Francis, Kevin Morgan (Handling Associate Editor: Emilio Di Maria)
Genotyping of the Alzheimer’s Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort
Abstract: The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer’s disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOE ε4 allele was identified (p=3.99x10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.

Pages 363-366

Ruth F. Itzhaki, Richard Lathe
Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link
Abstract: Three articles have very recently appeared that are of especial relevance to the causes of dementia and its potential treatment. The first two (Tsai et al., published in PLoS One in November 2017; Chen et al., published in the January/February 2018 issue of Journal of Clinical Psychiatry) demonstrate an increased risk of subsequent senile dementia (SD) development in patients with acute varicella zoster (herpes zoster) infection. These articles present data highly relevant to the third, and most important, paper—by Tzeng et al., published online in the journal Neurotherapeutics at the end of February 2018. These authors report that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing SD. Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia.

Pages 367-378
John M. Nolan, Riona Mulcahy, Rebecca Power, Rachel Moran, Alan N. Howard
Nutritional Intervention to Prevent Alzheimer’s Disease: Potential Benefits of Xanthophyll Carotenoids and Omega-3 Fatty Acids Combined
Abstract: Background: A growing body of scientific evidence suggests that enrichment of certain nutritional compounds in the brain may reduce the risk of Alzheimer’s disease (AD). Objective: To investigate the impact of supplemental xanthophyll carotenoids plus omega-3 fatty acids on disease progression in patients with AD. Methods: Three trial experiments were performed. In Trials 1 and 2 (performed on patients with AD over an 18-month period), 12 patients (AD status at baseline: 4 mild and 8 moderate) were supplemented with a xanthophyll carotenoid only formulation (Formulation 1; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day) and 13 patients (AD status at baseline: 2 mild, 10 moderate, and 1 severe) were supplemented with a xanthophyll carotenoid and fish oil combination (Formulation 2; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day plus 1 g/day of fish oil containing 430 mg docohexaenoic acid [DHA] and 90 mg eicopentaenoic acid [EPA]), respectively. In Trial 3, 15 subjects free of AD (the control group) were supplemented for 6 months with Formulation 1. Blood xanthophyll carotenoid response was measured in all trials by HPLC. Omega-3 fatty acids were profiled by direct infusion mass spectrometry. Results: Xanthophyll carotenoid concentration increases were significantly greater for Formulation 2 compared to Formulation 1 (p<0.05), and progression of AD was less for this group (p=0.003), with carers reporting functional benefits in memory, sight, and mood. Conclusion: This preliminary report suggests positive outcomes for patients with AD who consumed a combination of xanthophyll carotenoids plus fish oil, but further study is required to confirm this important observation.

Pages 379-392
Anne-Caroline Schmöle, Ramona Lundt, Gregor Toporowski, Jan N. Hansen, Eva Beins, Annett Halle, Andreas Zimmer (Handling Associate Editor: Ester Aso Pérez)
Cannabinoid Receptor 2-Deficiency Ameliorates Disease Symptoms in a Mouse Model with Alzheimer’s Disease-Like Pathology
Abstract: It is widely accepted that the endocannabinoid system (ECS) is a modulator of neuroinflammation associated with neurodegenerative disorders, including Alzheimer’s disease (AD). Thus, expression of the cannabinoid receptor 2 (CB2) is induced in plaque-associated microglia and astrocytes in brain tissues from AD patients and in genetic mouse models expressing pathogenic variants of the amyloid precursor protein (APP). However, the exact mechanism of CB2 signaling in this mouse model remains elusive, because the genetic deletion of CB2 and the pharmacological activation of CB2 both reduced neuroinflammation. Here, we demonstrate that CB2 deletion also improved cognitive and learning deficits in APP/PS1*CB2-/- mice. This was accompanied by reduced neuronal loss and decreased plaque levels and coincided with increased expression of Aβ degrading enzymes. Interestingly, plaque-associated microglia in APP/PS1*CB2-/- mice showed a less activated morphology, while plaques were smaller and more condensed than in APP/PS1 mice. Taken together, these results indicate a beneficial effect of CB2-deficiency in APP transgenic mice. CB2 appears to be part of a protective system that may be detrimental when engaged continuously.

Pages 393-404
Solveig Tiepolt*, Andreas Schäfer*, Michael Rullmann, Elisabeth Roggenhofer; Netherlands Brain Bank, Hermann-Josef Gertz, Matthias L. Schroeter, Marianne Patt, Pierre-Louis Bazin, Thies H. Jochimsen, Robert Turner, Osama Sabri*, Henryk Barthel* *These authors contributed equally to this work.
Quantitative Susceptibility Mapping of Amyloid-β Aggregates in Alzheimer’s Disease with 7T MR
Abstract: Background: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution. Objective: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging. Methods: Postmortem human Alzheimer’s disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo, 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE. Results: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus -0.008±0.003 ppm, p<0.001). In vivo, only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus -0.009±0.009 ppm; left: 0.293±0.014 versus -0.007±0.012 ppm, p<0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r=-0.69, p=0.001). Conclusion: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology.

Pages 405-415
Martin Scherr*, Lorenzo Pasquini*, Gloria Benson, Rachel Nuttall, Martin Gruber, Julia Neitzel, Felix Brandl, Christian Sorg for the Alzheimer's Disease Neuroimaging Initiative *These authors contributed equally to this work.
Decoupling of Local Metabolic Activity and Functional Connectivity Links to Amyloid in Alzheimer’s Disease
Abstract: Background: Both ongoing local metabolic activity (LMA) and corresponding functional connectivity (FC) with remote brain regions are progressively impaired in Alzheimer’s disease (AD), particularly in the posterior default mode network (pDMN); however, it is unknown how these impairments interact. It is well known that decreasing mean synaptic activity of a region, i.e., decreasing LMA, reduces the region’s sensitivity to afferent input from other regions, i.e., FC. Objective: We hypothesized progressive decoupling between LMA and FC in AD, which is linked to amyloid-β pathology (Aβ). Methods: Healthy adults (n=20) and Aβ+ patients without memory impairment (n=9), early MCI (n=21), late MCI (n=18) and AD (n=22) were assessed by resting-state fMRI, FDG-PET, and AV-45-PET to measure FC, LMA, and Aβ of the pDMN. Coupling between LMA and FC (rLA/FC) was estimated by voxelwise correlation. Results: RLMA/FC decreased with disease severity (F = 20.09, p < 0.001). This decrease was specifically associated with pDMN Aβ (r = -0.273, p = 0.029) but not global Aβ (r = -0.112, p = 0.378) and with the impact of Aβ on FC (i.e., rAβ/FC, r = -0.339; p = 0.006). In multiple regression models rLMA/FC was also associated with memory impairment, reduced cognitive speed and flexibility, outperforming global Aβ, pDMN Aβ, pDMN LMA, and pDMN FC, respectively. Conclusion: Results demonstrate increasing decoupling of LMA from its FC in AD. Data suggest that decoupling is driven by local Aβ and contributes to memory decline.

Pages 417-435
Diana Furcila, Javier DeFelipe, Lidia Alonso-Nanclares
A Study of Amyloid-β and Phosphotau in Plaques and Neurons in the Hippocampus of Alzheimer’s Disease Patients
Abstract: The main pathological hallmarks in Alzheimer’s disease (AD) are the presence of extracellular amyloid plaques, primarily consisting of amyloid-β (Aβ) peptide, and the accumulation of paired helical filaments of hyperphosphorylated tau protein (PHF-Tau) within neurons. Since CA1 is one of the most affected regions in AD, mainly at early stages, we have performed a detailed analysis of the CA1 region from 11 AD patients (demented and clinically homogeneous; Braak stages IV-VI) to better understand the possible relationship between the presence and distribution of different neurochemical types of Aβ plaques and PHF-Tau immunoreactive (-ir) neurons. Hence, we have examined hippocampal sections in confocal microscopy images from double and triple-immunostained sections, to study labeled plaques and PHF-Tau-ir neurons using specific software tools. There are four main findings in the present study. First, the pyramidal layer of proximal CA1 (close to CA2) contains the smallest number of both plaques and PHF-Tau-ir neurons. Second, a large proportion of Aβ-ir plaques were also characterized by the presence of PHF-Tau-ir. Third, all plaques containing one of the two PHF-Tau isoforms also express the other isoform, that is, if a plaque contains PHFpS396, it also contains PHFAT8, and vice versa. Fourth, the coexpression study of both PHF-Tau isoforms in CA1 neurons revealed that most of the labeled neurons express only PHFpS396. Our findings further support the idea that AD is not a unique entity even within the same neuropathological stage, since the microanatomical/neurochemical changes that occur in the hippocampus greatly vary from one patient to another.

Pages 437-445
Heli Järvinen, Heidi Taipale, Marjaana Koponen, Antti Tanskanen, Jari Tiihonen, Anna-Maija Tolppanen, Sirpa Hartikainen
Hospitalization after Oral Antibiotic Initiation in Finnish Community Dwellers with and without Alzheimer’s Disease: Retrospective Register-Based Cohort Study
Abstract: Background: Persons with Alzheimer’s disease (AD) are frequently hospitalized from infection-related causes. There are no previous studies investigating hospitalization associated with antibiotic initiation in persons with AD. Objective: To investigate the frequency and risk of hospitalization associated with oral antibiotic initiation among community dwellers with and without AD. Methods: We performed a retrospective register-based study utilizing register-based Medication Use and Alzheimer’s disease (MEDALZ) cohort. It includes all community dwellers diagnosed with AD during 2005-2011 in Finland and their matched comparison persons without AD. Antibiotic use was initiated by 34,785 persons with and 36,428 without AD. Drug use data were collected from Prescription Register and comorbidities from Special Reimbursement and Hospital Care Registers. Infection diagnoses were collected from the Hospital Care Register. Factors associated with hospitalization were estimated utilizing logistic regression models. Results: Risk of hospitalization following antibiotic initiation was higher among antibiotic initiators with AD than without AD (adjusted odds ratio, aOR, 1.37, 95 % Cl 1.28-1.46). Strongest association with hospitalization was found for oral glucocorticoid use, aOR 1.41 (1.25-1.59); epilepsy, aOR 1.33 (1.10-1.63); and active cancer, aOR 1.30 (1.14-1.49). Among initiators of cephalexin, pivmecillinam, amoxicillin/amoxicillin, and enzyme inhibitor and doxycycline, persons with AD were more frequently hospitalized than persons without AD. A quarter of hospitalized antibiotic initiators had infection diagnosis in their hospital care records. Conclusions: Persons with AD initiating an antibiotic had a higher risk for hospitalization than antibiotic initiators without AD. Further research is needed to determine whether infection-related hospitalization could be reduced.

Pages 447-457
Hasina Akhter, Wen-Tan Huang, Thomas van Groen, Hui-Chien Kuo, Toshio Miyata, Rui-Ming Liu
A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

Pages 459-471
Laura E. Korthauer, Elizabeth Awe, Marijam Frahmand, Ira Driscoll
Genetic Risk for Age-Related Cognitive Impairment Does Not Predict Cognitive Performance in Middle Age
Abstract: Alzheimer’s disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40-60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers.

Pages 473-481
Francisco Martínez-Sánchez Juan José G. Meilán, Juan Carro, Olga Ivanova (Handling Associate Editor: Eva Mª Arroyo-Anlló)
A Prototype for the Voice Analysis Diagnosis of Alzheimer’s Disease
Abstract: Background: Speech variations enable us to map the performance of cognitive processes of syntactic, semantic, phonological, and articulatory planning and execution. Speaking is one of the first functions to be affected by neurodegenerative complaints such as Alzheimer’s disease (AD), which makes the speech a highly promising biomarker for detecting the illness before the first preclinical symptoms appear. Objective: This paper has sought to develop and validate a technological prototype that adopts an automated approach to speech analysis among older people. Methods: It uses a mathematical algorithm based on certain discriminatory variables to estimate the probability of developing AD. Results and Conclusion: This device may be used at a preclinical stage by non-expert health professionals to determine the likelihood of the onset of AD.

Pages 483-496
Andrew C. Robinson, Yvonne S. Davidson, Michael A. Horan, Neil Pendleton*, David M.A. Mann* * These authors contributed equally to the study.
Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age
Abstract: The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III–VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOE ε4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOE ε2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

Pages 497-504
Martina Bocchetta, Juan Eugenio Iglesias, Marzia A. Scelsi, David M. Cash, M. Jorge Cardoso, Marc Modat, Andre Altmann, Sebastien Ourselin, Jason D. Warren, Jonathan D. Rohrer (Handling Associate Editor: Roser Sala-Llonch)
Hippocampal Subfield Volumetry: Differential Pattern of Atrophy in Different Forms of Genetic Frontotemporal Dementia
Abstract: Background: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD. Objectives: We aimed to investigate hippocampal subfield volumes in genetic FTD. Methods: We investigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1(3.4) years; 29 with MAPT, 28 with C9orf72, and 18 with GRN mutations) compared with 97 age-matched controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes. Results: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24-27%, p<0.0005). For C9orf72, the CA4, CA1, and dentate gyrus regions (8-11%, p<0.0005), and for GRN the presubiculum and subiculum (10-14%, p<0.0005) showed the largest differences from controls. Conclusions: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability.

Pages 505-513
Estrella Morenas-Rodríguez, Isabel Sala, Andrea Subirana, Elba Pascual-Goñi, Mª Belén Sánchez-Saudinós, Daniel Alcolea, Ignacio Illán-Gala, María Carmona-Iragui, Roser Ribosa-Nogué, Valle Camacho, Rafael Blesa, Juan Fortea, Alberto Lleó (Handling Associate Editor: Thomas Leyhe)
Clinical Subtypes of Dementia with Lewy Bodies Based on the Initial Clinical Presentation
Abstract: Background: Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. Objective: To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. Methods: 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation. Results: Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n=46) presented more frequently with cognitive symptoms (95.7%, n=44, p<0.001), and showed a longer duration from onset to DLB diagnosis (p<0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n=22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p<0.01), presented more frequently with psychotic symptoms (77.3%, n=17), and had a shorter duration until the onset of hallucinations (p<0.001). Patients in cluster III (parkinsonism-predominant, n=13) showed a shorter time from onset to presence of parkinsonism (p<0.001) and dementia (0.008). Conclusions: Three subtypes of clinical DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.

Pages 515-523
Miharu Nakanishi, Kayo Hirooka, Yasuaki Imai, Shintaro Inoue, Yukio Yukari, Chie Katayama, Yuki Miyamoto, Yumi Shindo, Hideki Ueno, Junichiro Toya, Yosuke Takano, Atsushi Nishida (Handling Associate Editor: Elena Mariani)
Dementia Care Competence Among Care Professionals and Reduced Challenging Behavior of Home-Dwelling Persons with Dementia: A Pre- and Post-Intervention Data Analysis
Abstract: Background: We developed a psychosocial dementia care program to help care managers and professional caregivers manage challenging behavior in home-dwelling persons with dementia in Japan. The program consists of a web-based tool for ongoing monitoring and assessment for challenging behavior, and multi-agency discussion meetings. Results of a cluster-randomized controlled trial indicate a reduction in challenging behavior through this program. Objective: The present study aimed to identify a key component of the developed program that is associated with a reduction in challenging behavior. Methods: We used consecutive data of the intervention and examined the association between challenging behavior in home-dwelling persons with dementia, professionals’ competence, and the frequency of revision of action plans. Challenging behavior was assessed using the total score of the Neuropsychiatric Inventory. A baseline and follow-up questionnaire was completed by care professionals using a Japanese version of the Sense of Competence in Dementia Care Staff scale. Results: A total of 86 care professionals completed a 6-month intervention with 219 persons with dementia. The 86 care professionals significantly improved in their dementia care competence. Challenging behavior was significantly reduced among the 219 persons with dementia at follow-up regardless of the level of professionals’ competence or the frequency of revision of action plans. Less pain was significantly related to the lower levels of challenging behavior. Conclusion: The ongoing multi-agency discussion meetings, with a focus on challenging behavior, may have been the key component in the psychosocial dementia care program. Pain management should be emphasized in action plans for challenging behavior.

Pages 525-532
Tommaso Schirinzi, Francesco Di Lorenzo, Giulia Maria Sancesario, Giulia Di Lazzaro, Viviana Ponzo, Antonio Pisani, Nicola Biagio Mercuri, Giacomo Koch, Alessandro Martorana (Handling Associate Editor: Marco Bozzali)
Amyloid-Mediated Cholinergic Dysfunction in Motor Impairment Related to Alzheimer’s Disease
Abstract: Background Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear. Objective: Through the combination of cerebrospinal fluid (CSF) biomarkers assessment and transcranial magnetic stimulation (TMS) protocols, here we provided a cross-sectional study to understand pathogenic mechanisms of Alzheimer’s disease (AD)-related early motor disturbances. Methods: The motor phenotype, as defined with Unified Parkinson’s Disease Rating Scale (UPDRS) part 2-3, Rating Scale for Gait Evaluation in Cognitive Deterioration (RSEGCD) and Tinetti scale, together with CSF profile of amyloid-β 42 (Aβ42), total-tau, and phosphorylated-tau were determined in 37 AD patients and compared to 18 patients with vascular dementia (VaD). A TMS protocol of short afferent inhibition (SAI) was further applied on a subset of AD patients. Clinical, biochemical, and neurophysiological data were then compared and correlated in order to find significant associations. Results: AD patients exhibited subtle locomotor impairment and slight extrapyramidal signs. Main motor features (UPDRS part 3, RSGECD, and Tinetti scale scores) correlate with Aβ42 levels but not with t-tau and p-tau. AD patients also presented SAI impairment directly related to UPDRS part 3 score and Aβ42 levels. Motor disturbances of VaD group did not differ statistically from AD and did not correlate with CSF biomarkers. Conclusions: The association of motor disturbances with low Aβ42 CSF levels and individual SAI suggests that amyloid-mediated degeneration of cholinergic system may account for early AD-related motor impairment, providing interesting insights either for frailty stratification of patients or personalized therapies.

Pages 533-542
Nicola M. Payton, Grégoria Kalpouzos, Debora Rizzuto, Laura Fratiglioni, Miia Kivipelto, Lars Bäckman, Erika J. Laukka
Combining Cognitive, Genetic, and Structural Neuroimaging Markers to Identify Individuals with Increased Dementia Risk
Abstract: Background: Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia. Objective: To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk. Methods: Neuropsychological assessment, genetic testing (apolipoprotein E – APOE), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60-97 years) from a population-based study (SNAC-K). Participants were followed for six years. Results: Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at six years. The most predictive individual markers were perceptual speed or carrying at least one APOE ε4 allele (AUC=0.875). The most predictive model (AUC=0.924) included variables from all three modalities (category fluency, general knowledge, any ε4 allele, hippocampal volume, white matter-hyperintensity volume). Conclusion: This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening.

Pages 543-549
Maria Ruiz, Alfonso Arias, Ernesto Sánchez-Llanos, Maria Pilar Gil, Ricard López-Ortega, Faridé Dakterzada, Francisco Purroy, Gerard Piñol-Ripoll
Minor Hallucinations in Alzheimer’s Disease
Abstract: Background: Hallucinations may have a broad spectrum and include so-called minor hallucinations (MHs). MH includes passage hallucinations (PHs), visual illusions, and presence hallucinations (PrHs). Objective: To determine the prevalence and characteristics of MH in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) patients, and to describe their potential relationship with cognition, behavioral symptoms, and use of psychoactive drugs. Methods: We have recruited prospectively and consecutively 268 subjects (90 AD mild-moderate drug-naïve patients, 78 aMCI, and 100 controls). All patients responded to a semi-structured questionnaire in order to rate psychotic phenomena. Clinical, neuropsychological, and demographic data of patients with and without MH were compared with those of age, sex, and education-matched controls. Results: The prevalence of MH was 21.1% (19) in AD, 12.8% (10) in aMCI, and 3% (3) in controls (p<0.01). The most frequent MH was PrH (9.3%), followed by PH (4.9%) and illusions (0.7%). Eight (27.8%) patients had more than one MH. After adjusting for age and gender, there was a negative correlation between the presence of MH and MMSE score (r = -0.261; p < 0.01) and a positive correlation between MH and Neuropsychiatric Inventory score (r=0.237; p< 0.01). We did not observe a significant relationship with the consumption of psychoactive drugs (p> 0.05). Conclusion: We have shown the presence of MHs in patients with newly diagnosed, untreated AD and aMCI more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MH as a clinical feature for this population.

Pages 551-561
Etienne Croteau, Christian-Alexandre Castellano, Marie Anne Richard, Mélanie Fortier, Scott Nugent, Martin Lepage, Simon Duchesne, Kevin Whittingstall, Éric E. Turcotte, Christian Bocti, Tamàs Fülöp, Stephen C. Cunnane (Handling Associate Editor: Russell Swerdlow)
Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer’s Disease
Abstract: Background: In Alzheimer’s disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. Objective: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. Methods: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n=11), followed by a wash-out and then tricaprylin (95%; n=6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. Results: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. Conclusion: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

Pages 563-585
Shohei Kawanishi, Kazuyuki Takata, Shouma Itezono, Hiroko Nagayama, Sayaka Konoya, Yugo Chisaki, Yuki Toda, Susumu Nakata, Yoshitaka Yano, Yoshihisa Kitamura, Eishi Ashihara
Bone-Marrow-Derived Microglia-Like Cells Ameliorate Brain Amyloid Pathology and Cognitive Impairment in a Mouse Model of Alzheimer’s Disease
Abstract: Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-β peptides (Aβ) in the brain triggers the onset of Alzheimer's disease (AD). Accordingly, promotion of Aβ clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aβ, and that transplantation of these cells ameliorates the Aβ burden in brains of Aβ-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aβ in vitro, with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aβ plaques. We also detected Aβ phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aβ plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD.

Pages 587-595
Eero A. Haapala, Jussi Paananen, Mikko Hiltunen, Timo A. Lakka (Handling Associate Editor: Patricia Manzine)
Associations of Genetic Susceptibility to Alzheimer’s Disease with Adiposity and Cardiometabolic Risk Factors among Children in a 2-Year Follow-up Study
Abstract: We investigated the associations of genetic risk score (GRS) for Alzheimer’s disease and apolipoprotein E (APOE) ε variant with cardiometabolic risk factors during 2-year follow-up in children and whether body fat percentage (BF%) modify these associations. A population-based sample of 469 children (246 boys, 223 girls) at baseline and 398 children (201 boys, 197 girls) at 2-year follow-up participated in the study. Genotyping was performed using the the Illumina Custom Infinium CardioMetabo BeadChip and the Illumina Infinium HumanCoreExome BeadChip. The GRS was calculated using information on nine independent gene variants available in our genomic data. We assessed BF%, waist circumference, insulin, glucose, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and systolic and diastolic blood pressure. We computed a cardiometabolic risk score and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). In boys, the GRS was not associated with cardiometabolic risk factors. In girls, GRS was directly associated with LDL cholesterol (β=0.133, 95% CI=0.002 to 0.262) at baseline and with a higher cardiometabolic risk score (β=0.154, 95% CI=0.015 to 0.294), glucose (β=0.143, 95% CI=0.003 to 0.284), and HOMA-IR (β=0.141, 95% CI=0.004 to 0.278) at 2-year follow-up. GRS was directly associated with a cardiometabolic risk score at baseline and 2-year follow-up among girls in the highest third of BF% at baseline, but not in other girls (p < 0.05 for interaction). Children with the APOE ε3/3 genotype had higher LDL cholesterol at and 2-year follow-up than those with the APOE ε2/3 genotype. In conclusion, GRS was associated with increased cardiometabolic risk in girls and especially those with higher BF%.

Pages 597-606
Jeannie-Marie S. Leoutsakos, Haijuan Yan, William S. Anderson, Wael F. Asaad, Gordon Baltuch, Anna Burke, M. Mallar Chakravarty, Kristen E. Drake, Kelly D. Foote, Lisa Fosdick, Peter Giacobbe, Zoltan Mari, Mary Pat McAndrews, Cynthia A. Munro, Esther S. Oh, Michael S. Okun, Jo Cara Pendergrass, Francisco A. Ponce, Paul B. Rosenberg, Marwan N. Sabbagh, Stephen Salloway, David F. Tang-Wai, Steven D. Targum, David Wolk, Andres M. Lozano, Gwenn S. Smith, Constantine G. Lyketsos
Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation
Abstract: Background: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants ≥ 65 years. Objective: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years. Methods: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. Results: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. Conclusion: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

Pages 607-616
Jong Bin Bae, Ji Won Han, Kyung Phil Kwak, Bong Jo Kim, Shin Gyeom Kim, Jeong Lan Kim, Tae Hui Kim, Seung-Ho Ryu, Seok Woo Moon, Joon Hyuk Park, Jong Chul Youn, Dong Young Lee, Dong Woo Lee, Seok Bum Lee, Jung Jae Lee, Jin Hyeong Jhoo, Ki Woong Kim (Handling Associate Editor: Ricardo Nitrini)
Impact of Mild Cognitive Impairment on Mortality and Cause of Death in the Elderly
Abstract: Background: Mild cognitive impairment (MCI) is a cognitive state that lies on the continuum between normal aging and dementia, and the prevalence of MCI is higher than dementia. However, the risk for mortality of people with MCI has been far less studied than that of people with dementia, and the population attributable risk percent (PAR%) of death attributable to MCI has not been estimated yet. Objective: To investigate the impact of MCI on mortality and the cause of death in the elderly, and to estimate the PAR% of deaths attributable to MCI. Methods: Data came from 7,315 elderly subjects aged ≥60 years without dementia from two cohort studies with diagnostic assessments of MCI at baseline. Deaths among participants were confirmed through the nationwide mortality database of Statistics Korea. Results: MCI increased the risk of mortality in a multivariate Cox proportional model adjusting for age, sex, education, smoking, alcohol drinking, chronic illness, depression, vascular components, and cohort (hazard ratio = 1.59, 95% confidence interval 1.30, 1.94). PAR% of death attributable to MCI was 10.7 for age 65–74 years, 16.0% for age 75–84 years, and 24.2% for age ≥85 years. In the elderly with MCI, mortality risks from cerebrovascular disease, respiratory disease, and external causes were higher than in the cognitively normal elderly. Conclusions: Our results suggest that the mortality risk of MCI in Asian countries may be comparable to that in Western countries, and MCI can contribute to the death of the elderly as much as dementia.

Pages 617-630
Kristen M. Craven, William R. Kochen, Carlos M. Hernandez, Jane M. Flinn
Zinc Exacerbates Tau Pathology in a Tau Mouse Model
Abstract: Hyperphosphorylated tau protein is a key pathology in Alzheimer’s disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson’s disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosophila model of AD. However, the interaction has never been assessed behaviorally or biochemically in mammals. Zinc supplementation is prevalent in society, finding use as a treatment for macular degeneration and cataracts, and is also taken as an immune system booster with high levels appearing in multivitamins marketed toward the elderly. Using a transgenic mouse model that contains the human gene for tau protein (P301L), we assessed the effects of excess chronic zinc supplementation on tau pathology. Behavioral tests included nest building, circadian rhythm, Morris Water Maze, fear conditioning, and open field. Biochemically, total tau and Ser396 phosphorylation were assessed using western blot. Number of tangles were assessed by Thioflavin-S and free zinc levels were assessed by Zinpyr-1. Tau mice demonstrated behavioral deficits compared to control mice. Zinc supplementation exacerbated tauopathic deficits in circadian rhythm, nesting behavior, and Morris Water Maze. Biochemically, zinc-supplemented tau mice showed increased phosphorylation at pSer396. Zinc supplementation in tau mice also increased tangle numbers in the hippocampus while decreasing free-zinc levels, demonstrating that tangles were sequestering zinc. These results show that zinc intensified the deficits in behavior and biochemistry caused by tau.

Pages 631-642
Josephine Barnes, Jonathan W. Bartlett, David A. Wolk, Wiesje M. van der Flier, Chris Frost (Handling Associate Editor: Fiona Kumfor)
Disease Course Varies According to Age and Symptom Length in Alzheimer’s Disease
Abstract: Health-care professionals, patients, and families seek as much information as possible about prognosis for patients with Alzheimer’s disease (AD); however, we do not yet have a robust understanding of how demographic factors predict prognosis. We evaluated associations between age at presentation, age of onset, and symptom length with cognitive decline as measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating sum-of-boxes (CDR-SOB) in a large dataset of AD patients. Age at presentation was associated with post-presentation decline in MMSE (p<0.001), with younger patients showing faster decline. There was little evidence of an association with change in CDR-SOB. Symptom length, rather than age, was the strongest predictor of MMSE and CDR-SOB at presentation, with increasing symptom length associated with worse outcomes. The evidence that younger AD patients have a more aggressive disease course implies that early diagnosis is essential.

Pages 643-655
Alessandra E. Thomann*, Nicolai Goettel*, Raphael J. Monsch, Manfred Berres, Thomas Jahn, Luzius A. Steiner, Andreas U. Monsch (Handling Associate Editor: Mark Bondi) *These authors contributed equally to this work.
The Montreal Cognitive Assessment: Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples
Abstract: Background: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered. Objective: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population. Methods: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥ 27/30 points) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (total score ≥ 85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach. Results: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (< 26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p < 0.001). Conclusion: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data.

Pages 657-668
Susanna C. Larsson, Hugh S. Markus
Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer’s Disease? A Systematic Review and Meta-Analysis
Abstract: Background: Epidemiological evidence has associated Alzheimer’s disease (AD) with vascular risk factors (VRFs), but whether treatment of VRFs reduces the incidence of dementia and AD is uncertain. Objective: To conduct a systematic review and meta-analysis to summarize available data on the impact of treatment of VRFs on dementia and AD incidence. Methods: Pertinent studies published until 1 January 2018 were identified from PubMed. Both randomized controlled trials (RCT) and prospective studies that investigated the impact of treatment of VRFs on dementia or AD incidence were included. Results: Eight RCTs and 52 prospective studies were identified. Antihypertensive treatment was associated with a nonsignificant reduced risk of dementia in RCTs (n=5; relative risk [RR], 0.84; 95% confidence interval [CI], 0.69–1.02) and prospective studies (n=3; RR, 0.77; 95% CI, 0.58–1.01) and with reduced AD risk in prospective studies (n=5; RR = 0.78; 95% CI, 0.66–0.91). In prospective studies, treatment of hyperlipidemia with statins, but not nonstatin lipid-lowering agents, was associated with reduced risk of dementia (n=17; RR, 0.77; 95% CI, 0.63–0.95) and AD (n=13; RR, 0.86; 95% CI, 0.80–0.92). The single RCT on statins and dementia incidence showed no association. Data from one RCT and six prospective studies did not support a beneficial impact of antidiabetic drugs or insulin therapy on dementia risk. Conclusion: Current evidence indicates that antihypertensives and statins might reduce the incidence of dementia and AD. Further trials to determine the effect of VRF on AD are needed.