Volume 69, Number 2, 2019

Pages 311-338
Hugo McGurran, Jordan M. Glenn, Erica N. Madero, Nicholas T. Bott (Handling Associate Editor: Mariagnese Barbera)
Prevention and Treatment of Alzheimer’s Disease: Biological Mechanisms of Exercise
Abstract: Alzheimer’s disease (AD) is the most common form of dementia. With an aging population and no disease modifying treatments available, AD is quickly becoming a global pandemic. A substantial body of research indicates that lifestyle behaviors contribute to the development of AD, and that it may be worthwhile to approach AD like other chronic diseases such as cardiovascular disease, in which prevention is paramount. Exercise is an important lifestyle behavior that may influence the course and pathology of AD, but the biological mechanisms underpinning these effects remain unclear. This review focuses on how exercise can modify four possible mechanisms which are involved with the pathology of AD: oxidative stress, inflammation, peripheral organ and metabolic health, and direct interaction with AD pathology. Exercise is just one of many lifestyle behaviors that may assist in preventing AD, but understanding the systemic and neurobiological mechanisms by which exercise affects AD could help guide the development of novel pharmaceutical agents and non-pharmacological personalized lifestyle interventions for at-risk populations.

Pages 339-353

Yuanting Ding, Lijuan Lei, Chencen Lai, Zhi Tang
Tau Protein and Zebrafish Models for Tau-Induced Neurodegeneration
Abstract: Tauopathies are a specific type of slow and progressive neurodegeneration, which involves intracellular deposition of fibrillar material composed of abnormal hyperphosphorylation of the microtubule associated protein (MAP) tau. Despite many years of intensive research, our understanding of the molecular events that lead to neurodegeneration is far from complete. No effective therapeutic treatments have been defined, and questions surround the validity and utility of existing animal models. It is an urgent need to develop a novel animal model to study the underlying neurodegenerative mechanisms of tauopathies. Zebrafish models of tauopathies could complement existing models by providing an in vivo platform for genetic and chemical screens in order to identify new therapeutic targets and compounds, meanwhile zebrafish models have permitted discovery of unique characteristics of these genes that could have been difficultly observed in other models. Novel transgenic zebrafish models expressing wild-type or mutant forms of human 4R-tau in neurons have recently been reported. These studies show disease-relevant changes including tau hyperphosphorylation, aggregation, and somato-dendritic relocalization. This review highlights the availability of transgenic tau zebrafish models that allow more detailed biochemical studies of tau in the zebrafish CNS to characterize solubility, fibril morphology and further clarify phosphorylation proceedings. Furthermore, a deeper knowledge of the zebrafish brain and a better characterization of tau caused by alterations in neurodegenerative disorders are needed.

Pages 355-362
Shiping Li*, Junxiang Yin*, Megan Nielsen, Thomas G. Beach, Li Guo, Jiong Shi *These authors contributed equally to this work.
Sirtuin 3 Mediates Tau Deacetylation
Abstract: Background: Emerging evidence shows tau acetylation has been observed in Alzheimer’s disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear. Objective: We studied the effects of Sirt3 on tau acetylation and its aggregations. Methods: We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 cells after Sirt3 knockdown or overexpression. Results: The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells. Conclusions: Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation.

Pages 363-375
Upasana Roy, Mónica T. Heredia-Muñoz, Lara Stute, Corinna Höfling, Jörg Matysik, Johanna H. Meijer, Steffen Roβner, A. Alia
Degeneration of the Suprachiasmatic Nucleus in an Alzheimer’s Disease Mouse Model Monitored by in vivo Magnetic Resonance Relaxation Measurements and Immunohistochemistry
Abstract: In Alzheimer’s disease (AD), disturbances in the circadian rhythm and sleep-wake cycle are frequently observed. Both are controlled by the master clock: the suprachiasmatic nucleus (SCN), which was reported in postmortem studies of AD subjects to be compromised. However, the influence of age and gender on the biophysical integrity and subtle microstructural changes of SCN and mechanistic connections between SCN dysfunction and AD progression in vivo remain to be explored. In the present study, we utilized state-of-the-art in vivo magnetic resonance relaxation measurements in combination with immunohistochemistry to follow microstructural changes in SCN of the Tg2576 mouse model of AD. Longitudinal monitoring of in vivo T2 relaxation with age shows significant shortening of T2 values in the SCN of transgenic mice and more substantially in female transgenic than aged-matched controls. Multiexponential T2 analysis detected a unique long T2 component in SCN of transgenic mice which was absent in wild-type mice. Immunohistochemical examination revealed significantly elevated numbers of activated astrocytes and an increase in the astrocyte to neuron ratio in SCN of transgenic compared to wild-type mice. This increase was more substantial in female than in male transgenic mice. In addition, low GABA production in SCN of transgenic mice was detected. Our results offer a brief appraisal of SCN dysfunction in AD and demonstrate that inflammatory responses may be an underlying perpetrator for the changes in circadian rhythmicity and sleep disturbance in AD and could also be at the root of marked sex disparities observed in AD subjects.

Pages 377-383
Pascal J.D. Goetghebeur, Keith A. Wesnes, Steven D. Targum
D-Cycloserine Improves Difficult Discriminations in a Pattern Separation Task in Alzheimer’s Disease Patients with Dementia
Abstract: Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer’s disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 weeks for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were ≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection.

Pages 385-399
J. Wesson Ashford, Franck Tarpin-Bernard, Curtis B Ashford, Miriam T. Ashford (Handling Associate Editor: Amos Korczyn)
A Computerized Continuous-Recognition Task for Measurement of Episodic Memory
Abstract: Based on clinical observations of severe episodic memory (EM) impairment in dementia of Alzheimer’s disease (AD), a brief, computerized EM test was developed for AD patient evaluation. A continuous recognition task (CRT) was chosen because of its extensive use in EM research. Initial experience with this computerized CRT (CCRT) showed patients were very engaged in the test, but AD patients had marked failure in recognizing repeated images. Subsequently, the test was administered to audiences, and then a two-minute online version was implemented (http://www.memtrax.com ). The online CCRT shows 50 images, 25 unique and 25 repeats, which subjects respectively either try to remember or indicate recognition as quickly as possible. The pictures contain 5 sets of 5 images of scenes or objects (e.g., mountains, clothing, vehicles, etc.). A French company (HAPPYneuron, SAS) provided the test for 2 years, with these results. Of 18,477 individuals, who indicated sex and age 21-99 years and took the test for the first time, 18,007 individuals performed better than chance. In this group, age explained 1.5% of the variance in incorrect responses and 3.5% of recognition time variance, indicating considerable population variability. However, when averaging for specific year of age, age explained 58% of percent incorrect variance and 78% of recognition time variance, showing substantial population variability but a major age effect. There were no apparent sex effects. Further studies are indicated to determine the value of this CCRT as an AD screening test and validity as a measure of EM impairment in other clinical conditions.

Pages 401-411
Martha Karran, Elizabeth Guerrero-Berroa, James Schmeidler, Pearl G. Lee, Neil Alexander, Martina Nabozny, Rebecca K. West, Michal Schnaider Beeri, Mary Sano, Jeremy M. Silverman (Handling Associate Editor: Feng Vankee Lin)
Recruitment of Older Veterans with Diabetes Risk for Alzheimer’s Disease for a Randomized Clinical Trial of Computerized Cognitive Training
Abstract: Background: Type 2 diabetes mellitus (T2DM) is prevalent in the general United States population, and in the veteran population. T2DM has consistently been linked to increased risk for cognitive impairment, dementia, and Alzheimer’s disease. Computerized cognitive training (CCT) is practical and inexpensive cognitive interventions that is an alternative to medication. Objective: To report the recruitment methods and challenges to date in an ongoing two-site randomized controlled trial (RCT) of CCT on cognitive function and T2DM management in an older non-demented veteran population. Methods: Veterans are recruited primarily by targeted mailings or by direct contact at clinics and presentations. Results: From 1,459 original contacts, 437 expressed initial interest, 111 provided informed consent, and 97 completed baseline assessments. Participants from the two VA Medical Centers differed in demographics and baseline characteristics. Comparing recruitment methods, the proportion of individuals contacted who were ultimately consented was significantly less from mailings (5%) than other sources (20%), primarily face–to-face clinic visits (χ2 (1) = 38.331, p < 0.001). Conclusions: Mailings are cost-effective, but direct contact improved recruitment. Not using or lacking access to computers and ineligibility were major reasons for non-participation. Within-site comparisons of demographically diverse sites can address confounding of demographic and other site differences.

Pages 413-421
Kimberley Yuen, Neda Rashidi-Ranjbar, Nicolaas Paul L.G. Verhoeff, Sanjeev Kumar, Damien Gallagher, Alastair J. Flint, Nathan Herrmann, Bruce G. Pollock, Benoit H. Mulsant, Tarek K. Rajji, Aristotle N. Voineskos, Corinne E. Fischer, Linda Mah, for the PACt-MD Study Group
Association between Sleep Disturbances and Medial Temporal Lobe Volume in Older Adults with Mild Cognitive Impairment Free of Lifetime History of Depression
Abstract: Background: Previous studies examining the link between neuropsychiatric symptoms (NPS) and biomarkers of Alzheimer’s disease (AD) may be confounded by remitted or past history of psychiatric illness, which in itself is associated with AD biomarkers such as reduced medial temporal lobe (MTL) volume. Objective: We examined associations between mood and anxiety-related NPS and MTL in older adults with mild cognitive impairment (MCI) free of lifetime history of depression. We hypothesized an inverse relationship between NPS severity and MTL. Methods: Forty-two MCI participants without current or past history of depression or other major psychiatric illness were assessed using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Correlation and regression analyses were performed between selected NPI-Q items and regional MTL volumes from structural magnetic resonance imaging. Results: Sleep disturbances was inversely associated with several regional volumes within the MTL. Sleep disturbances remained significantly correlated with left hippocampal and amygdala volume following correction for multiple comparisons. In contrast, depression and anxiety were not correlated with MTL. Conclusions: The relationship between reduced MTL and sleep, but not with depressed or anxious states, in MCI free of lifetime history of depression, suggests a potential mechanism for sleep as a risk factor for AD. The current findings highlight the importance of accounting for remitted psychiatric conditions in studies of the link between NPS and AD biomarkers and support the need for further research on sleep as clinical biomarker of AD and target for AD prevention.

Pages 423-432
Suzann Pershing, Victor W. Henderson, M. Kate Bundorf, Ying Lu, Moshiur Rahman, Chris A. Andrews, Mary Goldstein, Joshua D. Stein
Differences in Cataract Surgery Rates Based on Dementia Status
Abstract: Background: Cataract surgery substantially improves patient quality of life. Despite the rising prevalence of dementia in the US, little is known about use of cataract surgery among this group. Objective: To evaluate the relationship between dementia status and cataract surgery. Methods: Using administrative insurance claims for a representative sample of 1,125,387 US Medicare beneficiaries who received eye care between 2006 and 2015, we compared cataract surgery rates between patients with and without dementia via multivariable regression models to adjust for patient characteristics. Main outcome measures were annual rates of cataract surgery and hazard ratio and 95% confidence interval (CI) for receiving cataract surgery. Results: Cataract surgery was performed in 457,128 patients, 23,331 with a prior diagnosis of dementia. 16.7% of dementia patients underwent cataract surgery, compared to 43.8% of patients without dementia. 59 cataract surgeries were performed per 1000 dementia patients annually, versus 105 surgeries per 1000 nondementia patients. After adjusting for patient characteristics, dementia patients were approximately half as likely to receive cataract surgery compared to nondementia patients (adjusted HR=0.53, 95%CI 0.53-0.54). Among the subset of patients who received a first cataract surgery, those with dementia were also less likely to receive second-eye cataract surgery (adjusted HR=0.87, 95%CI 0.86-0.88). Conclusion: US Medicare patients with dementia are less likely to undergo cataract surgery than those without dementia. This finding has implications for quality of care and dementia progression. More information is necessary to understand why rates of cataract surgery are lower for these patients, and to identify conditions where benefits of surgery may outweigh risks.

Pages 433-441
Lena Johansson*, Mariella Guerra*, Martin Prince, Helena Hörder, Hanna Falk, Brendon Stubbs, A. Matthew Prina (Handling Associate Editor: Joshua Stott) *These authors contributed equally to this work.
Associations between Depression, Depressive Symptoms, and Incidence of Dementia in Latin America: A 10/66 Dementia Research Group Study
Abstract: Background: A growing body of evidence suggests that depression is related to dementia in older adults. Previous research has been done in high-income countries and there is a lack of studies in low- and middle income countries (LMICs). Objective: To examine the relationship between depressive symptoms and incidence of dementia in a population-based study of older adults in Latin America. Methods: The study is a part of the 10/66 Dementia Research Group’s population survey and includes 11,472 older adults (baseline mean age 74 years) from Cuba, Dominican Republic, Mexico, Peru, Puerto Rico, and Venezuela. The baseline examinations were done in 2003-2007 and the follow-up examinations 4 years later. Semi-structured psychiatric interviews gave information about ICD-10 depression and sub-syndromal depression (i.e., ≥4 depressive symptoms) at baseline. Information on dementia were collected at the follow-up examination. Competing risk models analyzed the associations between depression and incidence of dementia and the final model were adjusted for age, sex, education, stroke, and diabetes. Separate analyses were conducted for each site and then meta-analyzed by means of fixed effect models. Results: At baseline, the prevalence of depression was 26.0% (n=2,980): 5.4% had ICD-10 depression and 20.6% sub-syndromal depression. During the follow-up period, 9.3% (n=862) developed dementia and 14.3% (n=1,329) deceased. In the pooled analyses, both ICD-10 depression (adjusted sub-hazard ratio (sHR) 1.63, 95% confidence interval (CI) 1.26-2.11) and sub-syndromal depression (adjusted sHR 1.28, 95% CI: 1.09-1.51) were associated with increased incidence of dementia. The Higging I2 tests showed a moderate heterogeneity across the study sites. Conclusion: Our findings suggest that late-life depression is associated with the incidence of dementia in LMICs in Latin America, which support results from earlier studies conducted in high-income countries.

Pages 443-453
Elena O. Petukhova, Yana O. Mukhamedshina, Ilnur I. Salafutdinov, Ekaterina E. Garanina, Maxim S. Kaligin, Alina V. Leushina, Albert A. Rizvanov, Helton J. Reis, András Palotás, Andrey L. Zefirov, Marat A. Mukhamedyarov
Effects of Transplanted Umbilical Cord Blood Mononuclear Cells Overexpressing GDNF on Spatial Memory and Hippocampal Synaptic Proteins in a Mouse Model of Alzheimer’s Disease
Abstract: Background/Objective: Alzheimer’s disease (AD) is a progressive incurable neurodegenerative disorder. Glial cell line-derived neurotrophic factor (GDNF) is a prominent regulator of brain tissue and has an impressive potential for use in AD therapy. While its metabolism is still not fully understood, delivering neuropeptides such as GDNF via umbilical cord blood mononuclear cells (UCBMCs) to the sites of neurodegeneration is a promising approach in the development of innovative therapeutic avenues. Methods: UCBMCs were transduced with adenoviral vectors expressing GDNF and injected into AD transgenic mice. Various parameters including homing and survival of transplanted cells, expression of GDNF and synaptic proteins, as well as spatial memory were evaluated. Results: UCBMCs were observed in the hippocampus and cortex several weeks after transplantation, and their long-term presence was associated with improved spatial memory. Post-synaptic density protein 95 (PSD-95) and synaptophysin levels in the hippocampus were also effectively restored following the procedure in AD mice. Conclusions: Our data indicate that gene-cell therapy with GDNF-overexpressing UCBMCs may produce long-lasting neuroprotection and stimulation of synaptogenesis. Such adenoviral constructs could potentially possess a high therapeutic potential for the treatment of AD.

Pages 455-462
Mandy Roheger, Maria Eriksdotter, Karin Westling, Elke Kalbe , Sara Garcia-Ptacek
Diagnostic Work-Up Is More Complete in Rural than in Urban Areas for Patients with Dementia: Results of a Swedish Dementia Registry Study
Abstract: Background: Life in rural areas differs from life in urban areas not only in geographical conditions, but also in health care structure. Objective: Our aim is to compare the diagnostic process and the management of dementia in rural and urban areas of Sweden. Methods: We performed a cross-sectional study of patients with dementia living in rural (n = 16,428), intermediate (n = 18,033), and urban (n = 23,680) areas in Sweden including patients registered from 2007 through 2014 in the Swedish Dementia Registry (SveDem). Descriptive statistics are shown. Odds ratios with 95% CI are presented for basic diagnostic examinations in rural compared to intermediate and urban areas, adjusted for age, sex, type of care (primary versus specialist), and comorbidities. Analyses were also stratified for diagnostic care unit (primary versus specialist). Results: Patients who lived in rural areas were more likely to receive a complete basic examination, MMSE examination, Clock test, blood analysis, and neuro-imaging, compared to patients living in urban areas, and also compared to patients living in intermediate areas. Sex differences were seen in nearly all domains, with men receiving more diagnostic work-up than women. Stratified analyses show that in primary care, the complete basic examination is less frequently performed in urban and intermediate areas compared to rural areas. Conclusion: There are differences in diagnostic work-up for dementia between rural, intermediate, and urban areas in Sweden. These results should be considered in future healthcare decisions to ensure equality of health care across rural and urban areas.

Pages 463-478
S. Can Akerman*, Shireen Hossain*, Adeola Shobo, Yifei Zhong, Roland Jourdain, Mark A. Hancock, Kelly George, Lionel Breton, Gerhard Multhaup *These authors contributed equally to this work.
Neurodegenerative Disease-Related Proteins within the Epidermal Layer of the Human Skin
Abstract: There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues in neurodegenerative disorders such as Alzheimer’s or Parkinson’s diseases. However, the detection of these aggregation-prone proteins within the human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen human skin samples were analyzed for the expression and localization of neurodegenerative disease-related proteins. While α-synuclein was detected throughout the epidermal layer of the auricular samples (IHC and MALDI-MSI), tau and Aβ34 were also localized to the epidermal layer (IHC). In addition to Aβ peptides of varying length (e.g., Aβ42, Aβ40, Aβ34), we also were able to detect inflammatory markers within the same sample sets (e.g., thymosin β-4, psoriasin). While previous literature has described α-synuclein in the nucleus of neurons (e.g., Parkinson’s disease), our current detection of α-synuclein in the nucleus of skin cells is novel. Imaging of α-synuclein or tau revealed that their presence was similar between the young and old samples in our present study. Future work may reveal differences relevant for diagnosis between these proteins at the molecular level (e.g., age-dependent post-translational modifications). Our novel detection of Aβ34 in human skin suggests that, just like in the brain, it may represent a stable intermediate of the Aβ40 and Aβ42 degradation pathway.

Pages 479-487
Marte Kvello-Alme, Geir Bråthen, Linda R. White, Sigrid Botne Sando (Handling Associate Editor: David Knopman)
The Prevalence and Subtypes of Young Onset Dementia in Central Norway: A Population-Based Study
Abstract: Background: Young onset dementia poses several challenges for the individual, health care, and society that are not normally relevant for late onset dementia, but is little researched. Objective: To determine the prevalence and subtypes of young onset dementia in a defined catchment area in central Norway. Methods: The main sources of patient identification were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav’s Hospital), and Department of Psychiatry, Levanger Hospital. Both departments are the main sites for referral of young onset dementia (onset before age 65 years) in the county, covering approximately 90% of the catchment area of the study. Other sources included key persons in the communities, collaborating hospital departments examining dementia, and review of hospital records of all three hospitals in the area. Included patients met the DSM-IV criteria for dementia. The prevalence of dementias was calculated by sex and age. Results: All patients identified with dementia and onset before 65 years on census date were included in the study (n=390). Patients younger than 65 on census date were included in the calculation of prevalence, giving a result of 76.3 per 100 000 persons at risk in the age category of 30-65 years, and 163.1 per 100,000 for the category 45-64 years. Etiology was heterogeneous, but the main subtype of dementia was Alzheimer’s disease. Conclusions: Young onset dementia affects a significant number of people in central Norway. Prevalence figures are higher than previously reported from England and Japan, but are similar to a more recent study from Australia.

Pages 489-498
Maja Mustapic, Joyce Tran, Suzanne Craft, Dimitrios Kapogiannis (Handling Associate Editor: Monique Mulder)
Extracellular Vesicle Biomarkers Track Cognitive Changes Following Intranasal Insulin in Alzheimer’s Disease
Abstract: Background: Insulin resistance is implicated in Alzheimer’s disease (AD), whereas intranasal insulin is an experimental treatment in clinical trials. We previously proposed insulin signaling mediators in plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain insulin resistance. Objective: We sought to demonstrate the capacity of neuronal-enriched EV biomarkers to demonstrate target engagement in response to intranasal insulin and their ability to track treatment-associated cognitive changes in AD. Methods: We isolated neuronal-enriched EVs from plasma samples of participants with amnestic mild cognitive impairment or probable AD involved in a 4-month duration placebo-controlled clinical trial of 20 or 40 IU intranasal insulin. We measured insulin signaling mediators as biomarkers and examined treatment-associated changes and their relationship with cognitive performance (ADAS-Cog). Results: There were no EV biomarker changes from baseline in any of the treatment groups. In participants treated with 20 IU insulin, EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) showed strong positive correlations with ADAS-Cog changes, especially in ApoE ε4 non-carriers. Conclusion: Neuronal EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were associated with cognitive changes in response to low dose intranasal insulin suggesting engagement of the insulin cascade in neurons of origin.

Pages 499-512
Sourav Kumar*, Saurabh Srivastav*, Mahino Fatima, Rajat Subhra Giri, Bhubaneswar Mandal, Amal Chandra Mondal *These authors contributed equally to this work.
A Synthetic Pro-Drug Peptide Reverses Amyloid-β-Induced Toxicity in the Rat Model of Alzheimer’s Disease
Abstract: Background: Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, involves the formation of the extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. The current therapies against AD are symptomatic with limited benefits but associated with major side effects. Inhibition of self-aggregation of Aβ peptides into higher order cross-β structure is one of the potential therapeutic approach which may counter oligomerization of Aβ peptide. Objective: The present study aimed to evaluate the neuroprotective and anti-inflammatory potential of a synthetic Pro-Drug type peptide (PDp) against Aβ-induced toxicity in rat model of AD. Methods: Intra-hippocampal microinjection of toxic Aβ40 (IHAβ40) by stereotaxic surgery was performed in the male Sprague-Dawley rats to generate an Aβ-induced AD model. Sub-chronic toxicity of synthetic PDp using hematological, biochemical, and histopathological parameters was investigated. Evaluation of PDp on Aβ-induced neurodegeneration and neuroinflammation was performed. Results: PDp inhibits plaque formation with increase in Nissl granule staining in the rat hippocampus. Aβ-induced toxicity associated imbalance in reactive oxygen species and antioxidant enzymes activity such as superoxide dismutase and catalase in the rat brain was overcome by PDp treatment. Tau protein hyperphosphorylation was normalized with PDp treatment. Also, the neuroinflammatory response was suppressed with PDp treatment. Conclusion: The present study depicts the potential neuroprotective role of PDp against Aβ-induced toxicity in rat. PDp inhibits plaque formation thereby normalizing oxidative stress, inhibiting tau protein hyperphosphorylation, and suppressing neuroinflammatory responses. Future studies done in this direction will pave way for new therapeutic strategies.

Pages 513-520
Johanne Købstrup Zakarias, Christina Jensen-Dahm, Ane Nørgaard, Peter Roos, Christiane Gasse, Thien Kieu Thi Phung, Gunhild Waldemar
Geographical Variation in the Diagnostic Rate and Quality of Dementia Diagnoses
Abstract: Background: Early and accurate diagnosis of dementia opens the door to appropriate treatment, support, and counseling. Despite availability of evidence-based guidelines for diagnostic evaluation of dementia, the diagnostic rate in people with dementia is low and the quality of dementia diagnoses is unknown. Objective: The overall aim of this register-based study was to analyze the quality of diagnostic evaluation of dementia by assessing nationwide geographical variations in a range of indicators. Methods: A register-based cross-sectional study of the entire Danish population aged 65 years or older in 2015 was conducted. The surrogate indicators for diagnostic quality included 1) prevalence rates of dementia diagnoses, 2) incidence rates of dementia diagnoses, 3) age at first diagnosis of dementia, 4) medical specialty responsible for diagnosis, 5) diagnostic rate of dementia subtypes, and 6) use of anti-dementia medication. The indicators were compared across the five Danish regions. Results: The national prevalence and incidence of registered dementia diagnoses was 3.0% and 0.5%, respectively. The proportion of patients diagnosed at a dementia specialist department ranged from 60.9% to 90.5% across the five regions, subtype specific diagnosis ranged from 45.3% to 75.5%, and use of anti-dementia medication ranged from 29.2% to 58.3%. Conclusion: The observed geographical variations in dementia diagnoses and treatment indicate inequality in the access to appropriate diagnostic evaluation and care for patients with dementia. Our findings call for more awareness of the benefits of timely diagnosis and for improvement in the quality of diagnostic evaluation of dementia.

Pages 521-528
Jung-Min Pyun, Min Ju Kang, Younghwa Yun, Young Ho Park, SangYun Kim
APOE ε4 and REM Sleep Behavior Disorder as Risk Factors for Sundown Syndrome in Alzheimer’s Disease
Abstract: Background: Sundown syndrome (SS) in patients with Alzheimer’s disease (AD) is characterized by aggravation of behavioral problems at sunset. Disturbance of the circadian rhythm, a possible cause of SS, also facilitates amyloidopathy and reduces sleep quality. However, the associations of SS with amyloidopathy and sleep quality remain unclear. Objective: To investigate the prevalence of SS in patients with AD, the association between SS and APOE ε4 carrier, representing an enhanced amyloid pathology, and the relationship between SS and sleep quality in AD. Methods: We included 104 patients with late-onset AD and known APOE genotype. All participants underwent a structured interview via informant-based questionnaires to assess sleep quality and the presence of SS. Binary logistic regression analysis was performed to determine odds ratios (ORs) of APOE ε4 carrier and parameters of sleep quality for SS. Results: The prevalence of SS in AD was 27.8% (n = 29). Patients with SS were significantly more likely to be APOE ε4 carriers and to have rapid eye movement sleep behavior disorder (RBD) and a higher Clinical Dementia Rating (CDR) score compared to those without SS. In the multivariate regression analysis, APOE ε4 carrier (OR 3.158, CI 1.022–9.758), RBD (OR 2.166, CI 1.073–4.371), and higher CDR score (OR 2.453, CI 1.084–5.550) were associated with an increased risk of SS. Conclusion: The prevalence of SS in patients with AD was 27.8%. The presence of the APOE ε4 allele, RBD, and more severe dementia are associated with an increased risk of SS in AD.

Pages 529-538
Tomoyasu Bunai, Akihiro Kakimoto, Etsuji Yoshikawa, Tatsuhiro Terada, Yasuomi Ouchi (Handling Associate Editor: David Cook)
Biopathological Significance of Early-Phase Amyloid Imaging in the Spectrum of Alzheimer’s Disease
Abstract: Background: Amyloid imaging with positron emission tomography (PET) often comes with glucose metabolic imaging in diagnosis of Alzheimer’s disease (AD). Objective: The present purpose was to explore the clinical valence of early amyloid-β (Aβ) PET scans to determine whether they could substitute for other imaging biomarkers (early and delayed Aβ images of 11C-Pittsburgh compound B (PIB) and 18F-fluorodeoxyglucose (FDG) images) in the AD spectrum. Methods: Thirty healthy control subjects, 20 patients with mild cognitive impairment, and 45 patients with AD underwent 11C-PIB and 18F- FDG PET. Image analyses were performed with three-dimensional stereotactic surface projection and Brodmann’s area regions-of-interest methods. Since early accumulation of PIB (ePIB) reflects blood flow, we classified all subjects according to the level of ePIB in the posterior cingulate gyrus, precuneus, and lateral parietal cortex. We compared the PET parameters (ePIB, delayed-phase PIB accumulation or dPIB, FDG) to determine whether ePIB-based categorization reflected Aβ deposition in a Braak stage-related fashion. Results: We found that ePIB images were similar to 18F-FDG images and that the progress of Aβ deposition deduced from the reduction in ePIB index was similar to the pathological progress of Braak staging. A decrease in the ePIB level in the posterior cingulate gyrus, precuneus, and parietal cortex was shown to correspond to greater and wider Aβ deposition in the medial frontal, anterior, and posterior cingulate gyri. Conclusions: The early-phase 11C-PIB index can be an alternative to the neurogenerative markers of glucose hypometabolism and reflects the Braak stage of Aβ deposition in the living AD brain.

Pages 539-549
Marcia Cristina Nascimento Dourado, Bianca Torres Mendonça de Melo Fádel, José Pedro Simões Neto, Gilberto Alves, Cândida Alves
Facial Expression Recognition Patterns in Mild and Moderate Alzheimer’s Disease
Abstract: Facial expression recognition is one of the essential abilities for social cognition. We aimed to compare facial expression recognition among people with mild and moderate Alzheimer’s disease (AD) and to identify which factors were associated with impairment according to disease severity. We included 52 participants with either mild or moderate AD. FACES includes four subtasks requiring matching expressions with picture stimuli (tasks 1 and 2), labelling emotions (task 3), and recognizing situations with evident emotional content (task 4). There were significant differences between groups in FACES global scores, task 2 and task 4. In the mild AD group, FACES global score was influenced by educational background and cognitive performance, task 1 was associated with comprehension and constructive praxis, task 2 was associated with cognitive flexibility, and task 3 was associated with word finding. In subtask 4, no significant associations were found after adjusting for level of cognitive decline. In the moderate AD group, the awareness of emotional state domain was associated with FACES global score, task 1 was associated with constructive praxis, task 3 was associated with neuropsychiatric symptoms, and task 4 was associated with the ability to recognize emotions through situations. No significant associations were found on task 2, after adjusting for level of cognitive decline. Our findings suggest emotional processing difficulties across AD stages. However, when participants needed to recognize the most preponderant emotion in a situation with evident emotional content, our results suggest that in both groups there was no influence of cognitive impairment.

Pages 551-559
Tobias Skillbäck, Johannes Kornhuber, Kaj Blennow, Henrik Zetterberg, Piotr Lewczuk, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Sebastiaan Engelborghs)
Erlangen Score Predicts Cognitive and Neuroimaging Progression in Mild Cognitive Impairment Stage of Alzheimer’s Disease
Abstract: Background: To alleviate the interpretation of the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers, amyloid β1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau), the Erlangen Score (ES) interpretation algorithm has been proposed. Objective: In this study, we aim to assess the predictive properties of the ES algorithm on cognitive and neuroimaging outcomes in mild cognitive impairment (MCI). Methods: All MCI subjects with an available baseline CSF sample from ADNI-1 were included (n=193), and assigned an ES between 0 and 4 based on their baseline CSF biomarker profile. Structural magnetic resonance imaging brain scans and MMSE and ADAS-Cog scores were collected at up to 7 times in follow-up examinations. Results: We observed strong and significant correlations between the ES at baseline and neuroimaging and cognitive results with patients with neurochemically probable AD (ES = 4) progressing significantly (p ≤ 0.01) faster than those with a neurochemically improbable AD (ES = 0 or 1), and the subjects with neurochemically possible AD (ES = 2 or 3) in-between these two groups. Conclusion: This study further demonstrates the utility of the ES algorithm as a as a tool in predicting cognitive and imaging progression in MCI patients.

Pages 561-576
Tommaso Bucci*, Danilo Menichelli*, Pasquale Pignatelli, Massimo Triggiani, Francesco Violi, Daniele Pastori *These authors contributed equally to this work.
Relationship of Antiphospholipid Antibodies to Risk of Dementia: A Systematic Review
Abstract: Antiphospholipid antibodies (aPL) are well-known risk factors for venous and arterial thrombosis, but their association with cognitive dysfunction has not been widely investigated in the general population and in patients with primary and secondary antiphospholipid syndrome (APS). We performed a systematic review searching MEDLINE via PubMed and Cochrane (CENTRAL) databases for observational studies reporting on the association between aPL and dementia in the general population, in subjects carrying aPL, in patients with cognitive disorder/dementia, and in primary and secondary APS. Prevalence of anticardiolipin (aCL) IgG ranged from 5.9% to 31.1% in the general population, with aCL titers being more elevated in subjects with functional decline of cognitive functions or with neurological alterations as detected by imaging. The prevalence of aPL ranged from 6.0 to 56.6% in patients with vascular dementia. Regarding patients with primary and secondary APS, a severe cognitive deficit has been described in up to 60% of patients, 33.3% of systemic lupus erythematosus (SLE)-APS and 22.2% of SLE patients without aPL. Five studies included patients with primary APS with divergent results, while 18 studies investigated the association between aPL and cognitive impairment in patients with SLE. Of these, 14 reported a positive association between aPL, mostly aCL and LAC, and cognitive impairment while little evidence on anti β2-Glycoprotein I exists. Mechanisms leading to cognitive dysfunction are not well characterized and may include vascular aPL-induced micro and macro-thrombosis and immune-mediated neuronal toxicity pathways in the cerebral district.

Pages 577-583
Karel Kostev, Jens Bohlken, Louis Jacob
Analysis of the Effects of Selective Serotonin (and Noradrenaline) Reuptake Inhibitors on the Risk of Dementia in Patients with Depression
Abstract: Background: Previous studies focusing on the association between antidepressant use and dementia have reported controversial findings. Objective: This study aimed to compare the associations between the prescription of selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenaline reuptake inhibitors (SNRIs) and the occurrence of dementia in patients with depression followed in Germany. Methods: This study included 20,215 patients aged 70-90 diagnosed with depression and treated in general or neuropsychiatric practices in Germany between 2010 and 2015 (index date). The main outcome of the study was the rate of dementia within 10 years after the first prescription of SSRIs or SNRIs. For the first set of survival analyses, patients were followed until they received a dementia diagnosis or until the end of their antidepressant therapy, whereas for the second set of survival analyses, patients were followed until they received a dementia diagnosis or had their last documented visit to the practice. Results: Ten years after the index date, the rate of dementia ranged from 17.3% in escitalopram users to 36.0% in citalopram users in the first analysis, and from 30.8% in fluoxetine users to 40.4% in citalopram users in the second analysis. In the first regression model, fluoxetine (hazard ratio [HR]=0.58), venlafaxine (HR=0.74), and duloxetine (HR=0.74) were associated with a decreased dementia risk compared with citalopram. In the second model, only venlafaxine significantly decreased the odds of developing dementia (HR=0.81). Conclusion: SSRIs and SNRIs were differentially associated with the risk of dementia in patients with depression in Germany.

Pages 585-593
Sunkuk Kwon, Ines Moreno-Gonzalez, Kathleen Taylor-Presse, George Edwards III, Nazaret Gamez, Olivia Calderon, Banghe Zhu, Fred Christian Velasquez, Claudio Soto, Eva M. Sevick-Muraca
Impaired Peripheral Lymphatic Function and Cerebrospinal Fluid Outflow in a Mouse Model of Alzheimer’s Disease
Abstract: Cerebrospinal fluid (CSF) outflow from the brain occurs through absorption into the arachnoid villi and, more predominantly, through meningeal and olfactory lymphatics that ultimately drain into the peripheral lymphatics. Impaired CSF outflow has been postulated as a contributing mechanism in Alzheimer’s disease (AD). Herein we conducted near-infrared fluorescence imaging of CSF outflow into the peripheral lymph nodes (LNs) and of peripheral lymphatic function in a transgenic mouse model of AD (5XFAD) and wild-type (WT) littermates. CSF outflow was assessed from change in fluorescence intensity in the submandibular LNs as a function of time following bolus, an intrathecal injection of indocyanine green (ICG). Peripheral lymphatic function was measured by assessing lymphangion contractile function in lymphatics draining into the popliteal LN following intradermal ICG injection in the dorsal aspect of the hind paw. The results show 1) significantly impaired CSF outflow into the submandibular LNs of 5XFAD mice and 2) reduced contractile frequency in the peripheral lymphatics as compared to WT mice. Impaired CSF clearance was also evidenced by reduction of fluorescence on ventral surfaces of extracted brains of 5XFAD mice at euthanasia. These results support the hypothesis that lymphatic congestion caused by reduced peripheral lymphatic function could limit CSF outflow and may contribute to the cause and/or progression of AD.