Volume 63, Number 3, 2018

Pages 871-886

Paola Proserpio, Dario Arnaldi, Flavio Nobili, Lino Nobili
Integrating Sleep and Alzheimer's Disease Pathophysiology: Hints for Sleep Disorders Management
Abstract: Sleep represents an active phenomenon regulated by a highly integrated network of cortical and subcortical structures. This complex model results in disruptions at various levels during physiological aging and more deeply during neurodegenerative disorders, thus leading to different sleep alterations. In Alzheimer's disease (AD), sleep-wake abnormalities were described to occur even in the preclinical phase, thus suggesting they could be a possible AD biomarker. On the other hand, they also favor the progression of the disease. In this paper, we review current theories regarding sleep regulations and functions to highlight the pathophysiological mechanisms at the basis of the bidirectional relationship between sleep and AD. A better understanding of these complex interactions might also be useful to target both sleep disorder management and AD-related symptoms.

Pages 887-897

Samir Abu-Rumeileh, Sabina Capellari, Piero Parchi (Handling Associate Editor: Inga Zerr)
Rapidly Progressive Alzheimer's Disease: Contributions to Clinical-Pathological Definition and Diagnosis
Abstract: Rapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-β aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathologic, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinic-pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathologic data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group.

Pages 899-910

Nicole Cortés, Víctor Andrade, Ricardo B. Maccioni (Handling Associate Editor: Harish Pant)
Behavioral and Neuropsychiatric Disorders in Alzheimer’s Disease
Abstract: Alzheimer`s disease (AD) is the most frequent type of dementia in the elderly, severely affecting functional and executive skills of subjects suffering from this disease. Moreover, the distress of caregivers as well as the social implications constitute a critical issue for families. Furthermore, cognitive impairment, along with behavioral disorders and neuropsychiatric symptoms are characteristics of AD. Although these are present with variations in prevalence, intensity, and progression, an important core of them is visible before cognitive impairment, especially depression and apathy, which affect at least 50% of patients. The most updated literature shows that depression and/or behavioral and neuropsychiatric symptoms (BNS) are part of the initial phase of the disease rather than just a risk factor. Thus, mood disorders are associated with anomalies in specific brain regions that disturb the normal balance of neurotransmission. This in turn is linked with an inflammatory pathway that leads to microglial activation and aggregated neurofibrillary tangle formation, finally triggering neuronal loss, according to our neuroimmunomodulation theory. Altogether, inflammation and tau aggregation are observed in preclinical stages, preceding the BNS of patients, which in turn are exhibited earlier than cognitive and functional impairment detected in AD. This review is focused on the latest insights of cellular and molecular processes associated with BNS in asymptomatic early-onset stages of AD. An important medical research focus is to improve quality of life of patients, through prevention and treatments of AD, and the study of behavioral disorders and early event in AD pathogenesis has a major impact.

Pages 911-926

Yan Shi*, Ying-Yan Fang*, Yu-Ping Wei, Qian Jiang, Peng Zeng, Na Tang, Youming Lu, Qing Tian (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Melatonin in Synaptic Impairments of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage.

Pages 927-934

Nelson Arispe, Antonio De Maio
Memory Loss and the Onset of Alzheimer's Disease Could Be Under the Control of Extracellular Heat Shock Proteins
Abstract: Alzheimer's disease (AD) is a major contemporary and escalating malady in which amyloid-β (Aβ) peptides are the most likely causative agent. Aβ peptides spontaneously tend to aggregate in extracellular fluids following a progression from a monomeric state, through intermediate forms, ending in amyloid fibers and plaques. It is generally accepted now that the neurotoxic agents leading to cellular death, memory loss, and other AD characteristics are the Aβ intermediate aggregated states. However, Aβ peptides are continuously produced, released into the extracellular space, and rapidly cleared from healthy brains. Coincidentally, members of the heat shock proteins (hsp) family are present in the extracellular medium of healthy cells and body fluids, opening the possibility that hsps and Aβ could meet and interact in the extracellular milieu of the brain. In this perspective and reflection article, we place our investigation showing that the presence of Hsp70s mitigate the formation of low molecular weight A peptide oligomers resulting in a reduction of cellular toxicity, in context of the current understanding of the disease. We propose that it may be an inverse relationship between the presence of Hsp70, the stage of Aβ oligomers, neurotoxicity, and the incidence of AD, particularly since the expression and circulating levels of hsp decrease with aging. Combining these observations, we propose that changes in the dynamics of Hsp70s and Aβ concentrations in the circulating brain fluids during aging defines the control of the formation of Aβ toxic aggregates, thus determining the conditions for neuron degeneration and the incidence of AD.

Pages 935-939

Pravat K. Mandal, Deepika Shukla
Brain Metabolic, Structural, and Behavioral Pattern Learning for Early Predictive Diagnosis of Alzheimer's Disease
Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. Laboratory research and longitudinal clinical studies have helped to reveal various information about the disease but the exact causal process is not known yet. Patterns from alteration of neurochemicals (e.g., glutathione depletion, etc.), hippocampal atrophy, and brain effective connectivity loss as well as associated behavioral changes have generated important characteristics features. These imaging-based readouts and neuropsychological outcomes along with supervised clinical review are critical for developing a comprehensive artificial intelligence strategy for early predictive AD diagnosis and therapeutic development.

Pages 941-948
Mario F. Mendez, Negar Moheb, Randy E. Desarzant, Edmond H. Teng
The Progressive Acalculia Presentation of Parietal Variant Alzheimer’s Disease
Abstract: Background: Many patients with early-onset Alzheimer’s disease (EOAD; age of onset <65 years) have non-amnestic presentations involving language (logopenic primary progressive aphasia, lvPPA), visuospatial abilities (posterior cortical atrophy, PCA), and even asymmetric symptoms consistent with corticobasal syndrome (CBS). An inferior parietal lobule variant of EOAD commonly presents with progressive difficulty with calculations. Methods: We reviewed 276 EOAD patients for presentations with predominant acalculia. These patients were diagnosed with clinically probable Alzheimer’s disease (AD) verified by positron emission tomography (PET) or cerebrospinal fluid amyloid-β or tau biomarkers. Results: We identified 18 (9M/9F) (6.5%) EOAD patients with progressive acalculia that did not meet most criteria for lvPPA, visual PCA, or CBS. Their ages of onset and presentation were 56.6 (5.0) and 59.4 (6.5), respectively. Their acalculia was consistent with a primary acalculia (“anarithmetia”) not explained by language or visuospatial impairments. Many also had anomia (14/18), ideomotor apraxia (13/18), and the complete Gerstmann’s syndrome (7/18). Visual analysis of their diverse magnetic resonance imaging disclosed biparietal atrophy, disproportionately worse on the left. Conclusions: Primary acalculia may be the most common manifestation of an inferior parietal presentation of EOAD affecting the left intraparietal sulcus. This parietal variant also commonly involves progressive anomia, ideomotor apraxia, and other elements of Gerstmann’s syndrome. The early recognition of patients with this variant, which is distinguishable from lvPPA, visual PCA, or CBS, would be facilitated by its recognition as a unique subtype of EOAD.

Pages 949-956
Zvinka Z. Zlatar, Martha C. Muniz, Sarah Espinoza, Roberto Gratianne, Tamar H. Gollan, Douglas Galasko, David P. Salmon (Handling Associate Editor: Katie Gifford)
Subjective Cognitive Decline, Objective Cognition, and Depression in Older Hispanics Screened for Memory Impairment
Abstract: Subjective cognitive decline (SCD) is common in older adults and may be an early marker of future cognitive decline. Research suggest that SCD is more closely related to concurrent symptoms of depression than to objective cognitive performance in non-Hispanic Whites, but it is unknown whether the associations of SCD, cognition, and depression manifest differently in Hispanic older adults. We examined if SCD is associated with objective cognitive performance or with depression symptoms in 145 Hispanic individuals ages 60 or older referred by community health clinics for screening of cognitive complaints. All participants lived near the U.S.-Mexico border, spoke Spanish only, or were Spanish-English bilingual. Memory-only and global cognitive composites were created from scores on Spanish versions of several neuropsychological tests. The Geriatric Depression Scale (GDS) and a five-item SCD questionnaire developed by our group were also completed. Multiple regression analyses showed no significant associations between SCD and memory or global cognitive composite scores after adjusting for age, sex, education, and GDS score. In contrast, there was a significant association between GDS and SCD after adjusting for age, sex, education, global and memory composite scores. Findings suggest that SCD does not accurately reflect current cognitive status in older Hispanics who present to their primary care physician with cognitive complaints. Clinicians should interpret SCD in this population within the context of information about symptoms of depression. Longitudinal research is needed in older Hispanics to better characterize SCD in this population and to determine if it can predict future cognitive decline.

Pages 957-964
Teruyuki Matsuoka, Ayu Imai, Hiroshi Fujimoto, Yuka Kato, Keisuke Shibata, Kaeko Nakamura, Hajime Yokota, Kei Yamada, Jin Narumoto (Handling Associate Editor: Shunichiro Shinagawa)
Neural Correlates of Sleep Disturbance in Alzheimer’s Disease: Role of the Precuneus in Sleep Disturbance
Abstract: Background: Sleep disturbance may affect the development of Alzheimer’s disease (AD), but the neural correlates of sleep disturbance in AD have not been fully clarified. Objective: To examine the factors associated with sleep disturbance in AD. Methods: A retrospective study was performed in 63 patients with AD. None of the patients had been prescribed antidementia or psychoactive drugs, and all underwent brain magnetic resonance imaging (MRI) before medication. Sleep disturbance was defined as a score of at least 1 point on the sleep disturbance subscale of the Neuropsychiatric Inventory (NPI). Whole brain image analysis was performed using SPM8 and VBM8. A two-sample t-test was used to compare patients with AD with (n=19) and without (n=44) sleep disturbance, with age and gender included as covariates. The statistical thresholds were set to an uncorrected p-value of 0.001 at the voxel level and a corrected p-value of 0.05 at the cluster level. In addition, pineal gland volume (PGV) measured using MRI, and white matter hyperintensity (WMH) assessed with the modified Fazekas scale were compared between patients with AD with and without sleep disturbance using independent group t-tests. Results: In whole brain analysis, the precuneus volume in patients with AD with sleep disturbance was significantly smaller than those without sleep disturbance. There were no significant differences in PGV and WMH between the two groups. Conclusion: Sleep disturbance in AD was associated with reduction of precuneus volume. This suggests that the precuneus might be an important region in sleep disturbance in AD.

Pages 965-975
Joannee Zumkehr*, Carlos J. Rodriguez-Ortiz*, Rodrigo Medeiros, Masashi Kitazawa *These authors contributed equally to this paper.
Inflammatory Cytokine, IL-1β, Regulates Glial Glutamate Transporter via microRNA-181a in vitro
Abstract: Glutamate overload triggers synaptic and neuronal loss that potentially contributes to neurodegenerative diseases including Alzheimer’s disease (AD). Glutamate clearance and regulation at synaptic clefts is primarily mediated by glial glutamate transporter 1 (GLT-1). We determined that inflammatory cytokines significantly upregulated GLT-1 through microRNA-181a-mediated post-transcriptional modifications. Unveiling the key underlying mechanisms modulating GLT-1 helps better understand its physiological and pathological interactions with cytokines. Primary murine astrocyte and neuron co-culture received 20 ng/mL IL-1β, TNF-α, or IL-6 for 48 h. Soluble proteins or total RNA were extracted after treatment for further analyses. Treatment with inflammatory cytokines, IL-1β and TNF-α, but not IL-6, significantly increased GLT-1 steady-state levels (p ≤ 0.05) without affecting mRNA levels, suggesting the cytokine-induced GLT-1 was regulated through post-transcriptional modifications. Among the candidate microRNAs predicted to modulate GLT-1, only microRNA-181a was significantly decreased following the IL-1β treatment (p ≤ 0.05). Co-treatment of microRNA-181a mimic in IL-1β-treated primary astrocytes and neurons effectively blocked the IL-1β-induced upregulation of GLT-1. Lastly, we attempted to determine the link between GLT-1 and microRNA-181a in human AD brains. A significant reduction of GLT-1 was found in AD hippocampus tissues, and the ratio of mature microRNA-181a over primary microRNA-181a had an increasing tendency in AD. MicroRNA-181a controls rapid modifications of GLT-1 levels in astrocytes. Cytokine-induced inhibition of microRNA-181a and subsequent upregulation of GLT-1 may have physiological implications in synaptic plasticity while aberrant maturation of microRNA-181a may be involved in pathological consequences in AD.

Pages 977-987
Wha Jin Lee*, Cheol E Han*, Iman Aganj, Sang Won Seo, Joon-Kyung Seong (Handling Associate Editor: Maheen Adamson) *These authors contributed equally to this work.
Distinct Patterns of Rich Club Organization in Alzheimer's Disease and Subcortical Vascular Dementia: A White Matter Network Study
Abstract: Recent advances in neuroimaging technology have shown that rich club organization in human brain networks plays a crucial role in global communication and cognitive functionality. In this study, we investigated rich club organization within white matter structural brain networks in two common types of dementia, Alzheimer’s disease (AD) and subcortical vascular dementia (SVaD). We recruited 30 AD patients ([11C] Pittsburgh compound-B (PiB) PET positive), 39 SVaD patients (PiB negative), and 72 age-, gender-, and education-matched cognitively normal (CN) subjects. Rich club organization was significantly disrupted in both dementia patient groups, which exhibited higher rich club coefficients than the CN group. Rich club organization in the patient groups was primarily disrupted over the left frontal and left middle temporal areas when compared to the CN group. The number of rich club nodes was significantly reduced in the dementia groups, which was more severe in SVaD (p=0.0107, permutation-based t-test). Although rich club organization was disrupted both in the patient groups, its disruption pattern is different between them. The rich-club connections normalized by degree-and-strength preserved random networks were significantly increased in the dementia groups with SVaD more severely, and feeder connections were reduced more significantly than in AD. Furthermore, SVaD patients exhibited more sporadic disruption in white matter connectivity than AD patients, with local connections showing a more significant degree of deterioration. Combined with the distinct disruption in rich club nodes, these findings may imply a differing role for rich club organization in AD and SVaD, due to different pathological mechanisms.

Pages 989-1002
Chihiro Akiba, Madoka Nakajima, Masakazu Miyajima, Ikuko Ogino, Yumiko Motoi, Kaito Kawamura, Satoshi Adachi, Akihide Kondo, Hidenori Sugano, Takahiko Tokuda, Kazuhiro Irie, Hajime Arai
Change of Amyloid-β 1-42 Toxic Conformer Ratio After Cerebrospinal Fluid Diversion Predicts Long-Term Cognitive Outcome in Patients with Idiopathic Normal Pressure Hydrocephalus
Abstract: Background: Alzheimer’s disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-β 1-42 (Aβ42) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity. Objective: This observational study points to Aβ42 toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH. Methods: The first cohort consisted of patients with AD (n = 17) and iNPH (n = 17), and cognitively normal individuals (CN, n = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in Aβ42 toxic conformer ratio (%) [Aβ42 toxic conformer / Aβ42 x 100] (decreased- and increased-conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, Aβ42, and Aβ42 toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively. Results: In the first cohort, Aβ42 toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement. Conclusion: Change in Aβ42 toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group.

Pages 1003-1013
X. Anton Alvarez, Irene Alvarez, Manuel Aleixandre, Carlos Linares, Dafin Muresanu, Stefan Winter, Herbert Moessler (Handling Associate Editor: Eva Carro)
Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer’s Disease ApoE4 Carriers
Abstract: Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer’s disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p<0.05) and showed a progressive increase with clinical severity in the whole study population (p<0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p<0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p<0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

Pages 1015-1024
Roberta Baschi, Alessandra Nicoletti, Vincenzo Restivo, Deborah Recca, Mario Zappia, Roberto Monastero
Frequency and Correlates of Subjective Memory Complaints in Parkinson’s Disease with and without Mild Cognitive Impairment: Data from the Parkinson’s Disease Cognitive Impairment Study
Abstract: Subjective memory complaints (SMC) may represent the preclinical phase of mild cognitive impairment (MCI) due to Alzheimer’s disease. Dementia/MCI have been described with a high prevalence in Parkinson’s disease (PD), but whether SMC may predict the development of cognitive impairment has been barely explored. To evaluate the frequency and clinical correlates of isolated SMC (PD-SMC) or within the construct of MCI in subjects with PD, 147 PD patients from the PArkinson’s disease COgnitive impairment Study (PACOS) were consecutively recruited for the study. This is a multicenter study involving two Movement Disorder Centers in south Italy. All subjects underwent comprehensive neuropsychological evaluation and PD-MCI was diagnosed according to Litvan’s criteria. The Memory Assessment Clinics Questionnaire was used to assess SMC. Logistic regression analysis, adjusted for demographics and significant covariates, was used to evaluate clinical differences between groups. Forty-two (28.6%) individuals presented with PD without SMC and/or MCI (PDw), 40 (27,2%) with PD-SMC, 48 (32,6%) PD-SMC-MCI, and 17 (11,6%) PD-MCI without SMC (PD-MCI). When compared to PDw, PD-SMC was significantly associated with anxiety (OR=3.93, 95% CI=1.18-13.03), while PD-SMC-MCI related to motor progression (OR=5.29, 95% CI=1.12-24.86), and instrumental disability (OR=6.98, 95% CI=2.08-23.38). About 60% of patients showed SMC, in isolation or within the MCI frame. The role of SMC in PD seems to have a different etiology depending on the presence/absence of MCI. In particular, PD-SMC would represent a subjective reaction to the disease, while PD-SMC-MCI would depict motor progression and disability.

Pages 1025-1033
Carmen Lage, Andrea Gonzalez Suarez, Ana Pozueta, Javier Riancho, Martha Kazimierczak, Maria Bravo, Julio Jimenez Bonilla, María de Arcocha Torres, Remedios Quirce, Ignacio Banzo, Jose Luis Vazquez-Higuera, Gil D. Rabinovici, Eloy Rodriguez-Rodriguez, Pascual Sánchez-Juan
Utility of Amyloid and FDG-PET in Clinical Practice: Differences between Secondary and Tertiary Care Memory Units
Abstract: The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer’s disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using 2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating

Pages 1035-1044
Yun Jeong Hong*, Seong Hye Choi*, Jee Hyang Jeong, Kyung Won Park, Hae Ri Na (Handling Associate Editor: Sang-Won Seo) *These authors contributed equally to this work.
Effectiveness of Anti-Dementia Drugs in Extremely Severe Alzheimer’s Disease: A 12-Week, Multicenter, Randomized, Single-Blind Study
Abstract: Background/Objective: There is insufficient evidence to guide decisions concerning how long anti-dementia drug (ADD) regimens should be maintained in severe Alzheimer’s disease (AD). We investigated whether patients with extremely severe AD who were already receiving donepezil or memantine benefited from continuing treatment. Methods: In this randomized and rater-blinded trial, 65 AD patients with a Mini-Mental State Examination score from 0 to 5 and a score of 6c or worse on Functional Assessment Staging were randomly assigned to an ADD-continuation group (N = 30) or an ADD-discontinuation group (N = 35). The current use of donepezil or memantine was maintained for 12 weeks in the ADD-continuation group and was discontinued after baseline in the ADD-discontinuation group. Efficacy measures were obtained at baseline and 12 weeks. The primary efficacy variable was the change from baseline to the end of the study in Baylor Profound Mental State Examination (BPMSE) scores. Results: The change in the BPMSE from baseline to the end of the study in the ADD-continuation group (a 0.4-point improvement) was not equivalent to that in the ADD-discontinuation group (a 0.5-point decline), as determined by two one-sided tests of equivalence. Study withdrawals due to adverse events (11.4% versus 6.7%) were more frequent in the ADD-discontinuation group than in the ADD-continuation group. Conclusion: Continued treatment with donepezil or memantine seems unequal and might be superior to withdrawal of the drugs in terms of the effects on global cognition in patients with extremely severe AD. Current Controlled Trials number: KCT0000874 (CRIS).

Pages 1045-1054
András Horváth, Anna Szűcs, Zoltán Hidasi, Gábor Csukly, Gábor Barcs, Anita Kamondi
Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer’s Disease: An Ambulatory EEG Study
Abstract: Background: Alzheimer’s disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies. Objective: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG. Methods: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using logistic regression analysis. Results: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal-Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9). Conclusion: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage.

Pages 1055-1063
Joshua D. Grill, Dan Hoang, Daniel L. Gillen, Chelsea G. Cox, Adrijana Gombosev, Kirsten Klein, Steve O’Leary, Megan Witbracht, Aimee Pierce (Handling Associate Editor: Russell Swerdlow)
Constructing a Local Potential Participant Registry to Improve Alzheimer’s Disease Clinical Research Recruitment
Abstract: Potential participant registries are tools to address the challenge of slow recruitment to clinical research. In particular, registries may aid recruitment to secondary prevention clinical trials for Alzheimer’s disease (AD), which enroll cognitively normal older individuals meeting specific genetic or biomarker criteria. Evidence of registry effectiveness is sparse, as is guidance on optimal designs or methods of conduct. We report our experiences of developing a novel local potential participant registry that implemented online enrollment and data collection. In the first year of operation, 957 individuals submitted email addresses to the registry, of whom 592 self-reported demographic, family history, and medical data. In addition, registrants provided information related to their interest and willingness to be contacted about studies. Local earned media and community education were the most effective methods of recruitment into the registry. Seventy-six (26%) of 298 registrants contacted about studies in the first year enrolled in those studies. One hundred twenty-nine registrants were invited to enroll in a preclinical AD trial, of whom 25 (18%) screened and 6 were randomized. These results indicate that registries can aid recruitment and provide needed guidance for investigators initiating new local registries.

Pages 1065-1073
Jacqueline Dominguez, Ma. Fe de Guzman, Macario Reandelar, Jr, Thien Kieu Thi Phung (Handling Associate Editor: Kohi Abe)
Prevalence of Dementia and Associated Risk Factors: A Population-Based Study in the Philippines
Abstract: Background: The Philippines is experiencing rapid demographic aging and with it, the dementia epidemic. Prevalence of dementia and associated risk factors have not been studied in the Philippines. Objectives: The study aimed to provide a reliable estimate of dementia prevalence and identify associated risk factors in the Filipino population. Methods: 1460 participants 60 years and older were randomly selected from the Marikina City’s senior registry. A multidisciplinary team (nurse, psychologist, and neurologist) administered a comprehensive assessment to the study population: health history, neurological examination, Geriatric Depression Scale, Neuropsychiatric Inventory, Disability Assessment for Dementia, Alzheimer’s Disease 8, and Clinical Dementia Rating Scale. The neurologist analyzed all clinical data to diagnose dementia based on the DSM-IV criteria, Alzheimer’s Disease (AD) on the NINCDS-ADRDA criteria, vascular dementia (VaD) on the Hachinski Ischemic Scale, cognitive impairment no dementia (CIND) on a CDR score of 0.5 and not fulfilling DSM-IV criteria for dementia. Risk factors were correlated with dementia prevalence using multivariate binary logistic regression. Results: 1460 persons were randomly selected. 1367 agreed to participate and underwent all assessments. The response rate was 93.6%. Dementia prevalence was found to be 10.6 % (95% CI 9.0 to 12.4) with the breakdown 85.5% AD, 11.7 % VaD, and 2.7% other dementias. In this population, 82.0 % of men and 70.4% of women had at least one cardiovascular risk factor (hypertension, diabetes, dyslipidemia, smoking), which was associated with VaD prevalence but not AD. Conclusion: The prevalence of dementia, CIND, and cardiovascular risk factors are high in the Philippines.

Pages 1075-1088
Mikhail A. Tyumentsev, Natalia A. Stefanova, Natalia A. Muraleva, Yulia V. Rumyantseva, Elena Kiseleva, Valentin A. Vavilin, Nataliya G. Kolosova
Mitochondrial Dysfunction as a Predictor and Driver of Alzheimer’s Disease-Like Pathology in OXYS Rats
Abstract: Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer’s disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4–5 months), and at the well-pronounced stages (18–24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans.

Pages 1089-1107
Yangmei Huang*, Baihong Guo*, Bihua Shi, Qingtao Gao, Qiang Zhou (Handling Associate Editor: Jack de la Torre) *These authors contributed equally to this work.
Chinese Herbal Medicine Xueshuantong Enhances Cerebral Blood Flow and Improves Neural Functions in Alzheimer’s Disease Mice
Abstract: Reduced cerebral blood flow in Alzheimer’s disease (AD) may occur in early AD, which contributes to the pathogenesis and/or pathological progression of AD. Reversing this deficit may have therapeutic potential. Certain traditional Chinese herbal medicines (e.g., Saponin and its major component Xueshuantong [XST]) increase blood flow in humans, but whether they could be effective in treating AD patients has not been tested. We found that systemic XST injection elevated cerebral blood flow in APP/PS1 transgenic mice using two-photon time-lapse imaging in the same microvessels before and after injection. Subchronic XST treatment led to improved spatial learning and memory and motor performance in the APP/PS1 mice, suggesting improved neural plasticity and functions. Two-photon time lapse imaging of the same plaques revealed a reduction in plaque size after XST treatment. In addition, western blots experiments showed that XST treatment led to reduced processing of amyloid-β protein precursor (AβPP) and enhanced clearance of amyloid-β (Aβ) without altering the total level of AβPP. We also found increased synapse density in the immediate vicinity of amyloid plaques, suggesting enhanced synaptic function. We conclude that targeting cerebral blood flow can be an effective strategy in treating AD.

Pages 1109-1117
María José Gil, María Sagrario Manzano, María Luz Cuadrado, Cristina Fernández, Elena Góméz, Carmen Matesanz, Miguel Calero, Alberto Rábano
Argyrophilic Grain Pathology in Frontotemporal Lobar Degeneration: Demographic, Clinical, Neuropathological, and Genetic Features
Abstract: Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FLTD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p<0.001) and was associated with higher ages at onset (p<0.001) and death (p<0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p=0.055; p=0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p=0.094) and higher prevalence of Alzheimer (p=0.002) and vascular pathology (p=0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p=0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences.

Pages 1119-1127
Jinlei Li, Matthew Ogrodnik, Vijaya B. Kolachalama, Honghuang Lin, Rhoda Au
Assessment of the Mid-Life Demographic and Lifestyle Risk Factors of Dementia Using Data from the Framingham Heart Study Offspring Cohort
Abstract: Background: Dementia is the leading cause of dependence and disability in the elderly population worldwide. However, currently there is no effective medication for dementia treatment. Therefore, identifying life-related risk factors including some that are modifiable may provide important strategies for reducing risk of dementia. Objective: This study aims to highlight associations between easily obtainable life risk factors in mid-life and dementia in later adulthood. Methods: Using data from the Framingham Heart Study Offspring cohort, we leveraged well-known classification models (decision tree classifier and random forests) to associate demographic and lifestyle behavioral data with dementia status. We then evaluated model performance by computing area under receiver operating characteristic (ROC) curve. Results: As expected, age was strongly associated with dementia. The analysis also identified a marital status of ‘widowed,’ lower BMI, and less sleep at mid-life as risk factors of dementia. The areas under the ROC curves were 0.79 for the decision tree, and 0.89 for the random forest model. Conclusion: Demographic and lifestyle factors that are non-invasive and inexpensive to implement can be assessed in midlife and used to potentially modify the risk of dementia in late adulthood. Classification models can help identify associations between dementia and midlife lifestyle risk factors. These findings inform further research, in order to help public health officials develop targeted programs for dementia prevention.

Pages 1129-1139
Jules J. Claus*, Mirthe Coenen*, Salka S. Staekenborg, Jacqueline Schuur, Caroline E.M. Tielkes, Pieter Koster, Philip Scheltens *These authors contributed equally to this work.
Cerebral White Matter Lesions have Low Impact on Cognitive Function in a Large Elderly Memory Clinic Population
Abstract: Background: Evidence suggests that cerebral white matter lesions (WML) play a role in cognitive decline. Objective: To assess the impact of cerebral WML on cognitive function relative to absence or presence of medial temporal atrophy (MTA) in a large single-center memory clinic population. Methods: Patients included had subjective cognitive impairment (SCI, n=333), mild cognitive impairment (MCI, n=492) and Alzheimer’s disease (AD, n=832). The relationships between visually rated WML (Fazekas scale, 0-3) on brain Computed Tomography and CAMCOG memory and non-memory function were investigated with regression analysis adjusted for age, gender and education in combined patient groups. We assessed possible interaction versus addition effects of these relationships with visually rated MTA (Scheltens scale). Results: The highly statistical significant relationship between WML and memory function was no longer significant when MTA was taken into account. However, the strong significant relationship between WML and non-memory function remained significant after adjustment for MTA, but the explained variance attributed to WML was only 1.3%. There was no interaction between WML and MTA on CAMCOG test scores. In addition, shown by a 2x2 factorial model by presence versus absence of WML and MTA, WML affected non-memory function only in the presence of MTA. Conclusion: Our data suggest that presence of WML is associated with lower non-memory cognitive function but this effect is conditional on the presence of pre-existing MTA. The very small explained variance suggests little impact of WML to the clinical profile of a memory clinic patient.

Pages 1141-1159
Yacoubou Abdoul Razak Mahaman, Fang Huang, Mengjuan Wu, Yuman Wang, Zhen Wei, Jian Bao, Maibouge Tanko Mahamane Salissou, Dan Ke, Qun Wang, Rong Liu, Jian-Zhi Wang, Bin Zhang, Dan Chen, Xiaochuan Wang
Moringa Oleifera Alleviates Homocysteine-Induced Alzheimer’s Disease-Like Pathology and Cognitive Impairments
Abstract: Alzheimer’s disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin1, and Synaptophysin and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T-231, S-396, and S-404, and at the same time decreased Aβ production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Aβ pathology in an HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies.

Pages 1161-1172
Pamela Nardiello*, Daniela Pantano*, Andrea Lapucci, Massimo Stefani, Fiorella Casamenti (Handling Associate Editor: Tommaso Cassano) *These authors contributed equally to this work.
Diet Supplementation with Hydroxytyrosol Ameliorates Brain Pathology and Restores Cognitive Functions in a Mouse Model of Amyloid-β Deposition
Abstract: Alzheimer’s disease is the most common form of dementia affecting a large proportion of aged people. Plant polyphenols have been reported to be potentially useful in the prevention of AD due to their multiple pharmacological activities. The aim of the present study was to assess whether the previously reported neuroprotective and anti-inflammatory effects resulting from oleuropein aglycone administration were reproduced by diet supplementation with similar amounts of its metabolite hydoxytyrosol (HT). Four-month-old TgCRND8 and wild type mice were treated for 8 weeks with a low-fat diet (5%) supplemented with HT (50 mg/kg of diet). We found that HT supplementation significantly improved cognitive functions of TgCRND8 mice and significantly reduced Aβ42 and pE-3Aβ plaque area and number in the cortex; in the hippocampal areas of HT-fed TgCRND8 mice, we found a significant reduction in the pE-3Aβ plaque number together with a tendency toward a reduction in Aβ42 load and pE-3Aβ plaque area, associated with a marked reduction of TNF-α expression and astrocyte reaction. Macroautophagy induction and modulation of MAPKs signaling were found to underlie the beneficial effects of HT. Our findings indicate that HT administration reproduces substantially the beneficial effects on behavioral performance and neuropathology previously reported in TgCRND8 mice fed with oleuropein aglycone, resulting in comparable neuroprotection.

Pages 1173-1189
Abhik Sen, Thomas J. Nelson, Daniel L. Alkon, Jarin Hongpaisan
Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer’s Disease Hippocampus
Abstract: Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer’s disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCε). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCε levels and subsequent PKCε-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCε, MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients. In cultured human primary hippocampal neurons, spherical aggregation of Aβ (amylospheroids) decreased PKCε and MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the oxidative DNA/RNA damage marker, 8-OHG, and Aβ levels, but reduced PKCε, MnSOD, BDNF, and cultured neuron density. These changes were reversed with the PKCε activators, bryostatin and DCPLA-ME. PKCε knockdown suppressed PKCε, MnSOD, and BDNF but increased Aβ. In cultured neurons, the increase in reactive oxygen species (ROS) associated with reduced PKCε during neurodegeneration was inhibited by the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong oxidative stress suppresses PKCε level. Reduction of PKCε and MnSOD was prevented with the PKCε activator bryostatin in 5–6-month-old Tg2576 AD transgenic mice. In conclusion, oxidative stress and Aβ decrease PKCε expression. Reciprocally, a depression of PKCε reduces BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented with the PKCε-specific activators.

Pages 1191-1205
Minesh Kapadia, M. Firoz Mian, Bernadeta Michalski, Amber Azam, Donglai Ma, Patrick Salwierz, Adam Christopher, Elyse Rosa, Iva Zovkic, Paul Forsythe, Margaret Fahnestock, Boris Sakic
Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice
Abstract: The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer’s disease (AD) because it develops both amyloid-β (Aβ) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life, they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both sexes were examined for T-cell phenotype (CD3+, CD8+, and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Aβ levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2 variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Aβ and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2 variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as epigenetic changes of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients.