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Volume 53, Number 4, 2016

Pages 1237-1256
Review

Etheresia Pretorius, Janette Bester, Douglas B. Kell
A Bacterial Component to Alzheimer’s-Type Dementia Seen via a Systems Biology Approach that Links Iron Dysregulation and Inflammagen Shedding to Disease
Abstract: The progression of Alzheimer’s disease (AD) is accompanied by a great many observable changes, both molecular and physiological. These include oxidative stress, neuroinflammation, and (more proximal to cognitive decline) the death of neuronal and other cells. A systems biology approach seeks to organize these observed variables into pathways that discriminate those that are highly involved (i.e., causative) from those that are more usefully recognized as bystander effects. We review the evidence that iron dysregulation is one of the central causative pathway elements here, as this can cause each of the above effects. In addition, we review the evidence that dormant, non-growing bacteria are a crucial feature of AD, that their growth in vivo is normally limited by a lack of free iron, and that it is this iron dysregulation that is an important factor in their resuscitation. Indeed, bacterial cells can be observed by ultrastructural microscopy in the blood of AD patients. A consequence of this is that the growing cells can shed highly inflammatory components such as lipopolysaccharides (LPS). These too are known to be able to induce (apoptotic and pyroptotic) neuronal cell death. There is also evidence that these systems interact with elements of vitamin D metabolism. This integrative systems approach has strong predictive power, indicating (as has indeed been shown) that both natural and pharmaceutical iron chelators might have useful protective roles in arresting cognitive decline, and that a further assessment of the role of microbes in AD development is more than highly warranted.

Pages 1257-1270
Review
Reginald C. Adiele, Chiedukam A. Adiele
Mitochondrial Regulatory Pathways in the Pathogenesis of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is an age-associated neurodegenerative brain disorder with progressive cognitive decline that leads to terminal dementia and death. For decades, amyloid-beta (Aβ) and neurofibrillary tangle (NFT) aggregation hypotheses have dominated studies on the pathogenesis and identification of potential therapeutic targets in AD. Little attention has been paid to the mitochondrial molecular/biochemical pathways leading to AD. Mitochondria play a critical role in cell viability and death including neurons and neuroglia, not only because they regulate energy and oxygen metabolism but also because they regulate cell death pathways. Mitochondrial impairment and oxidative stress are implicated in the pathogenesis of AD. Interestingly, current therapeutics provide symptomatic benefits to AD patients resulting in the use of preventive trials on presymptomatic subjects. This review article elucidates the pathophysiology of AD and emphasizes the need to explore the mitochondrial pathways to provide solutions to unanswered questions in the prevention and treatment of AD.

Pages 1271-1276
Review

Herbert B. Allen
Alzheimer’s Disease: Assessing the Role of Spirochetes, Biofilms, the Immune System, and Amyloid-β with Regard to Potential Treatment and Prevention
Abstract: Alzheimer’s disease (AD) is an infectious disease caused by spirochetes, and these spirochetes form biofilms, which attract the innate immune system. The innate immune system first responder, Toll-like receptor 2, generates both NF-κB and TNF-α which try to kill the spirochetes in the biofilm, but cannot penetrate the “slime”. NF-κB is also responsible for the generation of amyloid-β (Aβ) which itself is anti-microbial. Aβ cannot penetrate the biofilm either, and its accumulation leads to destruction of the cerebral neurocircuitry. Treatment with penicillin (as in tertiary syphilis, the comparator to AD) is outlined; a biofilm dispersing agent may need to be added to the protocol.

Pages 1277-1285
Kolbjørn Brønnick, Monica H. Breitve, Arvid Rongve, Dag Aarsland
Neurocognitive Deficits Distinguishing Mild Dementia with Lewy Bodies from Mild Alzheimer’s Disease are Associated with Parkinsonism
Abstract: Background: The cognitive profile of mild dementia with Lewy bodies (DLB) versus mild Alzheimer’s disease (AD) has not been extensively studied, and the relation of cognitive deficits to the core diagnostic criteria for DLB (fluctuations, visual hallucinations, and parkinsonism) remains poorly understood. Objective: To compare the cognitive profile in patients with mild DLB to patients with mild AD and investigate the relation between cognitive deficits distinguishing DLB from AD and the core diagnostic features in DLB. Methods: Patients with mild dementia were recruited from the southwestern part of Norway and patients diagnosed with probable AD (n=113) or probable DLB (n=77) were included. The DLB core diagnostic symptoms were assessed using standardized clinical measures, and standardized neurocognitive tests assessing attention, language, memory, and visuospatial functions were administered. Univariate and multivariate comparisons of cognitive tests were performed, and tests distinguishing between AD and DLB were subjected to correlational analyses with the core diagnostic symptoms. Results: DLB patients performed worse than AD patients on test of visuoconstruction, but not visual perception and on all tests involving attention and executive functions, except verbal fluency. The multivariate model distinguished between DLB and AD with a sensitivity of 74% and a specificity of 82%. Tests where DLB performed worse than AD were highly correlated with degree of parkinsonism, but not with cognitive fluctuations or visual hallucinations. Conclusions: The cognitive profile in mild DLB can be useful in distinguishing AD from DLB. The strong relation between relative deficits in DLB and parkinsonism warrants further studies.

Pages 1287-1297
Everard G.B. Vijverberg, Mike P, Wattjes, Annemiek Dols, Welmoed A. Krudop, Christiane Möller, Anne Peters, Cora J. Kerssens, Flora Gossink, Niels D. Prins, Max L. Stek, Philip Scheltens, Bart N.M. van Berckel, Frederik Barkhof, Yolande A.L. Pijnenburg
Diagnostic Accuracy of MRI and Additional [18F]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes
Abstract: Background: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown. Objective: To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes. Methods: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging. Results: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52-85%) with a specificity of 93% (95% CI 86-97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66-100%) with a specificity of 68% (95% CI 56-79%). The sensitivity of combined neuroimaging was 96% (95% CI 85-100%) with a specificity of 73% (95% CI 63-81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis. Conclusion: A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation.

Pages 1299-1314
Grégory Ben-Sadoun, Guillaume Sacco, Valeria Manera, Jérémy Bourgeois, Alexandra König, Pierre Foulon, Baptiste Fosty, François Bremond, Fabienne d’Arripe-Longueville, Philippe Robert (Handling Associate Editor: Russell Swerdlow)
Physical and Cognitive Stimulation Using an Exergame in Subjects with Normal Aging, Mild and Moderate Cognitive Impairment
Abstract: Background: The use of Serious exerGames (SeG) as enriched environments (EE), which promotes cognitive simulation with physical activity in a positive emotional context, has been proposed to represent a powerful method to slow down the decline due to neurodegenerative diseases (ND), such as Alzheimer’s disease (AD). However, so far, no SeG targeting EE has been tested in ND subjects. Objective: This study aimed at evaluating the usability and short-term training effects of X-Torp, an action SeG designed for elderly ND subjects with mild cognitive impairment (MCI) and AD. Methods: X-Torp is a SeG played using the Microsoft® Kinect™. 10 ND subjects and 8 healthy elderly controls (HEC) were enrolled in a 1-month program with three training sessions per week. Usability was evaluated through game time, game performance, the aerobic intensity level reached, perceived emotions, and perceived usability. Results: All participants successfully completed the training program. ND subjects played less and had a lower game performance compared to HEC. During the sessions, ND subjects maintained a light intensity of aerobic activity, while HEC maintained a moderate intensity. Both groups experienced only positive emotions, and reported a ‘moderate’ to ‘high’ perceived competence, a ‘moderate’ game difficulty, and a ‘high’ interest in the game. Conclusion: Usability results suggest that X-Torp represents a usable EE for healthy subjects and persons with MCI and AD. However, in order to reach moderate or high intensity of aerobic activity, X-Torp control modes should be adapted to become more physically stimulating.

Pages 1315-1323
Elissa H. Wilker, Sergi Martinez-Ramirez, Itai Kloog, Joel Schwartz, Elizabeth Mostofsky, Petros Koutrakis, Murray A. Mittleman, Anand Viswanathan (Handling Associate Editor: Lilian Calderón-Garcidueñas)
Fine Particulate Matter, Residential Proximity to Major Roads, and Markers of Small Vessel Disease in a Memory Study Population
Abstract: Background: Long-term exposure to ambient air pollution has been associated with impaired cognitive function and vascular disease in older adults, but little is known about these associations among people with concerns about memory loss. Objective: To examine associations between exposures to fine particulate matter and residential proximity to major roads and markers of small vessel disease. Methods: From 2004-2010, 236 participants in the Massachusetts Alzheimer’s Disease Research Center Longitudinal Cohort participated in neuroimaging studies. Residential proximity to major roads and estimated 2003 residential annual average of fine particulate air pollution (PM2.5) were linked to measures of brain parenchymal fraction (BPF), white matter hyperintensities (WMH), and cerebral microbleeds. Associations were modeled using linear and logistic regression and adjusted for clinical and lifestyle factors. Results: In this population (median age [interquartile range]=74[12], 57% female) living in a region with median 2003 PM2.5 annual average below the current Environmental Protection Agency (EPA) standard, there were no associations between living closer to a major roadway or for a 2 µg/m3 increment in PM2.5 and smaller BPF, greater WMH volume, or a higher odds of microbleeds. However, a 2 µg/m3 increment in PM2.5 was associated with -0.19 (95% Confidence Interval (CI): -0.37, -0.005) lower natural log-transformed WMH volume. Other associations had wide confidence intervals. Conclusions: In this population, where median 2003 estimated PM2.5 levels were below the current EPA standard, we observed no pattern of association between residential proximity to major roads or 2003 average PM2.5 and greater burden of small vessel disease or neurodegeneration.

Pages 1325-1340
Marcos Pietto*, Mario A. Parra*, Natalia Trujillo, Facundo Flores, Adolfo M. García, Julian Bustin, Pablo Richly, Facundo Manes, Francisco Lopera, Agustín Ibáñez, Sandra Baez *These authors contributed equally to this work.
Behavioral and Electrophysiological Correlates of Memory Binding Deficits in Patients at Different Risk Levels for Alzheimer’s Disease
Abstract: Deficits in visual short-term memory (VSTM) binding have been proposed as an early and specific marker for Alzheimer’s disease (AD). However, no studies have explored the neural correlates of this domain in clinical categories involving prodromal stages with different risk levels of conversion to AD. We assessed underlying electrophysiological modulations in patients with mild cognitive impairment (MCI), patients in the MCI stages of familial AD carrying the mutation E280A of the presenilin-1 gene (MCI-FAD), and healthy controls. Moreover, we compared the behavioral performance and neural correlates of both patient groups. Participants completed a change-detection VSTM task assessing recognition of changes between shapes or shape-color bindings, presented in two consecutive arrays (i.e., study and test) while event related potentials (ERPs) were recorded. Changes always occurred in the test array and consisted of new features replacing studied features (shape only) or features swapping across items (shape-color binding). Both MCI and MCI-FAD patients performed worse than controls in the shape-color binding condition. Early electrophysiological activity (100-250 ms) was significantly reduced in both clinical groups, particularly over fronto-central and parieto-occipital regions. However, shape-color binding performance and their reduced neural correlates were similar between MCI and MCI-FAD. Our results support the validity of the VSTM binding test and their neural correlates in the early detection of AD and highlight the importance of studies comparing samples at different risk for AD conversion. The combined analysis of behavioral and ERP data gleaned with the VSTM binding task can offer a valuable memory biomarker for AD.

Pages 1341-1351
Josep Garre-Olmo*, Sara Garcia-Ptacek*, Laia Calvó-Perxas, Oriol Turró-Garriga, Secundino López-Pousa, Maria Eriksdotter (Handling Associate Editor: Martha Dlugaj Jokisch) *These authors contributed equally to this work.
Diagnosis of Dementia in the Specialist Setting: A Comparison Between the Swedish Dementia Registry (SveDem) and the Registry of Dementias of Girona (ReDeGi)
Abstract: The aim of this study was to compare the frequency of dementia diagnoses from two dementia registries in Europe. Patients registered between 2007 and 2013 in the Swedish Dementia Registry (SveDem; Sweden) and in the Registry of Dementias of Girona (ReDeGi; North-East of Spain) were selected. We compared sociodemographic data, Mini-Mental State Examination (MMSE) scores, dementia subtype, and medication consumption of 22,384 cases from SveDem and 5,032 cases from ReDeGi. The average age (78.1 years SveDem versus 79.7 years ReDeGi) and the gender (female 58.2% SveDem versus 61.5% ReDeGi) did not greatly differ. MMSE score at diagnosis was higher for SveDem cases (22.1 versus 17.8). Alzheimer’s disease (AD) accounted for the main dementia subtype (36.6% SveDem versus 55.6% ReDeGi). The proportion of vascular dementia (VaD) and mixed dementia was higher in SveDem (18.8% versus 6.4% and 24.9 versus 13.4%), with an odds ratio (OR) and 95% confidence interval (CI) for SveDem relative to the ReDeGi of 3.41 (3.03-3.84) for VaD, and 2.15 (1.97-2.35) for mixed dementia. This was at the expense of a lower frequency of AD in SveDem (OR 0.41; 95% CI 0.39-0.44). Other dementia diagnoses such as frontotemporal dementia or dementia with Lewy bodies did not significantly differ between registries (2.3% versus 2.9%; 1.9 versus 3.1%). Large differences in medication consumption at the time of dementia diagnosis were detected (4.7 treatments SveDem versus 6.8 ReDeGi). Northern and southern European dementia cohorts differ in demographic characteristics, MMSE score at diagnosis, and drug treatment profile.

Pages 1353-1363
Carl-Henrik Andersson, Oskar Hansson, Lennart Minthon, Niels Andreasen, Kaj Blennow, Henrik Zetterberg, Ingmar Skoog, Anders Wallin, Staffan Nilsson, Petronella Kettunen (Handling Associate Editor: Daniela Galimberti)
A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of developing cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Therefore, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.

Pages 1365-1373
Renaud David, Valeria Manera, Roxane Fabre, Christian Pradier, Philippe Robert, Karim Tifratene
Evolution of the Rate of Antidepressant Prescriptions in Alzheimer’s Disease and Related Disorders Between 2010 and 2014: Results from the French National Database on Alzheimer’s Disease (BNA)
Abstract: Background: Safety warnings from health authorities are currently intended to limit the use of psychotropic agents in dementia-related conditions. Evidence concerning the use of antidepressants in dementia is, however, scarce and contradictory. Objective: To evaluate antidepressant use among individuals with Alzheimer’s disease (AD) and related disorders in the French population between 2010 and 2014. Method: Antidepressant prescriptions in individuals with AD, mixed dementia (MD), and vascular dementia (VaD) in the French National Alzheimer Database between 2010 and 2014 were analyzed (N=199,544). Results: Multivariate analysis showed an annual significant increase (p<0.001) in the prescription rate of antidepressants from 26% (2010) to 31% (2014), and identified female gender, younger age, higher education, living in long-term facilities, more severe cognitive decline, and presence of vascular signs (VaD and MD) as associated factors for antidepressant prescribing. Conclusion: The annual increase of antidepressant prescribing among individuals with AD, MD, and VaD in French specialized settings may be partially related to the lack of current valuable medications for dementia-related behavioral symptoms.

Pages 1375-1388
Antonino Naro, Francesco Corallo, Simona De Salvo, Angela Marra, Giuseppe Di Lorenzo, Nunzio Muscarà, Margherita Russo, Silvia Marino, Rosaria De Luca, Placido Bramanti, Rocco Salvatore Calabrò
Promising Role of Neuromodulation in Predicting the Progression of Mild Cognitive Impairment to Dementia
Abstract: The differential diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is not always straightforward, and the rate of progression of MCI to dementia is not negligible. Thus, there is a need for para-clinical approaches that can improve the differential diagnosis and identify patients that are at risk of progression. There is a growing interest, at present, in the role of the deterioration of brain oscillations as a predictor of MCI-to-AD conversion. For this reason, we experimentally modulated γ-band oscillations (GBO) in a sample of MCI and AD patients and an age-matched healthy elderly group, using a transcranial alternating current stimulation (tACS) protocol that was applied to different cortical sites. We correlated the after-effects of tACS on the GBO and the neuropsychological data, in an attempt to differentiate MCI from AD patients and identify, among the MCI patients, those that could be at potential risk of MCI-to-dementia conversion. MCI patients showed a partial GBO increase and improvement in some neuropsychological tests whereas AD individuals did not show significant tACS after-effects. Notably, some MCI subjects lacked significant neuropsychological and electrophysiological after-effects, similar to AD individuals. In a two-year follow-up, such MCI individuals had converted into AD. Therefore, our data suggest that tACS may support the clinical differential diagnosis of MCI and AD and identify MCI patients who could be at risk of developing dementia. This prediction index may help the clinician to adopt a better prevention/follow-up strategy in such a disabling neurodegenerative disease.

Pages 1389-1393
Commentary

Paolo Maria Rossini, Riccardo Di Iorio, Giuseppe Granata, Francesca Miraglia, Fabrizio Vecchio
From Mild Cognitive Impairment to Alzheimer’s Disease: A New Perspective in the “Land” of Human Brain Reactivity and Connectivity
Abstract:In a recent study, analyzing the modulation of γ-band oscillations, Naro and colleagues demonstrated that transcranial alternating current stimulation could drive the gamma rhythms in the human EEG in cognitive healthy elderly subjects but not in mild cognitive impairment (MCI) prodromal to Alzheimer’s disease (AD) and in early AD patients. Therefore, this method is proposed to intercept early in the disease course those MCI subjects who are in a pre-symptomatic stage of an already established AD. This prediction index may help the clinician to adopt a better prevention/follow-up strategy. In this direction, the novel advances in EEG analysis for the evaluation of brain reactivity and connectivity—namely via innovative mathematical approach, i.e., graph theory—represent a promising tool for a non-invasive and easy-to-perform neurophysiological marker that could be used for the pre-symptomatic diagnosis of AD and to predict MCI progression to dementia.

Pages 1395-1404
Ross Penninkilampi, Holly M. Brothers, Guy D. Eslick
Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer’s Disease Patients: A Systematic Review and Meta-Analysis
Abstract: Background: Drugs targeting γ-secretase in Alzheimer’s disease (AD) have failed to demonstrate efficacy in clinical trials. Objective: To perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of drugs targeting γ-secretase in AD. Methods: Ten trials were identified involving 5,227 patients using electronic databases and manual review of reference lists. RCTs of at least two weeks duration involving a drug targeting γ-secretase were eligible. The main outcomes examined were adverse events and cognitive measures (ADAS-cog, MMSE, ADCS-ADL, and CDR-sb). A sub-group analysis was performed, excluding the γ-secretase modulator tarenflurbil, to evaluate the safety and efficacy of γ-secretase inhibitors only. Results: There was an increased risk of adverse events (Odds Ratio (OR) 1.38, 95% CI 1.09-1.73; p=0.01), serious adverse events (OR 1.50, 95% CI 1.22-1.84; p<0.001), and skin cancers (OR 4.77, 95% CI 2.83-8.06; p<0.001). There was significantly increased risk of infections (OR 1.36, 95% CI 1.13-1.63; p<0.001) in the subgroup analysis excluding tarenflurbil. Pooled results also revealed a worsening in ADAS-cog (difference in means 1.33, 95% CI 0.58-2.08; p<0.001) and MMSE (difference in means -0.66, 95% CI -0.96 to 0.35; p<0.001), but not ADCS-ADL or CDR-sb. Conclusion: The use of γ-secretase inhibitors is associated with significantly increased risk of serious adverse events including skin cancers, and worsening in cognitive indicators. This evidence indicates that γ-secretase may not be an appropriate target for clinical treatment of AD.

Pages 1405-1410
Esma Idrizbegovic, Christina Hederstierna, Ulf Rosenhall
Mismatch Negativity and Ear Laterality in Alzheimer’s Disease and in Mild Cognitive Impairment
Abstract: Background: Cortical auditory event-related potentials (ERPs) were studied in order to measure mismatch negativity (MMN). Three groups of subjects were studied: patients with Alzheimer’s disease (AD, n=32), mild cognitive impairment (MCI, n=44), and subjective memory complaints without cognitive decline (SMC, n=27). A bottom up strategy was applied, and the right and left ears were stimulated monaurally. Objective: To investigate MMN in AD and MCI, and in a clinical reference group. Methods: ERPs were carried out with 500 tone pulses at 80 dBnHL. Each sequence included 80% standard tones (500 Hz) (f), and 20% deviant tones (1000 Hz) (r). MMN measurements were carried out by comparing the amplitudes of (f) and (r) recordings and to calculate the amplitude difference in µV for each group. The right and the left ears were analyzed separately. Results: A left ear advantage (LEA) of MMN amplitude was demonstrated in the two groups with better cognition (the MCI and the SMC groups), but not in the AD group. Discussion: The absence of MMN asymmetry in the AD group is possibly caused by a dysfunction to apprehend changes of tonal stimuli.

Pages 1411-1418
Julien Dumurgier, Jean-François Dartigues, Audrey Gabelle, Claire Paquet, Magali Prevot, Jacques Hugon, Christophe Tzourio
Time Orientation and 10 Years Risk of Dementia in Elderly Adults: The Three-City Study
Abstract: Time disorientation is commonly observed in dementia, however very few is known about the pathological significance of minor time errors in community-dwelling population. Our objective was to investigate the relationship between time orientation and risk of dementia in a population of older adults. Analyses relies on 8611 dementia-free subjects from the Three-City Study, France. Participants were followed up for 10 years for incident dementia. Time orientation was assessed by asking for the date, the day of the week, the month, the season and the year. At baseline, 905 subjects made at least one error in time orientation. During 57,073 person-years of follow-up, 827 participants developed dementia. After controlling for age, gender and education level, subjects with one error in time had a greater risk of dementia (hazard ratio [HR] 1.44 [1.18-1.77]), while those with at least 2 errors had a more than three-fold increased risk (HR 3.10 [1.98-4.83]). This association was particularly marked for the diagnosis of probable Alzheimer’s disease. Time disorientation was associated with an increased risk of dementia in a large population of cognitively normal older people followed during up to 10 years and should not be underestimated in clinical setting.

Pages 1419-1432
Yulei Deng, Jing Wei, Jia Cheng, Ping Zhong, Zhe Xiong, Aiyi Liu, Lin Lin, Shengdi Chen, Zhen Yan
Partial Amelioration of Synaptic and Cognitive Deficits by Inhibiting Cofilin Dephosphorylation in an Animal Model of Alzheimer’s Disease
Abstract: The loss of synaptic structure and function has been linked to the cognitive impairment of Alzheimer’s disease (AD). Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD. In this study, we found that glutamate receptor surface expression and synaptic function in frontal cortical neurons were significant diminished in a familial AD (FAD) model, which was correlated with the reduction of phosphorylated cofilin, a key protein regulating the dynamics of actin filaments. Injecting a cofilin dephosphorylation inhibitory peptide to FAD mice led to the partial rescue of the surface expression of AMPA and NMDA receptor subunits, as well as the partial restoration of AMPAR- and NMDAR-mediated synaptic currents. Moreover, the impaired working memory and novel object recognition memory in FAD mice were partially ameliorated by injections of the cofilin dephosphorylation inhibitory peptide. These results suggest that targeting the cofilin-actin signaling holds promise to mitigate the physiological and behavioral abnormality in AD.

Pages 1433-1441
Mohammad Abdullah, Hiroshi Takase, Mari Nunome, Hiroyuki Enomoto, Jin-ichi Ito, Jian-Sheng Gong, Makoto Michikawa
Amyloid-β Reduces Exosome Release from Astrocytes by Enhancing JNK Phosphorylation
Abstract: Exosomes are small extracellular vesicles secreted by variety of cell types such as neurons, astrocytes, and oligodendrocytes. It is suggested that exosomes play essential role in the maintenance of the neuronal functions and also in the clearance of amyloid-β (Aβ) from the brain. Aβ is well known to cause neuronal cell death, whereas little is known about its effect on astrocytes. In this study, we examined the effect of Aβ on release of exosome from astrocytes in culture. We analyzed release of exosomes and apoE, both of which are known to remove/clear Aβ from the brain, in the culture medium of astrocytes. We found that exosome and apoE-HDL were successfully separated by density gradient ultracentrifugation demonstrated by distribution of their specific markers, flotillin and HSP90, and cholesterol, and morphological analysis using electron microscopy. Exosome release was significantly reduced by Aβ1-42 treatment in cultured astrocytes accompanied by an increased JNK phosphorylation. Whereas, apoE-HDL release remained unchanged. A JNK inhibitor restored the decreased levels of exosome release induced by Aβ treatment to levels similar to those of control, suggesting that Aβ1-42 inhibits exosome release via stimulation of JNK signal pathway. Because exosome is shown to remove Aβ in the brain, our findings suggest that increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway.

Pages 1443-1458
Shiran Salomon-Zimri, Micaela Johanna Glat, Yael Barhum, Ishai Luz, Anat Boehm-Cagan, Ori Liraz, Tali Ben-Zur, Daniel Offen, Daniel M. Michaelson (Handling Associate Editor: Debomoy Lahiri)
Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment
Abstract: Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α. We next set to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aβ42, and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aβ42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aβ42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD.

Pages 1459-1473
Judith Miklossy
Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques
Abstract: It has long been known that spirochetes form clumps or micro colonies in vitro and in vivo. Cortical spirochetal colonies in syphilitic dementia were considered as reproductive centers for spirochetes. Historic and recent data demonstrate that senile plaques in Alzheimer’s disease (AD) are made up by spirochetes. Spirochetes, including Borrelia burgdorferi, are able to form biofilm in vitro. Senile plaques are also reported to contain elements of biofilm constituents. We expected that AβPP and Aβ (the main components of senile plaques) also occur in pure spirochetal biofilms, and bacterial DNA (an important component of biofilm) is also present in senile plaques. Histochemical, immunohistochemical, and in situ hybridization techniques and the TUNEL assay were used to answer these questions. The results obtained demonstrate that Aβ and DNA are key components of both pure spirochetal biofilms and senile plaques in AD and confirm the biofilm nature of senile plaques. These observations validate previous observations that AβPP and/or an AβPP-like amyloidogenic protein are an integral part of spirochetes, and indicate that bacterial amyloid is a constituent of senile plaques. DNA fragmentation in senile plaques further confirms their bacterial nature and provides biochemical evidence for spirochetal cell death. Spirochetes evade host defenses, locate intracellularly, form more resistant atypical forms and notably biofilms, which contribute to and sustain chronic infection and inflammation and explain the slowly progressive course of dementia in AD. To consider co-infecting microorganisms is equally important, as multi-species biofilms may result in a higher resistance to treatments and a more severe dementia.

Pages 1475-1484
Hannah Glonnegger, Aline Beyle, Bernhard Cerff, Susanne Gräber, Ilona Csoti, Daniela Berg, Inga Liepelt-Scarfone
The Multiple Object Test as a Performance Based Tool to Assess Cognitive Driven Activity of Daily Living Function in Parkinson’s Disease
Abstract: Background: There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinson’s disease (PD). Objective: To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment. Methods: 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinson’s disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed. Results: Total time and number of MOT errors was increased in PD patients compared to controls (p<0.001). These parameters also differentiated PDD patients from other cognitive groups (p<0.05). No control subject had ≥4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p<0.001) and mislocation (p<0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p=0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function. Conclusion: Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD.

Pages 1485-1497
Matteo Stravalaci, Laura Tapella, Marten Beeg, Alessandro Rossi, Pooja Joshi, Erika Pizzi, Michele Mazzanti, Claudia Balducci, Gianluigi Forloni, Emiliano Biasini, Mario Salmona, Luisa Diomede, Roberto Chiesa, Marco Gobbi (Handling Associate Editor: Rakez Kayed)
The Anti-Prion Antibody 15B3 Detects Toxic Amyloid-β Oligomers
Abstract: 15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42, an aggregating peptide implicated in the pathogenesis of Alzheimer’s disease (AD). The 15B3 antibody: i) inhibits the binding of synthetic Aβ42 oligomers to recombinant PrP and neuronal membranes; ii) prevents oligomer-induced membrane depolarization; iii) antagonizes the inhibitory effects of oligomers on the physiological pharyngeal contractions of the nematode Caenorhabditis elegans; and iv) counteracts the memory deficits induced by intracerebroventricular injection of Aβ42 oligomers in mice. Thus this antibody binds to pathologically relevant forms of Aβ, and offers a potential research, diagnostic, and therapeutic tool for AD.

Pages 1499-1516
Hisham Qosa, Loqman A. Mohamed, Sweilem B. Al Rihani, Yazan S. Batarseh, Quoc-Viet Duong, Jeffrey N. Keller, Amal Kaddoumi (Handling Associate Editor: Eva Carro)
High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity
Abstract: The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer’s disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76-4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

Pages 1517-1522
Enzo Grossi, Andrea Stoccoro, Pierpaola Tannorella, Lucia Migliore, Fabio Coppedè
Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer’s Disease
Abstract: Background: There is increasing interest in DNA methylation studies in Alzheimer’s disease (AD), but little is still known concerning the relationship between gene-promoter methylation and circulating biomarkers of one-carbon metabolism in patients. Objective: To detect the connections among circulating folate, homocysteine (hcy) and vitamin B12 levels and promoter methylation levels of PSEN1, BACE1, DNMT1, DNMT3A, DNMT3B, and MTHFR genes in blood DNA. Methods: We applied a data mining system called Auto Contractive Map to an existing database of 100 AD and 100 control individuals. Results: Low vitamin B12 was linked to the AD condition, to low folates, and to high hcy. Low PSEN1 methylation was linked to low folate levels as well as to low promoter methylation of BACE1 and DNMTs genes. Low hcy was linked to controls, to high folates and vitamin B12, as well as to high methylation levels of most of the studied genes. Conclusions: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12.

Pages 1523-1538
Ann De Vos, Hanne Struyfs, Dirk Jacobs, Erik Fransen, Tom Klewansky, Ellen De Roeck, Caroline Robberecht, Christine Van Broeckhoven, Charles Duyckaerts, Sebastiaan Engelborghs, Eugeen Vanmechelen
The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer’s Disease
Abstract: Background: In diagnosing Alzheimer’s disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42/tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers. Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42, Aβ1-40, and Aβ1-38. All six analytes were considered as single parameters as well as ratios. Methods: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinically and neuropsychologically (MMSE) examinations for at least one year. Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio. Conclusion: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline.

Pages 1549-1552
Bing Han, Lulu Yu, Yuan Geng, Li Shen, Hualong Wang, Yanyong Wang, Jinhua Wang, Mingwei Wang (Handling Associate Editor: Maria Ramirez)
Chronic Stress Aggravates Cognitive Impairment and Suppresses Insulin Associated Signaling Pathway in APP/PS1 Mice
Abstract: Differences in brain function are a central determinant of individual variability in the stress response. Brain dysfunction, resulting from aging, illness, or genetic mutations, could reduce the tolerance of glucocorticoid stress hormones. When glucocorticoids exceed tolerable limits in the brain, especially in the hippocampus, this state can cause or aggravate structural or functional damage. However, the underlying mechanisms are not well understood. This study investigated the effects of chronic unpredictable mild stress (CUMS) in APP/PS1 and control mice. We showed that 4 weeks of CUMS exposure increased the levels of glucocorticoids, reduced glucocorticoids receptor expression, and promoted senile plaque deposition, neuronal injury, and cognitive impairment in APP/PS1 mice compared to controls. The phosphorylation of insulin receptor, insulin receptor substrate 1 and associated signaling pathways (Akt, mTOR, p70S6K, ERK1/2, and PTEN) were decreased in hippocampus in APP/PS1 mice compared to control mice, while no changes were found in GSK3 and TSC2 phosphorylation. Furthermore, insulin and Akt/mTOR signaling pathways were further decreased in APP/PS1 mice after CUMS, which may be related to the activation of the stress-activated protein kinase JNK, while no alterations in the levels of phosphorylated ERK1/2, GSK3, PTEN, or TSC2 were observed. These results suggest that chronic stress may affect the insulin and Akt/mTOR pathway, accelerating the progression of Alzheimer's disease in vulnerable individuals.

Pages 1553-1562
Katherine J. Bangen, Jayandra J. Himali, Alexa S. Beiser, Daniel A. Nation, David J. Libon, Caroline S. Fox, Sudha Seshadri, Philip A. Wolf, Ann C. McKee, Rhoda Au, Lisa Delano-Wood (Handling Associate Editor: Jason Brandt)
Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer’s Disease Pathology
Abstract: Elevated blood glucose and the apolipoprotein (APOE) ε4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer’s disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ε4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ε4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

Pages 1563-1576
Seokjo Kang*, Hyobin Jeong*, Je-Hyun Baek, Seung-Jin Lee, Sun-Ho Han, Hyun Jin Cho, Hee Kim, Hyun Seok Hong, Young Ho Kim, Eugene C. Yi, Sang Won Seo, Duk L. Na, Daehee Hwang, Inhee Mook-Jung (Handling Associate Editor: Bhumsoo Kim) *These authors contributed equally to this work.
PiB-PET Imaging-Based Serum Proteome Profiles Predict Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Development of a simple, non-invasive early diagnosis platform of Alzheimer’s disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD.

Pages 1577-1584
Xudong Li, Shuhong Jia, Zhi Zhou, Chunlei Hou, Wenjing Zheng, Pei Rong, Jinsong Jiao (Handling Associate Editor: Jintai Yu)
The Gesture Imitation in Alzheimer’s Disease Dementia and Amnestic Mild Cognitive Impairment
Abstract: Background: Alzheimer’s disease dementia (ADD) has become an important health problem in the world. Visuospatial deficits are considered to be an early symptom besides memory disorder. Objectives: The gesture imitation test was devised to detect ADD and amnestic mild cognitive impairment (aMCI). Methods: A total of 117 patients with ADD, 118 with aMCI, and 95 normal controls were included in this study. All participants were administered our gesture imitation test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Clock Drawing Test (CDT), and the Clinical Dementia Rating Scale (CDR). Results: Patients with ADD performed worse than normal controls on global scores and had a lower success rate on every item (p<0.001). The area under the curve (AUC) for the global scores when comparing the ADD and control groups was 0.869 (p<0.001). Item 4 was a better discriminator with a sensitivity of 84.62% and a specificity of 67.37%. The AUC for the global scores decreased to 0.621 when applied to the aMCI and control groups (p=0.002). After controlling for age and education, the gesture imitation test scores were positively correlated with the MMSE (r=0.637, p<0.001), the MoCA (r=0.572, p<0.001), and the CDT (r=0.514, p<0.001) and were negatively correlated with the CDR scores (r=-0.558, p<0.001). Conclusions: The gesture imitation test is an easy, rapid tool for detecting ADD, and is suitable for the patients suspected of mild ADD and aMCI in outpatient clinics.

Pages 1585-1595
Wenzhu B. Mowrey, Richard B. Lipton, Mindy J. Katz, Wendy S. Ramratan, David A. Loewenstein, Molly E. Zimmerman, Herman Buschke (Handling Associate Editor: Josep Garre-Olmo)
Memory Binding Test Predicts Incident Amnestic Mild Cognitive Impairment
Abstract: Background: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly. Objective: We aimed to assess the predictive validity of the MBT for incident aMCI. Methods: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately. Results: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR)=2.44, 95% confidence interval: 1.30−4.56, p=0.005). When varying the prediction window from 4−7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33−3.12, p: 0.0007−0.04). Conclusion: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease.

Pages 1597-1608
Erica C. Camargo*, Galit Weinstein*, Alexa Beiser, Zaldy S. Tan, Charles DeCarli, Margaret Kelly-Hayes, Carlos Kase, Joanne M. Murabito, Sudha Seshadri *These authors contribute equally to this work.
Association of Physical Function with Clinical and Subclinical Brain Disease: The Framingham Offspring Study
Abstract: Background: Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking. Objective: To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer’s disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample. Methods: Framingham Offspring (n=2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors. Results: Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95%CI: 1.12-2.70/SDU, p=0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction. Conclusion: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.

Pages 1609-1616
Janina Krell-Roesch, Hanna Ruider, Val J. Lowe, Gorazd B. Stokin, Anna Pink, Rosebud O. Roberts, Michelle M. Mielke, David S. Knopman, Teresa J. Christianson, Mary M. Machulda, Clifford R. Jack, Ronald C. Petersen, Yonas E. Geda
FDG-PET and Neuropsychiatric Symptoms among Cognitively Normal Elderly Persons: The Mayo Clinic Study of Aging
Abstract: One of the key research agenda of the field of aging is investigation of presymptomatic Alzheimer’s disease (AD). Furthermore, abnormalities in brain glucose metabolism (as measured by FDG-PET) have been reported among cognitively normal elderly persons. However, little is known about the association of FDG-PET abnormalities with neuropsychiatric symptoms (NPS) in a population-based setting. Thus, we conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging in order to examine the association between brain glucose metabolism and NPS among cognitively normal (CN) persons aged > 70 years. Participants underwent FDG-PET and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). Cognitive classification was made by an expert consensus panel. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals after adjusting for age, sex, and education. For continuous variables, we used linear regression and Spearman rank-order correlations. Of 668 CN participants (median 78.1 years, 55.4% males), 205 had an abnormal FDG-PET (i.e., standardized uptake value ratio

Pages 1617-1630
Jannik E. Jakobsen, Marianne G. Johansen, Mette Schmidt, Ying Liu, Rong Li, Henrik Callesen, Margarita Melnikova, Mette Habekost, Carmela Matrone, Yvonne Bouter, Thomas A. Bayer, Anders Lade Nielsen, Monika Duthie, Paul E. Fraser, Ida E. Holm, Arne Lund Jørgensen
Expression of the Alzheimer’s Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs
Abstract: Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide AβPP cause early-onset Alzheimer’s disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42-specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer’s disease.

Pages 1631-1640
Massimo Venturelli, Alessio Sollima, Emiliano Cè, Eloisa Limonta, Angela V. Bisconti, Anna Brasioli, Ettore Muti, Fabio Esposito (Handling Associate Editor: Jeff Burns)
Effectiveness of Exercise- and Cognitive-Based Treatments on Salivary Cortisol Levels and Sundowning Syndrome Symptoms in Patients with Alzheimer’s Disease
Abstract: Sundowning syndrome (SDS) in patients with Alzheimer’s disease (AD) is characterized by the intensification of behavioral disorders at sunset. Despite SDS etiology being unclear, a strong relationship between high cortisol levels and SDS has been reported. Aerobic exercise (AE) and cognitive training (CT) can reduce cortisol levels. However, whether SDS would benefit from AE and CT is still unknown. Therefore, the aim of this study was to investigate whether AE and CT treatments are effective in reducing SDS via downregulation of cortisol levels. The possible additive effects of combined AE+CT were also assessed. Eighty AD patients were randomly assigned to AE (n=20), CT (n=20), AE+CT (n=20), and standard therapy (no treatment, NT; n=20). Treatments were administered for 3 months, 5 days/week, 1 hour before sunset. Before and after treatments, salivary cortisol levels were sampled at 7, 11, 15, at sunset, and 20 (time of day). Blind assessment of behavioral disorders (neuropsychiatric inventory, NPI) and agitation (agitated behavior scale, ABS) were also performed. After interventions, cortisol levels were reduced in AE and AE+CT by ~26%. In the same groups, NPI and ABS decreased by ~50%. By contrast, cortisol and behavioral disorders were similar to baseline in CT and NT. Changes in NPI and ABS were significantly correlated with the reduction in cortisol levels. AE or AE+CT effects on SDS and cortisol levels and the lack of effect of CT alone indicate the effectiveness of an exercise-based treatment on SDS, suggesting a possible hypothalamic–pituitary–adrenal axis dysregulation underpinning SDS.

Pages 1641-1652
Michael Malek-Ahmadi, Sylvia E. Perez, Kewei Chen, Elliott J. Mufson
Neuritic and Diffuse Plaque Associations with Memory in Non-Cognitively Impaired Elderly
Abstract: The presence of Alzheimer’s disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ε4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ε4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ε4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p = 0.002), Episodic Memory (p = 0.03), Semantic Memory (p = 0.009), and Visuospatial performance (p = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ε4 status, and Braak stage are taken into consideration.