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Volume 57, Number 3, 2017

Pages 645-665
Review

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

Pages 667-681
Review

Mario F. Mendez
What is the Relationship of Traumatic Brain Injury to Dementia?
Abstract: There is a long history linking traumatic brain injury (TBI) with the development of dementia. Despite significant reservations, such as recall bias or concluding causality for TBI, a summary of recent research points to several conclusions on the TBI-dementia relationship. 1) Increasing severity of a single moderate-to-severe TBI increases the risk of subsequent Alzheimer’s disease (AD), the most common type of dementia. 2) Repetitive, often subconcussive, mild TBIs increases the risk for chronic traumatic encephalopathy (CTE), a degenerative neuropathology. 3) TBI may be a risk factor for other neurodegenerative disorders that can be associated with dementia. 4) TBI appears to lower the age of onset of TBI-related neurocognitive syndromes, potentially adding “TBI cognitive-behavioral features”. The literature further indicates several specific risk factors for TBI-associated dementia: 5) any blast or blunt physical force to the head as long as there is violent head displacement; 6) decreased cognitive and/or neuronal reserve and the related variable of older age at TBI; and 7) the presence of apolipoprotein E ε4 alleles, a genetic risk factor for AD. Finally, there are neuropathological features relating TBI with neurocognitive syndromes: 8) acute TBI results in amyloid pathology and other neurodegenerative proteinopathies; 9) CTE shares features with neurodegenerative dementias; and 10) TBI results in white matter tract and neural network disruptions. Although further research is needed, these ten findings suggest that dose-dependent effects of violent head displacement in vulnerable brains predispose to dementia; among several potential mechanisms is the propagation of abnormal proteins along damaged white matter networks.

Pages 683-696
Review

Udo Rüb, Katharina Stratmann, Helmut Heinsen, Kay Seidel, Mohamed Bouzrou, Horst-Werner Korf
Alzheimer’s Disease: Characterization of the Brain Sites of the Initial Tau Cytoskeletal Pathology Will Improve the Success of Novel Immunological Anti-Tau Treatment Approaches
Abstract: Alzheimer’s disease (AD) represents the most frequent neurodegenerative disease of the human brain worldwide. Currently practiced treatment strategies for AD only include some less effective symptomatic therapeutic interventions, which unable to counteract the disease course of AD. New therapeutic attempts aimed to prevent, reduce, or remove the extracellular depositions of the amyloid-β protein did not elicit beneficial effects on cognitive deficits or functional decline of AD. In view of the failure of these amyloid-β-based therapeutic trials and the close correlation between the brain pathology of the cytoskeletal tau protein and clinical AD symptoms, therapeutic attention has since shifted to the tau cytoskeletal protein as a novel drug target. The abnormal hyperphosphorylation and intraneuronal aggregation of this protein are early events in the evolution of the AD-related neurofibrillary pathology, and the brain spread of the AD-related tau aggregation pathology may possibly follow a corruptive protein templating and seeding-like mechanism according to the prion hypothesis. Accordingly, immunotherapeutic targeting of the tau aggregation pathology during the very early pre-tangle phase is currently considered to represent an effective and promising therapeutic approach for AD. Recent studies have shown that the initial immunoreactive tau aggregation pathology already prevails in several subcortical regions in the absence of any cytoskeletal changes in the cerebral cortex. Thus, it may be hypothesized that the subcortical brain regions represent the “port of entry” for the pathogenetic agent from which the disease ascends anterogradely as an “interconnectivity pathology”.

Pages 697-703
Short Communication

Gemma Lombardi, Valentina Berti, Andrea Tedde, Silvia Bagnoli, Irene Piaceri, Cristina Polito, Giulia Lucidi, Camilla Ferrari, Andrea Ginestroni, Marco Moretti, Alberto Pupi, Benedetta Nacmias, Sandro Sorbi (Handling Associate Editor: Daniela Galimberti)
Low Florbetapir PET Uptake and Normal Aβ1-42 Cerebrospinal Fluid in an APP Ala 713Thr Mutation Carrier
Abstract: According to the literature, the APP Ala713Thr mutation is associated with Alzheimer’s disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.

Pages 705-710
Short Communication

Willem H. Bouvy, Hugo J. Kuijf, Jaco J.M. Zwanenburg, Huiberdina L. Koek, L. Jaap Kappelle, Peter R. Luijten, M. Kamran Ikram, Geert Jan Biessels on behalf of the Utrecht Vascular Cognitive Impairment (VCI) Study group (Handling Associate Editor: Jurgen Claassen)
Abnormalities of Cerebral Deep Medullary Veins on 7 Tesla MRI in Amnestic Mild Cognitive Impairment and Early Alzheimer’s Disease: A Pilot Study
Abstract: Cerebral small vessel disease (SVD) contributes to cognitive impairment and dementia. SVD may affect veins, but veins are difficult to detect with 1.5 and 3T MRI. We compared deep medullary veins (DMVs) visualized on 7T-MRI between patients with early Alzheimer’s disease (eAD; n=17) or amnestic MCI (aMCI; n=12) and controls (n=40). The number and density of DMVs was similar in patients and controls, but tortuosity was higher in eAD (Cohen’s d=0.7, 95% CI: 0.1–1.2, p=0.02) and aMCI (Cohen’s d=0.8, 95% CI: 0.2–1.5, p=0.01), independent of brain atrophy. Venous changes provide a new perspective on vascular involvement in dementia.

Pages 711-716
Short Communication

Hee Jin Kim, Hanna Cho, David J. Werring, Young Kyoung Jang, Yeo Jin Kim, Jin San Lee, Juyoun Lee, Soomin Jun, Seongbeom Park, Young Hoon Ryu, Jae Yong Choi, Young Seok Cho, Seung Hwan Moon, Duk L. Na, Chul Hyoung Lyoo, Sang Won Seo (Handling Associate Editor: Andreas Charidimou)
18F-AV-1451 PET Imaging in Three Patients with Probable Cerebral Amyloid Angiopathy
Abstract: Cerebrovascular deposition of amyloid-β, known as cerebral amyloid angiopathy (CAA), is associated with MRI findings of lobar hemorrhage, cerebral microbleeds, and cortical superficial siderosis. Although pathological studies suggest that tau may co-localize with vascular amyloid, this has not yet been investigated in CAA in vivo. Three patients with probable CAA underwent 11C-Pittsburgh Compound B (PiB) PET or 18F-florbetaben PET to evaluate amyloid burden, and 18F-AV-1451 PET to evaluate paired helical filament tau burden. Regions that had cerebral microbleeds or cortical superficial siderosis largely overlapped with those showing increased 18F-AV-1451 and increased 11C-PiB uptake. Our preliminary study raised the possibility that lobar cerebral microbleeds, and cortical superficial siderosis, which are characteristic markers of vascular amyloid, may be associated with local production of paired helical filament tau.

Pages 717-721
Short Communication

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

Pages 723-734
Lu-shan Liu, Xue-qin Bai, Ya Gao, Qi Wu, Zhong Ren, Qing Li, Li-hong Pan, Ni-ya He, JuanPeng, Zhi-han Tang
PCSK9 Promotes oxLDL-Induced PC12 Cell Apoptosis Through the Bcl-2/Bax-Caspase 9/3 Signaling Pathway
Abstract: Background: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases. Objective: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer’s disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL). Methods: Cultured PC12 cells were serum-starved and incubated with different concentrations of oxLDL for 24 h. Intracytoplasmic lipid droplets were observed by oil red O staining. Morphological assessment of apoptotic cells was performed using Hoechst 33258 staining and flow cytometry analysis. The expression of mRNA and protein was detected by reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses, respectively. Transfection of small interfering RNA (siRNA) into PC12 cells was conducted using HiperFect Transfection Reagent. Concentrations of Aβ40 and Aβ42 were detected by enzyme-linked immunosorbent assay (ELISA) kit. Results: Intracellular lipid content, the number of apoptotic cells, and PCSK9 expression were increased in PC12 cells after oxLDL treatment. Transfection with PCSK9 siRNA reduced the oxLDL-induced apoptosis of PC12 cells. We further confirmed the involvement of Bcl-2/Bax-Caspase (9, 3) signaling pathway in the regulation of PC12 cells apoptosis. β-Secretase 1, another target gene of PCSK9, was downregulated in PC12 cells in response to oxLDL treatment. Aβ40 and Aβ42 contents were also decreased. Conclusion: PCSK9 promotes oxLDL-induced PC12 cell apoptosis through the Bcl-2/Bax-Caspase 9/3 signaling pathway.

Pages 735-745
Emily J. Mason, Erin P. Hussey, Robert J. Molitor, Philip C. Ko, Manus J. Donahue, Brandon A. Ally (Handling Associate Editor: Kirk Daffner)
Family History of Alzheimer’s Disease is Associated with Impaired Perceptual Discrimination of Novel Objects
Abstract: Early detection may be the key to developing therapies that will combat Alzheimer’s disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40-60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects’ medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.

Pages 747-763
Michael A Gregory, Narlon C. Boa Sorte Silva, Dawn P. Gill, Cheri L. McGowan, Teresa Liu-Ambrose, J. Kevin Shoemaker, Vladimir Hachinski, Jeff Holmes, Robert J. Petrella
Combined Dual-Task Gait Training and Aerobic Exercise to Improve Cognition, Mobility, and Vascular Health in Community-Dwelling Older Adults at Risk for Future Cognitive Decline
Abstract: This 6-month experimental case series study investigated the effects of a dual-task gait training and aerobic exercise intervention on cognition, mobility, and cardiovascular health in community-dwelling older adults without dementia. Participants exercised 40 min/day, 3 days/week for 26 weeks on a Biodex GaitTrainer2 treadmill. Participants were assessed at baseline (V0), interim (V1: 12-weeks), intervention endpoint (V2: 26-weeks), and study endpoint (V3: 52-weeks). The study outcomes included: cognition [executive function (EF), processing speed, verbal fluency, and memory]; mobility: usual & dual-task gait (speed, step length, and stride time variability); and vascular health: ambulatory blood pressure, carotid arterial compliance, and intima-media thickness (cIMT). Fifty-six participants [age: 70(6) years; 61% female] were included in this study. Significant improvements following the exercise program (V2) were observed in cognition: EF (p = 0.002), processing speed (p < 0.001), verbal fluency [digit symbol coding (p < 0.001), phonemic verbal fluency (p < 0.001)], and memory [immediate recall (p < 0.001) and delayed recall (p < 0.001)]; mobility: usual & dual-task gait speed (p = 0.002 and p < 0.001, respectively) and step length (p = 0.001 and p = 0.003, respectively); and vascular health: cIMT (p = 0.002). No changes were seen in the remaining outcomes. In conclusion, 26 weeks of dual-task gait training and aerobic exercise improved performance on a number of cognitive outcomes, while increasing usual & dual-task gait speed and step length in a sample of older adults without dementia.

Pages 765-773
Shizuo Hatashita, Daichi Wakebe
Amyloid-β Deposition and Long-Term Progression in Mild Cognitive Impairment due to Alzheimer’s Disease Defined with Amyloid PET Imaging
Abstract: The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11C]-PIB over a follow-up of 5.7 ±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n=39, p <0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n=39, p <0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n=16, p <0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r=−0.47, n=28, p<0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition.

Pages 775-786
Federica Barocco, Marco Spallazzi, Letizia Concari, Simona Gardini, Annalisa Pelosi, Paolo Caffarra
The Progression of Alzheimer’s Disease: Are Fast Decliners Really Fast? A Four-Year Follow-Up
Abstract: Background. The rate of cognitive and functional decline in Alzheimer’s disease (AD) changes across individuals. Objectives. Our purpose was to assess whether the concept of “fast decline” really fits its definition and whether cognitive and functional variables at onset can predict the progression of AD. Methods. 324 AD patients were included. We retrospectively examined their Mini-Mental State Examination (MMSE) total score and sub-items, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) at baseline and every six months for a 4-year follow-up. Patients were divided into “fast decliners” (n=62), defined by a loss ≥ 5 points on the MMSE score within the first year from the baseline; “intermediate decliners” (n=37), by a loss ≥ 5 points after the first year and before the 18th month; or “slow decliners” (n=225), composed of the remaining patients. Results. At baseline, the groups did not differ on demographic, clinical, and cognitive variables. The decline at the end of the 4-year follow-up period seems to be similar among the different decline clusters. Predictors of disease progression have not been identified; only the MMSE total score at 12 months <14/30 was indicative of a poor prognosis. Conclusions. Even with the limitation due to the small sample size, the lack of differences in the disease progression in time in the different clusters suggest the inconsistency of the so-called “fast decliners”. This study was unable to show any significant difference among clusters of AD progression within a 4-year time interval. Further studies should better clarify whether a more consistent distinction exists between slow and fast decliners.

Pages 787-795
Milica G. Kramberger, Bjørn Auestad, Sara Garcia-Ptacek, Carla Abdelnour, Josep Garre Olmo, Zuzana Walker, Afina W. Lemstra, Elisabet Londos, Frederic Blanc, Laura Bonanni, Ian McKeith, Bengt Winblad, Frank Jan de Jong, Flavio Nobili, Elka Stefanova, Maria Petrova, Cristian Falup-Pecurariu, Irena Rektorova, Sevasti Bostantjopoulou, Roberta Biundo, Daniel Weintraub, Dag Aarsland on behalf of the E-DLB
Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort
Abstract: Background/Objective: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) patients. Methods: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features. Results: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p=0.07 compared to DLB) and 1.8 in PDD (p=0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features. Conclusions: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

Pages 797-812
Catherine Reed, Michael Happich, Josep Maria Argimon, Josep Maria Haro, Anders Wimo, Giuseppe Bruno, Richard Dodel, Roy W. Jones, Bruno Vellas, Mark Belger
What Drives Country Differences in Cost of Alzheimer’s Disease? An Explanation from Resource Use in the GERAS Study
Abstract: Background: Country differences in resource use and costs of Alzheimer’s disease (AD) may be driven by differences in health care systems and resource availability. Objective: To compare country resource utilization drivers of societal costs for AD dementia over 18 months. Methods: GERAS is an observational study in France (n = 419), Germany (n = 550), and the UK (n = 526). Resource use of AD patients and caregivers contributing to >1% of total societal costs (year 2010) was assessed for country differences, adjusting for participant characteristics. Results: Mean 18-month societal costs per patient were France €33,339, Germany €38,197, and UK €37,899 (£32,501). Caregiver time spent on basic and instrumental activities of daily living (ADL) contributed the most to societal costs (54% France, 64% Germany, 65% UK). Caregivers in France spent less time on ADL than UK caregivers and missed fewer work days than in other countries. Compared with other countries, patients in France used more community care services overall and were more likely to use home aid. Patients in Germany were least likely to use temporary accommodation or to be institutionalized at 18 months. UK caregivers spent the most time on instrumental ADL, UK patients used fewest outpatient resources, and UK patients/caregivers were most likely to receive financial support. Conclusion: Caregiver time on ADL contributed the most to societal costs and differed across countries, possibly due to use of community care services and institutionalization. Other resources had different patterns of use across countries, reflecting country-specific health and social care systems.

Pages 813-824
May A. Beydoun, Alyssa A. Gamaldo, Hind A. Beydoun, Danielle Shaked, Alan B. Zonderman*, Shaker M. Eid* *Co-senior authors
Trends, Predictors, and Outcomes of Healthcare Resources Used in Patients Hospitalized with Alzheimer’s Disease with at Least One Procedure: The Nationwide Inpatient Sample
Abstract: We assessed trends, predictors and outcomes of resource utilization in hospital inpatient discharges with a principal diagnosis of Alzheimer’s disease (AD) with at least one procedure. Using Nationwide Inpatient Sample data (NIS, 2002-2012), discharges primarily diagnosed with AD, aged ≥60 y and with ≥1 procedure, were selected (Weighted N=92,300). Hospital resource utilization were assessed using ICD-9-CM codes, while hospitalization outcomes included total charges (TC, 2012$), length of stay (LOS, days), and mortality risk (MR, %). Brain and respiratory/gastrointestinal procedure utilization both dropped annually by 3-7%, while cardiovascular procedures/evaluations, blood evaluations, blood transfusion, and resuscitation (“CVD/Blood”) as well as neurophysiological and psychological evaluation and treatment (“Neuro”) procedures increased by 5-8%. Total charges, length of stay, and mortality risk were all markedly higher with use of respiratory/gastrointestinal procedures as opposed to being reduced with use of “Brain” procedures. Procedure count was positively associated with all three hospitalization outcomes. In sum, patterns of hospital resources that were used among AD inpatients changed over-time, and were associated with hospitalization outcomes such as total charges, length of stay, and mortality risk.

Pages 825-843
Michela Pievani, Lorenzo Pini, Clarissa Ferrari, Francesca B. Pizzini, Ilaria Boscolo Galazzo, Chiara Cobelli, Maria Cotelli, Rosa Manenti, Giovanni B. Frisoni
Coordinate-Based Meta-Analysis of the Default Mode and Salience Network for Target Identification in Non-Invasive Brain Stimulation of Alzheimer’s Disease and Behavior Variant Frontotemporal Dementia Networks
Abstract: Background: The accurate choice of the site of non-invasive brain stimulation (NIBS) is an important factor in trial design. Objective: Based on the observation that Alzheimer’s disease (AD) and behavioral frontotemporal dementia (bvFTD) affect specific large-scale networks, i.e., the default mode network (DMN) and the salience network (SN), respectively, we aimed to identify population-average coordinates of these networks that could be used as potential targets in NIBS trials aiming to modulate these circuits. Methods: A systematic literature search of resting-state functional MRI studies reporting DMN and SN stereotactic coordinates was performed according to PRISMA guidelines. Coordinate-based meta-analyses were conducted to identify consistent nodes of the DMN and SN using GingerALE BrainMap software and the activation likelihood estimation method. Results: DMN coordinates mapped primarily to mesial areas (posterior cingulate cortex/precuneus [Brodmann Area - BA 23/31] and medial prefrontal cortex [BA 9/10/32]). More superficial areas mapped to the bilateral parietal (angular gyrus [BA 39]), temporal (middle gyrus [BA 21]) and dorsolateral prefrontal (superior gyrus [BA 8]) cortex. SN coordinates mapped primarily to mesial and deep frontal areas (anterior insula, anterior cingulate cortex [BA 24/32]), but more superficial areas mapped to the bilateral parietal (supramarginal gyrus [BA 40]) and the right dorsolateral prefrontal (middle gyrus [BA 9/10]) cortex. Conclusions: NIBS should target the bilateral angular, the middle temporal cortex, or superior frontal gyri in AD for DMN modulation, and the right middle frontal or supramarginal gyri in bvFTD for SN modulation.

Pages 845-856
Theresa J. Chirles, Katherine Reiter, Lauren R. Weiss, Alfonso J. Alfini, Kristy A. Nielson, J. Carson Smith
Exercise Training and Functional Connectivity Changes in Mild Cognitive Impairment and Healthy Elders
Abstract: Background: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer’s disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. Objective: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. Methods: Sixteen MCI and 16 healthy elders (age range = 60-88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps. Results: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. Conclusion: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated.

Pages 857-871
Margherita Romeo, Matteo Stravalaci, Marten Beeg, Alessandro Rossi, Fabio Fiordaliso, Alessandro Corbelli, Mario Salmona, Marco Gobbi, Alfredo Cagnotto, Luisa Diomede (Handling Associate Editor: Oxana Galzitskaya)
Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity
Abstract: The 24-residue peptide humanin (HN) has been proposed as a peptide-based inhibitor that are able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously, HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action.

Pages 873-883
Ramit Ravona-Springer, Michal Schnaider-Beeri, Uri Goldbourt
Triceps and Subscapular Skinfold in Men Aged 40-65 and Dementia Prevalence 36 Years Later
Abstract: Background: The relationship of obesity with risk for dementia is complex and may change with age. Objective: To analyze the relationship between measures of obesity at age 40-65 and dementia prevalence in survivors 36 years later. Methods: Obesity-related measures of triceps and subscapular skinfold thickness were assessed in 1963 in n=9,760 men aged 40-65 participating in the Israel Ischemic Heart Disease study. Cognitive evaluation and assessment of dementia prevalence were performed in n=1,643 participants of the original cohort who survived until 1999/2000 (age ≥ 76 years) and had anthropometric measures in 1963. Results: Age-adjusted prevalence of dementia in survivors in 1999/2000 by baseline triceps skinfold quintile was 20.5%, 21.2%, 17.6%, 15.6%, and 14.5%, respectively, from lowest to highest (p=0.006 in trend test). Using logistic regression, a 6-mm increment of triceps skinfold was associated with an age and BMI-adjusted odds ratio of 0.81 (95% CI, 0.70-0.94) for dementia prevalence among survivors. Age-adjusted risk for dementia by subscapular skinfold quintile demonstrated 20.5%, 17.1%, 15.7%, 19.4%, and 18.1%, respectively, in groups of subjects by subscapular skinfold quintile from lowest to highest (p=0.6 in trend test). Conclusions: Lower triceps skinfold at age 40-65, reflecting diminished peripheral fat, was associated with higher dementia prevalence in late life, potentially suggesting a protective role of peripheral fat to brain health.

Pages 885-897
Yan Huang*, Wei Shen*, Jie Su, Bin Cheng, Dong Li, Gang Liu, Wen-Xia Zhou, Yong-Xiang Zhang *These two authors contributed equally to this work.
Modulating the Balance of Synaptic and Extrasynaptic NMDA Receptors Shows Positive Effects against Amyloid-β-Induced Neurotoxicity
Abstract: Alzheimer’s disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect. In Aβ ICV-injected animals, the combination of ifenprodil and D-cycloserine (a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests (nest building, novel object recognition, and Morris water maze) than ifenprodil (Morris water maze) or D-cycloserine (nest building) alone. Signal pathway analysis showed that Aβ disturbed the GluN2A/GluN2B-related pathway. The ratio of GluN2A to GluN2B decreased in Aβ-treated animals, and TORC dephosphorylation and ERK1/2 activation, which could be initiated by GluN2A, also decreased in the hippocampal tissues of Aβ-treated animals. As a result, the activation of CREB and the content of brain-derived BDNF decreased. The combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone, indicating that Aβ-induced toxicology was mediated both by functionally inhibiting GluN2A and enhancing GluN2B. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Aβ-induced neurotoxicity, suggesting that modulation of the balance between GluN2A and GluN2B could be a potential strategy for AD drug development and therapy.

Pages 899-906
Meng Wei*, Beiyu Zhao*, Kang Huo, Yongning Deng, Suhang Shang, Jie Liu, Yanbo Li, Louyan Ma, Yu Jiang, Liangjun Dang, Chen Chen, Shan Wei, Juanli Zhang, Hailei Yang, Fan Gao, Qiumin Qu *These authors contributed equally to this work.
Sleep Deprivation Induced Plasma Amyloid-β Transport Disturbance in Healthy Young Adults
Abstract: Background: Sleep is an important physiological process and beneficial in the removal of brain metabolites and functional recovery. Prior studies have shown that sleep disorders are significant risk factors for Alzheimer's disease (AD). Objective: The present study was designed to characterize the effect of short-term total sleep deprivation (TSD) on plasma amyloid-β (Aβ) concentrations. Methods: A clinical trial was conducted between March 1, 2016, and April 1, 2016. Twenty volunteers (age 27.3±3.4 years) with normal cognitive function and sleeping habits were recruited from the local population. Participants underwent 24 h of TSD. Periprocedural blood samples were collected to compare the changes of plasma Aβ42, Aβ40, low-density lipoprotein receptor-related protein (sLRP-1), soluble receptors for advanced glycation end products (sRAGE), and serum superoxide dismutase (SOD) and malonaldehyde (MDA). Results: TSD increased morning plasma Aβ40 levels by 32.6% (p<0.001) and decreased the Aβ42/Aβ40 ratio by 19.3% (p<0.001). A positive relationship was found between TSD duration and plasma Aβ40 level (r=0.51, p<0.001) and Aβ40/Aβ42 ratio (r=0.25, p=0.003). Plasma concentrations of sLRP1 (p=0.018) and sRAGE (p=0.001) decreased significantly after TSD. Aβ40 and Aβ42 plasma concentrations correlated with plasma levels of sLRP1 and sRAGE. Serum SOD decreased after TSD (p=0.005), whereas serum MDA was increased (p=0.001). Conclusion: Sleep deprivation can lead to an elevation of plasma Aβ40 and decrease of the Aβ42/Aβ40 ratio. The underlying mechanisms may be related to increased oxidative stress and impaired peripheral Aβ clearance as pathomechanisms of AD.

Pages 907-925
Gurdeep Marwarha, Stephen Rostad, Jaclyn Lilek, Mason Kleinjan, Jared Schommer, Othman Ghribi (Handling Associate Editor: Bernard Schreurs)
Palmitate Increases β-site AβPP-Cleavage Enzyme 1 Activity and Amyloid-β Genesis by Evoking Endoplasmic Reticulum Stress and Subsequent C/EBP Homologous Protein Activation
Abstract: Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer’s disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) were shown to inversely correlate with cognitive function. However, the cellular mechanisms by which sFFA may increase the risk for AD are not well known. Endoplasmic reticulum (ER) stress has emerged as one of the signaling pathways initiating and fostering the neurodegenerative changes in AD by increasing the aspartyl protease β-site AβPP cleaving enzyme 1 (BACE1) and amyloid-β (Aβ) genesis. In this study, we determined the extent to which palmitate increases BACE1 and Aβ levels in vitro and in vivo as well as the potential role of ER stress as cellular mechanism underlying palmitate effects. We demonstrate, in palmitate-treated SH-SY5Y neuroblastoma cells and in the hippocampi of palmitate-enriched diet-fed mice, that palmitate evokes the activation of the C/EBP Homologous Protein (CHOP), a transcription factor that is specifically responsive to ER stress. Induction of CHOP expression is associated with increased BACE1 mRNA, protein and activity levels, and subsequent enhanced amyloidogenic processing of amyloid-β protein precursor (AβPP) that culminates in a substantial increase in Aβ genesis. We further show that CHOP is an indispensable molecular mediator of palmitate-induced upregulation in BACE1 activity and Aβ genesis. Indeed, we show that Chop-/- mice and CHOP knocked-down SH-SY5Y neuroblastoma cells do not exhibit the same commensurate degree of palmitate-induced increase in BACE1 expression levels and Aβ genesis.

Pages 927-935
Grazia D’Onofrio, Daniele Sancarlo, Francesco Ricciardi, Francesco Panza, Davide Seripa, Filippo Cavallo, Francesco Giuliani, Antonio Greco
Information and Communication Technologies for the Activities of Daily Living in Older Patients with Dementia: A Systematic Review
Abstract: Background: Significant innovations have been introduced in recent years in the application of information and communication technologies (ICTs) to support healthcare for patients with dementia. Objective: In the present systematic review, our goal is to keep track of ICT concepts and approaches to support the range of activities of daily living for people with dementia and to provide a snapshot of the effect that technology is having on patients’ self-reliance. Methods: We reviewed the literature and identified systematic reviews of cohort studies and other authoritative reports. Our selection criteria included: (1) activities of daily living, (2) ICT, and (3) dementia. Results: We identified 56 studies published between 2000 and 2015, of which 26 met inclusion criteria. The present systematic review revealed many ICT systems that could purportedly support the range of activities of daily living for patients with dementia. The results showed five research bodies: 1) technologies used by patients with dementia, 2) technologies used by caregivers, 3) monitoring systems, 4) ambient assistive living with ICTs, and 5) tracking and wayfinding. Conclusions: There is a potential for ICTs to support dementia care at home and to improve quality of life for caregivers, reducing healthcare costs and premature institutional care for these patients.

Pages 937-951
J. Antonio García-Casal, Miguel Goñi-Imizcoz, M. Victoria Perea-Bartolomé, Felipe Soto-Pérez, Sarah Jane Smith, Sara Calvo-Simal, Manuel Franco-Martín
The Efficacy of Emotion Recognition Rehabilitation for People with Alzheimer’s Disease
Abstract: Background: The ability to recognize emotional expression is essential for social interactions, adapting to the environment, and quality of life. Emotion recognition is impaired in people with Alzheimer’s disease (AD), thus rehabilitation of these skills has the potential to elicit significant benefits. Objective: This study sought to establish whether emotion recognition capacity could be rehabilitated in people with AD. Methods: Thirty-six participants with AD were assigned to one of three conditions: an experimental group (EG) that received 20 sessions of rehabilitation of emotion recognition and 20 sessions of cognitive stimulation therapy (CST), a control group (CG) that received 40 sessions of CST, and a treatment as usual group (TAU). Results: A positive treatment effect favoring the EG was found; participants were better able to correctly identify emotions (p=0.021), made fewer errors of commission (p=0.002), had greater precision of processing (p=0.021), and faster processing speed (p=0.001). Specifically, the EG were better able to identify sadness (p=0.016), disgust (p=0.005), and the neutral expression (p=0.014), with quicker processing speed for disgust (p=0.002). These gains were maintained at one month follow-up with the exception of processing speed for surprise, which improved. Conclusion: Capacity to recognize facial expressions of emotions can be improved through specific rehabilitation in people with AD, and gains are still present at a one month follow up. These findings have implications for the design of rehabilitation techniques for people with AD that may lead to improved quality of life and social interactions for this population.

Pages 953-968
Michael L. Alosco*, Jonathan Duskin*, Lilah M. Besser, Brett Martin, Christine E. Chaisson, John Gunstad, Neil W. Kowall, Ann C. McKee, Robert A. Stern, Yorghos Tripodis (Handling Associate Editor: Kaarin Anstey) *These authors contributed equally to this work.
Modeling the Relationships Among Late-Life Body Mass Index, Cerebrovascular Disease, and Alzheimer’s Disease Neuropathology in an Autopsy Sample of 1,421 Subjects from the National Alzheimer’s Coordinating Center Data Set
Abstract: The relationship between late-life body mass index (BMI) and Alzheimer’s disease (AD) is poorly understood due to the lack of research in samples with autopsy-confirmed AD neuropathology (ADNP). The role of cerebrovascular disease (CVD) in the interplay between late-life BMI and ADNP is unclear. We conducted a retrospective longitudinal investigation and used joint modeling of linear mixed effects to investigate causal relationships among repeated antemortem BMI measurements, CVD (quantified neuropathologically), and ADNP in an autopsy sample of subjects across the AD clinical continuum. The sample included 1,421 subjects from the National Alzheimer’s Coordinating Center’s Uniform Data Set and Neuropathology Data Set with diagnoses of normal cognition (NC; n=234), mild cognitive impairment (MCI; n=201), or AD dementia (n=986). ADNP was defined as moderate to frequent neuritic plaques and Braak stage III-VI. Ischemic Injury Scale (IIS) operationalized CVD. Joint modeling examined relationships among BMI, IIS, and ADNP in the overall sample and stratified by initial visit Clinical Dementia Rating score. Subject-specific random intercept for BMI was the predictor for ADNP due to minimal BMI change (p=0.3028). Analyses controlling for demographic variables and APOE ε4 showed lower late-life BMI predicted increased odds of ADNP in the overall sample (p<0.001), and in subjects with CDR of 0 (p=0.0021) and 0.5 (p=0.0012), but not ≥1.0 (p=0.2012). Although higher IIS predicted greater odds of ADNP (p<0.0001), BMI did not predict IIS (p=0.2814). The current findings confirm lower late-life BMI confers increased odds for ADNP. Lower late-life BMI may be a preclinical indicator of underlying ADNP.