Journal of Alzheimer's Disease - Volume 57, issue 1

Authors: Hane, Francis T. | Lee, Brenda Y. | Leonenko, Zoya

Article Type: Review Article

Abstract: The field of Alzheimer’s disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer ’s Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet …comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the “hottest” fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, pathology, reviews amyloid-β, tau, prions, brain structure, and functional changes with AD and the neuroimmune response of AD. Show more

Keywords: Aggregation, Alzheimer’s disease, amyloid, brain structure, connectome, neuroinflammation, pathology, prion, signaling, tau

DOI: 10.3233/JAD-160882

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 1-28, 2017

Authors: Li, Wei | Huang, Edgar | Gao, Sujuan

Article Type: Review Article

Abstract: Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving …only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia. Show more

Keywords: Cognitive impairments, diabetic ketoacidosis, microangiopathy, severe hypoglycemia, type 1 diabetes mellitus

DOI: 10.3233/JAD-161250

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 29-36, 2017

Authors: Balietti, Marta | Giuli, Cinzia | Fattoretti, Patrizia | Fabbietti, Paolo | Papa, Roberta | Postacchini, Demetrio | Conti, Fiorenzo

Article Type: Short Communication

Abstract: A comprehensive intervention (CI) on patients with Alzheimer’s disease was assessed by measuring plasmabrain-derived neurotrophic factor (pBDNF) and ADAS-Cog score (ADAS-Cogscore ) before, immediately after (FU1), and 6 (FU2) and 24 months (FU3) after the CI. Baseline pBDNF was higher in patients with moderate AD (but not mild AD) than in healthy controls. At FU1, pBDNF and ADAS-Cogscore decreased significantly. At FU2 and FU3, patients’ cognitive status worsened and pBDNF further increased versus baseline, suggesting that CI interruption may be a stress event that prevents return to homeostasis. CI exerted positive short-term effects, but more information is needed on long-term consequences.

Keywords: Alzheimer disease, comprehensive intervention, brain-derived neurotrophic factor, plasma, time

DOI: 10.3233/JAD-161168

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 37-43, 2017

Authors: Isserles, Moshe | Daskalakis, Zafiris J. | Kumar, Sanjeev | Rajji, Tarek K. | Blumberger, Daniel M.

Article Type: Research Article

Abstract: Background: Dementia frequently presents with aggression, agitation, and disorganized behavior for which current treatment is partially effective and is associated with significant adverse effects. Objective: The aim of this study was to retrospectively assess the clinical effectiveness and tolerability of electroconvulsive therapy (ECT) in a sample of patients with neuropsychiatric symptoms of dementia (NPS) and to explore factors associated with response and with cognitive adverse effects. Methods: We examined the clinical records of 25 patients with dementia and a pre-existing psychiatric disorder treated with ECT at an academic mental health hospital between April 1, 2010 …and January 28, 2016. Twenty-nine acute ECT courses and fifteen maintenance courses were reviewed. We assessed treatment effectiveness and cognitive adverse effects as well as factors associated with response to treatment, including pre-existing psychiatric disorders, concomitant pharmacological treatment and types of dementia. Results: ECT resulted in a clinically meaningful response in 72% of acute treatment courses. Cognitive adverse effects affecting functioning were reported in 7% of the acute treatment courses. Maintenance treatment was effective in sustaining the response in 87% of treatment courses with two reports of significant cognitive adverse effects. One patient fell and experienced a hip fracture a day after treatment. Use of antipsychotic or antidepressant medications, pre-existing psychiatric disorder, or gender were not associated with response. Conclusion: This study shows meaningful clinical effectiveness and good tolerability of ECT in patients with severe NPS of dementia. Furthermore, maintenance ECT was effective in sustaining treatment response. Show more

Keywords: Alzheimer’s disease, dementia, electroconvulsive therapy, neuropsychiatric symptoms

DOI: 10.3233/JAD-161000

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 45-51, 2017

Authors: Sanin, G¨nter | Benke, Thomas

Article Type: Research Article

Abstract: Background/objective: Unimanual gesture production or imitation has often been studied in Alzheimer’s disease (AD) during apraxia testing. In the present study, it was hypothesized that bimanual motor tasks may be a sensitive method to detect impairments of motor cognition in AD due to increased demands on the cognitive system. Methods: We investigated bimanual, meaningless gesture imitation in 45 AD outpatients, 38 subjects with mild cognitive impairment (MCI), and 50 normal controls (NC) attending a memory clinic. Participants performed neuropsychological background testing and three tasks: the Interlocking Finger Test (ILF), Imitation of Alternating Hand Movements (AHM), and Bimanual …Rhythm Tapping (BRT). Results: The tasks were short and easy to administer. Inter-rater reliability was high across all three tests. AD patients performed significantly poorer than NC and MCI participants; a deficit to imitate bimanual gestures was rarely found in MCI and NC participants. Sensitivity to detect AD ranged from 0.5 and 0.7, specificity beyond 0.9. ROC analyses revealed good diagnostic accuracy (0.77 to 0.92). Impairment to imitate bimanual gestures was mainly predicted by diagnosis and disease severity. Conclusion: Our findings suggest that an impairment to imitate bimanual, meaningless gestures is a valid disease marker of mild to moderate AD and can easily be assessed in memory clinic settings. Based on our preliminary findings, it appears to be a separate impairment which can be distinguished from other cognitive deficits. Show more

Keywords: Alzheimer’s disease, Bimanual gesture imitation

DOI: 10.3233/JAD-160680

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 53-59, 2017

Authors: Fenoll, Raquel | Pujol, Jesus | Esteba-Castillo, Susanna | de Sola, Susana | Ribas-Vidal, Núria | García-Alba, Javier | Sánchez-Benavides, Gonzalo | Martínez-Vilavella, Gerard | Deus, Joan | Dierssen, Mara | Novell-Alsina, Ramón | de la Torre, Rafael

Article Type: Research Article

Abstract: Background: Neural tissue alterations in Down syndrome are fully expressed at relatively late developmental stages. In addition, there is an early presence of neurodegenerative changes in the late life stages. Objective: The aims of this study were both to characterize white matter abnormalities in the brain of adult Down syndrome patients using diffusion tensor imaging (DTI) and to investigate whether degenerative alterations in white matter structure are detectable before dementia is clinically evident. Methods: Forty-five adult non-demented Down syndrome patients showing a wide age range (18–52 years) and a matched 45-subject control group were assessed. …DTI fractional anisotropy (FA) brain maps were generated and selected cognitive tests were administered. Results: Compared with healthy controls, non-demented Down syndrome patients showed lower DTI FA in white matter involving the major pathways, but with more severe alterations in the frontal-subcortical circuits. White matter FA decreased with age at a similar rate in both DS and control groups. Conclusions: Our results contribute to characterizing the expression of white matter structural alterations in adult Down syndrome. However, an accelerated aging effect was not demonstrated, which may suggest that the FA measurements used are not sufficiently sensitive or, alternatively, age-related white matter neurodegeneration is not obvious prior to overt clinical dementia. Show more

Keywords: Accelerated aging, diffusion tensor imaging, magnetic resonance imaging, neurodegeneration

DOI: 10.3233/JAD-161112

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 61-70, 2017

Authors: Monroe, Todd B. | Beach, Paul A. | Bruehl, Stephen P. | Dietrich, Mary S. | Rogers, Baxter P. | Gore, John C. | Atalla, Sebastian W. | Cowan, Ronald L.

Article Type: Research Article

Abstract: Background: It is currently unknown why people with Alzheimer’s disease (AD) receive less pain medication and report pain less frequently. Objective: The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures. Methods: Controls (n  = 23, 13 = female) and age-matched people with AD (n  = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated …in sensory and affective dimensions of pain, descending pain modulation, and the default mode network. Results: People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only. Conclusions: While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration. Show more

Keywords: Acute pain, Alzheimer’s disease, brain mapping, dementia, experimental thermal pain, functional connectivity, neurobiology, neuroimaging, pain perception, pain threshold, psychophysics

DOI: 10.3233/JAD-161187

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 71-83, 2017

Authors: Satoh, Masayuki | Ogawa, Jun-ichi | Tokita, Tomoko | Nakaguchi, Noriko | Nakao, Koji | Kida, Hirotaka | Tomimoto, Hidekazu

Article Type: Research Article

Abstract: Background: Recent studies suggest that combined non-pharmacological interventions are more beneficial than single interventions for primary and secondary prevention of dementia. We previously reported enhanced effects of physical exercise with music (ExM) on cognitive function in normal elderly people compared to exercise alone. Objective: To identify if ExM improves cognitive function and activities of daily livings (ADLs) in dementia patients over cognitive stimulation (CS). Methods: We enrolled 85 patients with mild to moderate dementia. Forty-three subjects performed ExM developed by the Yamaha Music Foundation, and 42 subjects performed cognitive stimulation using portable game consoles and …drills involving easy calculations, mazes, and mistake-searching in pictures. Interventions were performed once a week for 40 minutes. Before and after the six-month intervention, patients were assessed using neuropsychological batteries, and ADLs were assessed by patients’ caregivers using the functional independence measure (FIM). Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) was used to assess medial temporal lobe atrophy. Results: Twenty-three subjects dropped out during the intervention. Thirty-one patients from each group were analyzed. Post-intervention, both groups showed significantly improved visuospatial function. Significant benefits were observed in psychomotor speed or memory in the ExM or CS groups, respectively. FIM scores, reflecting ADLs, and VSRAD scores were significantly preserved in the ExM group, but significantly worsened in the CS group. Conclusions: ExM produced greater positive effects on cognitive function and ADLs in patients with mild to moderate dementia than CS, excluding memory. Optimal interventions for dementia will likely be achieved by combining ExMand CS. Show more

Keywords: Activities of daily living, functional independence measure, neuropsychological assessments, physical exercise with music, psychomotor speed, Voxel-based specific regional analysis system for Alzheimer’s disease

DOI: 10.3233/JAD-161217

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 85-96, 2017

Authors: Lambracht-Washington, Doris | Fu, Min | Wight-Carter, Mary | Riegel, Matthew | Rosenberg, Roger N.

Article Type: Research Article

Abstract: A pathological hallmark of Alzheimer’s disease (AD) are amyloid plaques in the brain consisting of aggregated amyloid-β 42 peptide (Aβ42 ) derived from cellular amyloid-β protein precursor (AβPP). Based on successful experiments in mouse AD models, active immunization with Aβ42 peptide and passive immunizations with anti-Aβ42 antibodies were started in clinical trials. Active Aβ42 peptide immunization in humans had led to an inflammatory autoimmune response, and the trial was stopped. Passive immunizations had shown some effects in slowing AD pathology. Active DNA Aβ42 immunizations administered with the gene gun into the skin elicits a different immune …response and is non-inflammatory. While in rodents, good responses had been found for this type of immunization, positive results in larger mammals are missing. We present here results from sixteen New Zealand White Rabbits, which underwent intradermal DNA Aβ42 immunization via gene gun. The humoral immune response was analyzed from blood throughout the study, and cellular immune responses were determined from spleens at the end of the study. A good anti-Aβ antibody response was found in the rabbit model. The T cell response after re-stimulation in cell culture showed no IFNγ producing cells when ELISPOT assays were analyzed from PBMC, but low numbers of IFNγ and IL-17 producing cells were found in ELISPOTS from spleens (both 5 immunizations). Brains from immunized rabbits showed no signs of encephalitis. Based on these results, DNA Aβ42 immunization is highly likely to be safe and effective to test in a possible clinical AD prevention trial in patients. Show more

Keywords: Alzheimer’s disease, amyloid-β, antibody response, DNA vaccination, immunotherapy, Th2 immune response

DOI: 10.3233/JAD-160947

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 97-112, 2017

Authors: Kishi, Taro | Matsunaga, Shinji | Iwata, Nakao

Article Type: Research Article

Abstract: We conducted a systematic review and meta-analysis on whether memantine was beneficial for the treatment of depressive symptoms in major depressive disorder (MDD) and bipolar disorder (BD). The analysis included double-blind, randomized, placebo-controlled trials of memantine in MDD and BD. The primary outcome measures for efficacy and safety were response rate and all-cause discontinuation, respectively. Risk ratio (RR) and standardized mean difference with 95% confidence intervals (95% CI) were calculated. We identified six trials including 451 patients: MDD, four trials (n  = 189), three of which studied memantine augmentation for antidepressants; BD, two trials (n  = 262), both on memantine augmentation for …mood stabilizers. The mean study duration was 8.33 weeks, and the mean age of patients was 39.9 years. Memantine was not superior to placebo with regard to response rate (RR = 0.92, 95% CI = 0.70–1.20, I2  = 72%), remission rate, improvement of depressive symptoms scale score, all-cause discontinuation (RR = 0.84, 95% CI = 0.60–1.18, I2  = 0%), discontinuation due to inefficacy and adverse events, or incidence of individual adverse events including decreased appetite, dizziness, nausea, and sedation. Although we conducted sensitivity analyses of the response rate to determine the reasons for the heterogeneity (diagnosis, age of patients, memantine dose, memantine augmentation, geographical region, and statistical population), we did not seek confounding factors. Memantine did not improve the treatment efficacy for depressive symptoms in MDD and BD patients. Long-term study of memantine for depression is required. Show more

Keywords: Bipolar disorder, major depressive disorder, memantine, meta-analysis, systematic review

DOI: 10.3233/JAD-161251

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 113-121, 2017

Authors: O’Caoimh, Rónán | Gao, Yang | Svendovski, Anton | Gallagher, Paul | Eustace, Joseph | Molloy, D. William

Article Type: Research Article

Abstract: Background: Although required to improve the usability of cognitive screening instruments (CSIs), the use of cut-off scores is controversial yet poorly researched. Objective: To explore cut-off scores for two short CSIs: the Standardized Mini-Mental State Examination (SMMSE) and Quick Mild Cognitive Impairment (Qmci ) screen, describing adjustments in scores for diagnosis (MCI or dementia), age (≤, >75 years), and education (<, ≥12 years), comparing two methods: the maximal accuracy approach, derived from receiver operating characteristic curves, and Youden’s Index. Methods: Pooled analysis of assessments from patients attending memory clinics in Canada between 1999–2010 : 766 with mild …cognitive impairment (MCI) and 1,746 with dementia, and 875 normal controls. Results: The Qmci was more accurate than the SMMSE in differentiating controls from MCI or cognitive impairment (MCI and dementia). Employing the maximal accuracy approach, the optimal SMMSE cut-off for cognitive impairment was <28/30 (AUC 0.86, sensitivity 74%, specificity 88%) versus <63/100 for the Qmci (AUC 0.93, sensitivity 85%, specificity 85%). Using Youden’s Index, the optimal SMMSE cut-off remained <28/30 but fell slightly to <62/100 for the Qmci (sensitivity 83%, specificity 87%). The optimal cut-off for MCI was <29/30 for the SMMSE and <67/100 for the Qmci , irrespective of technique. The maximal accuracy approach generally produced higher Qmci cut-offs than Youden’s Index, both requiring adjustment for age and education. There were no clinically meaningful differences in SMMSE cut-off scores by age and education or method employed. Conclusion: Caution should be exercised selecting cut-offs as these differ by age, education, and method of derivation, with the extent of adjustment varying between CSIs. Show more

Keywords: Cognitive screening, cut-offs, dementia, mild cognitive impairment, Quick Mild Cognitive Impairment screen, Standardized Mini-Mental State Examination

DOI: 10.3233/JAD-161204

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 123-133, 2017

Authors: Mehta, Pankaj D. | Blain, Jean-Francois | Freeman, Emily A. | Patrick, Bruce A. | Barshatzky, Marc | Hrdlicka, Lori A. | Mehta, Sangita P. | Frackowiak, Janusz | Mazur-Kolecka, Bozena | Wegiel, Jerzy | Patzke, Holger | Miller, David L.

Article Type: Research Article

Abstract: Secreted soluble amyloid-β 1–37 (Aβ37 ) peptide is one of the prominent Aβ forms next to Aβ40 , and is found in cerebrospinal fluid (CSF) and blood. Recent studies have shown the importance of quantitation of CSF Aβ37 levels in combination with Aβ38 , Aβ40 , and Aβ42 to support the diagnosis of patients with probable Alzheimer’s disease (AD), and the value of antibody to Aβ37 to facilitate drug discovery studies. However, the availability of reliable and specific monoclonal antibody to Aβ37 is very limited. Our aims were: 1) to generate and partially characterize rabbit monoclonal …antibody (RabmAb) to Aβ37 , and 2) to determine whether the antibody detects changes in Aβ37 levels produced by a γ -secretase modulator (GSM). Our generated RabmAb to Aβ37 was found to be specific to Aβ37 , since it did not react with Aβ36 , Aβ38 , Aβ39 , Aβ40 , and Aβ42 in an ELISA or immunoblotting. The epitope of the antibody was contained in the seven C-terminal residues of Aβ37 . The antibody was sensitive enough to measure CSF and plasma Aβ37 levels in ELISA. Immunohistological studies showed the presence of Aβ37 -positive deposits in the brain of AD, and Down syndrome persons diagnosed with AD. Our studies also showed that the antibody detected Aβ37 increases in CSF and brains of rodents following treatment with a GSM. Thus, our antibody can be widely applied to AD research, and in a panel based approach it may have potential to support the diagnosis of probable AD, and in testing the effect of GSMs to target AD. Show more

Keywords: Alzheimer disease, amyloid-β peptide, Down syndrome, ELISA, immunoblotting, immunohistochemistry, rabbit monoclonal antibodies to Aβ37

DOI: 10.3233/JAD-161207

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 135-145, 2017

Authors: Rouch, Isabelle | Pongan, Elodie | Trombert, Béatrice | Fabre, Florence | Auguste, Nicolas | Sellier, Claire | Freulon, Magalie | Jacqueline, Sophie | Federico, Denis | Mouchoux, Christelle | Martin-Gaujard, Géraldine | Krolak-Salmon, Pierre | Laurent, Bernard | Dorey, Jean-Michel

Article Type: Research Article

Abstract: Background: The 2008–2012 French Alzheimer’s Plan has provided hospital Cognitive and Behavioral Units (CBU) to improve the management of patients with productive behavioral and psychological symptoms of dementia (BPSD). Little is known concerning the behavioral outcome of these patients after discharge. Objective: The present study investigated the long-term evolution of BPSD over one year after CBU discharge. Methods: The EVITAL cohort included 221 participants admitted to the CBUs of 3 French hospitals. BPSD were collected using the Neuropsychiatric Inventory (NPI) at admission and 3, 6, and 12 months after hospitalization. The global NPI score evolution …was assessed using a linear mixed-effect model. A four-factor model of the NPI including behavioral dyscontrol, psychosis, mood, and agitation subscores was also analyzed. Results: Our analysis focused on 148 patients followed up during 12 months and evaluated at each visit. The global NPI score was 48.5 (SD 21.7) at baseline, 28.8 (SD 18.7) at 3-month, 23.2 (SD 16.4) at 6-month and 20.9 (SD 15.9) at 12-month follow-up. The score significantly decreased from baseline to follow-up (F = 109.3 p  < 0.0001). Moreover, the decrease was observed for each NPI subscores. The Clinical Dementia Rating (CDR) scale score was significantly linked to the baseline NPI score (t  = 2.76, p  = 0.009). Conversely, the NPI decline was observed whatever the CDR level. Conclusion: The present study showed a decrease in the global NPI score and all its subscores during the year following the CBU hospitalization, regardless of the initial CDR score. Show more

Keywords: Alzheimer’s disease, behavioral disorders, BPSD, dementia, longitudinal study

DOI: 10.3233/JAD-161023

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 147-155, 2017

Authors: Yang, Jing | Zhang, Rui | Shi, Changhe | Mao, Chengyuan | Yang, Zhihua | Suo, Zhenhe | Torp, Reidun | Xu, Yuming

Article Type: Research Article

Abstract: Amyloid-β deposition in senile plaques is one of the main pathological changes in Alzheimer’s disease (AD). We previously reported that aquaporin-4 (AQP4) is redistributed within the astrocytes in cerebral amyloid angiopathy in the tg-ArcSwe mouse model of AD, suggesting that AQP4 may participate in amyloid-β deposition. However, the role of AQP4 in plaque formation is not currently clear. The objective of the current study was to explore the AQP4 distribution within plaques in the tg-ArcSwe mice in more depth by the combined application of immunofluorescence cytochemistry and immunogold electron microscopy. In addition, the astrocyte marker, glial fibrillary acidic protein (GFAP), …was studied in association with AQP4. We demonstrated a robust upregulation of AQP4 expression in areas of plaques. Compared to GFAP, AQP4 appeared predominantly at later stages of plaque formation, in older mice, and within the processes of astrocytes. In combination with GFAP, AQP4 differentiated plaques into three progression stages under light microscopy. This suggests that AQP4 expression was associated with amyloid deposition and astrocyte pathology in the Tg-ArcSwe mouse model of AD. This provides novel proof for the involvement of AQP4 in the process of amyloid deposition in AD. Show more

Keywords: Alzheimer’s disease, aquaporin 4, astrocyte, glial fibrillary acidic protein, senile plaques

DOI: 10.3233/JAD-160957

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 157-169, 2017

Authors: Yamazaki, Kiyohiro | Yoshino, Yuta | Mori, Takaaki | Yoshida, Taku | Ozaki, Yuki | Sao, Tomoko | Mori, Yoko | Ochi, Shinichiro | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background/Objective: The aim of this study was to examine the blood gene expression and methylation of ATP-binding cassette sub-family A member 7 gene (ABCA7) as a biological marker of AD. Methods: AD subjects (n  = 50; 11 males, 77.7±6.05 years old) and age- and sex-matched healthy controls (n  = 50) were recruited. A single nucleotide polymorphism in ABCA7 (rs3764650), methylation rates of CpG sites in the ABCA7 promoter region, and ABCA7 mRNA expression levels in peripheral blood were examined. Results: The distribution of the rs3764650 polymorphism in AD subjects was not different from that of controls. Although …the methylation rates of AD subjects were not significantly different from those of controls, the ABCA7 mRNA expression level in AD subjects was significantly higher than that in controls. Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimer’s Disease Assessment Scale total score, and the Clinical Dementia Rating score. We also found a significant correlation between the ABCA7 mRNA expression level and duration of illness. Conclusion: The ABCA7 mRNA expression level in peripheral blood may be a marker for early stages of AD and disease progression regardless of rs3764650 and the methylation rate of its promoter. Show more

Keywords: Alzheimer’s disease, ATP-binding cassette sub-family A member 7 gene, epigenetics, mRNA, single nucleotide polymorphism

DOI: 10.3233/JAD-161195

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 171-181, 2017

Authors: Cardoso, Bárbara R. | Hare, Dominic J. | Bush, Ashley I. | Li, Qiao-Xin | Fowler, Christopher J. | Masters, Colin L. | Martins, Ralph N. | Ganio, Katherine | Lothian, Amber | Mukherjee, Soumya | Kapp, Eugene A. | Roberts, Blaine R. | The AIBL research group

Article Type: Research Article

Abstract: Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer’s disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry …to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete. Show more

Keywords: Alzheimer’s disease, cognition, selenium, selenocysteine, selenoproteins

DOI: 10.3233/JAD-160622

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 183-193, 2017

Authors: Meyer, Michelle L. | Palta, Priya | Tanaka, Hirofumi | Deal, Jennifer A. | Wright, Jacqueline | Knopman, David S. | Griswold, Michael E. | Mosley, Thomas H. | Heiss, Gerardo

Article Type: Research Article

Abstract: Background: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. Objective: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. Methods: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI …and dementia versus no cognitive impairment. Results: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. Conclusion: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults. Show more

Keywords: Alzheimer’s disease, brain, cognition, dementia, mild cognitive impairment, pulse wave velocity

DOI: 10.3233/JAD-161041

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 195-204, 2017

Authors: Salgado-Puga, Karla | Rodríguez-Colorado, Javier | Prado-Alcalá, Roberto A. | Peña-Ortega, Fernando

Article Type: Research Article

Abstract: In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP ) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer’s disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., …inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD. Show more

Keywords: Amyloid-β protein, burrowing, hippocampal population activity, learning and memory, long-term depression, long-term potentiation, sulphonylurea

DOI: 10.3233/JAD-160543

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 205-226, 2017

Authors: Wang, Jianhui | Liu, Yang | Cheng, Xiaorui | Zhang, Xiaorui | Liu, Feng | Liu, Gang | Qiao, Shanyi | Ni, Ming | Zhou, Wenxia | Zhang, Yongxiang | Li, Fei

Article Type: Research Article

Abstract: The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a robust experimental model for developing preventative and therapeutic treatments for Alzheimer’s disease (AD), a neurodegenerative disease which cannot be effectively prevented, halted, or cured. Our previous studies showed that LW-AFC, a new formula derived from the classical traditional Chinese medicinal prescription Liuwei Dihuang decoction, ameliorates cognitive deterioration in PrP-hAβPPswe/PS1Δ E9 transgenic mice and SAMP8 mice. This study aims to investigate the mechanism that mediates how LW-AFC improves cognitive deficit on the basis of the transcriptome. We conducted a genome-wide survey of gene expression in the hippocampus in mice from …the senescence accelerated mouse resistant 1 (SAMR1) strain, from SAMP8 and from LW-AFC treated SAMP8. The results showed that LW-AFC reversed the transcriptome in the hippocampus of SAMP8 mice. The specific investigation of altered gene expression in subtypes defined by cognitive profiles indicated that the systemic lupus erythematosus pathway, spliceosomes, amyotrophic lateral sclerosis, and the insulin signaling were involved in the improvement of cognitive ability by LW-AFC. The expression of genes Enpp2, Etnk1, Epdr1, and Gm5900 in the hippocampus were correlated with that of LW-AFC’s ameliorating cognitive impairment in SAMP8 mice. Because LW-AFC is composed of polysaccharides, glycosides, and oligosaccharides, we infer that LW-AFC has direct or indirect effects on altering gene expressions and regulating pathways in the hippocampus of SAMP8 mice. These data are helpful for the enhanced identification of LW-AFC as new therapeutic modalities to AD. Show more

Keywords: Alzheimer’s disease, LW-AFC, senescence-accelerated mouse prone 8 strain, traditional Chinese medicine, transcriptome

DOI: 10.3233/JAD-161079

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 227-240, 2017

Authors: Rhea, Elizabeth M. | Humann, Samantha R. | Nirkhe, Surabhi | Farr, Susan A. | Morley, John E. | Banks, William A.

Article Type: Research Article

Abstract: Insulin delivered to the level of the cribriform plate (intranasal insulin) is being investigated for its ability to enhance memory in people with Alzheimer’s disease (AD). Recent work has shown intranasal insulin can be detected in young CD-1 mice within 5 min and is still present 60 min after injection. The current study determined whether intranasal insulin transport and the subsequent brain distribution of insulin varies in young, healthy mice (CD-1) compared to those with an AD-like phenotype (aged SAMP8) or those pre-disposed to develop such a phenotype (young SAMP8). We showed transport does not vary among these three mouse cohorts, suggesting …that intranasal uptake and brain pharmacokinetics do not differ with AD-like signs or the genetic predisposition to developing them. We found that co-administration with bovine serum albumin increased levels of insulin in most brain regions. In addition, the insulin receptor inhibitor, S961, decreases the amount of insulin transported throughout the brain after intranasal injection. These results show insulin delivery to the brain by intranasal administration can be modified with agents such as albumin, may be dependent on the insulin receptor, and is not affected by an AD-like phenotype as presented by the SAMP8 mouse. Show more

Keywords: Alzheimer’s disease, insulin, intranasal administration, pharmacokinetics

DOI: 10.3233/JAD-161095

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 241-252, 2017

Authors: Amen, Daniel G. | Krishnamani, Pavitra | Meysami, Somayeh | Newberg, Andrew | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Depression and cognitive disorders (CDs) are two common co-morbid afflictions that commonly present with overlapping symptoms. Objective: To evaluate if perfusion neuroimaging with brain SPECT can distinguish persons with depression from those with CDs or both conditions. Methods: Inclusion criteria were DSM-IV defined depression or CDs (Alzheimer’s disease, vascular dementia, dementia not otherwise specified, and amnestic disorders not otherwise specified) including persons with both (total n  = 4,541; 847 CDs, 3,269 depression, 425 with both). Perfusion differences between the groups were calculated using two-sampled t -tests corrected for multiple comparisons. Diagnostic separation was determined with …discriminant analysis. Feature selection revealed predictive regions in delineating depression from CDs and comorbid cases. Results: Persons with CDs had lower cerebral perfusion compared to depression. In co-morbid persons, cerebral hypoperfusion was additive, with regions showing lower regional cerebral blood flow compared to either diagnosis alone. Both baseline and concentration SPECT regions yielded correct classification of 86% and leave one out cross-validation of 83%. AUC analysis for SPECT regions showed 86% accuracy, 80% sensitivity and 75% specificity. Discriminant analysis separated depression and CDs from comorbid cases with correct classification of 90.8% and cross validated accuracy of 88.6%. Area under the curve was 83% with sensitivity of 80% and specificity of 70%. Feature selection identified the most predictive regions in left hippocampus, right insula, cerebellar, and frontal lobe regions. Conclusion: Quantitative perfusion SPECT neuroimaging distinguishes depression from dementia and those with both co-morbidities. Perfusion brain SPECT can be utilized clinically to delineate between these two disorders. Show more

Keywords: Dementia, depression, neuroimaging, SPECT

DOI: 10.3233/JAD-161232

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 253-266, 2017

Authors: Nakayama, Sachiko | Suda, Akimitsu | Nakanishi, Atsushi | Motoi, Yumiko | Hattori, Nobutaka

Article Type: Research Article

Abstract: Behavioral and psychological symptoms of dementia (BPSD) occur in up to 80% of AD patients and represent one of the largest factors contributing to caregiver burden. To analyze the effect of galantamine on BPSD and caregiver burden, we treated a total of 50 patients with mild AD for 12 weeks and evaluated them using the Neuropsychiatric Inventory (NPI) and Japanese version of the Zarit Caregiver Burden Interview (ZBI). We also performed regional cerebral blood flow single photon emission computed tomography (rCBF SPECT) at baseline using three-dimensional sterotatic surface projections. Total NPI and ZBI scores did not significantly change after 12-week …galantamine treatment. To identify the characteristics of patients who showed improvement after galantamine treatment, we divided patients into two groups, those with and those without sub-items on the NPI. Patients with aggression showed improvement in ZBI scores (p  < 0.05). A comparison of rCBF SPECT between these two groups indicated that patients with aggression exhibited increased rCBF in the right prefrontal cortex compared with those without aggression. In a patient with aggression, 20-month treatment with galantamine inhibited increases in the rCBF area in the right prefrontal lobe. These results suggest that galantamine response may be related to aggression and dysfunction of the prefrontal cortex. Show more

Keywords: Alzheimer’s disease, agitation, galantamine, prefrontal cortex

DOI: 10.3233/JAD-160902

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 267-273, 2017

Authors: Marioni, Riccardo E. | Campbell, Archie | Hagenaars, Saskia P. | Nagy, Reka | Amador, Carmen | Hayward, Caroline | Porteous, David J. | Visscher, Peter M. | Deary, Ian J.

Article Type: Research Article

Abstract: Stratification by genetic risk factors for Alzheimer’s disease (AD) may help identify groups with the greatest disease risk. Biological changes that cause late-onset AD are likely to occur years, if not decades prior to diagnosis. Here, we select a subset of the Generation Scotland: Scottish Family Health Study cohort in a likely preclinical age-range of 60–70 years (subset n  = 3,495 with cognitive and genetic data). We test for cognitive differences by polygenic risk scores for AD. The polygenic scores are constructed using all available SNPs, excluding those within a 500 kb distance of the APOE locus. Additive and multiplicative effects …of APOE status on these associations are investigated. Small memory decrements were observed in those with high polygenic risk scores for AD (standardized beta –0.04, p  = 0.020). These associations were independent of APOE status. There was no difference in AD polygenic scores across APOE haplotypes (p  = 0.72). Individuals with high compared to low polygenic risk scores for AD (top and bottom 5% of the distribution) show cognitive decrements, albeit much smaller than for APOE ɛ 4ɛ 4 compared to ɛ 3ɛ 3 individuals (2.3 versus 3.5 fewer points on the processing speed test, and 1.8 versus 2.8 fewer points on the memory test). Polygenic risk scores for AD may help identify older individuals at greatest risk of cognitive decline and preclinical AD. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cognitive function, genetics, polygenic traits

DOI: 10.3233/JAD-161070

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 275-283, 2017

Authors: El Haj, Mohamad | Gallouj, Karim | Antoine, Pascal

Article Type: Research Article

Abstract: We investigated whether an external memory aid (i.e., Google Calendar) would alleviate prospective memory compromise in a patient with mild Alzheimer’s disease. The patient was asked in the baseline phase to perform three prospective targeted events (e.g., attending her weekly bridge game at the community club) and three prospective control events (e.g., buying her weekly magazine). The same six prospective events were assessed in the intervention phase but the targeted-events were cued by Google Calendar while the control-events were not. Results showed less omission of the targeted events in the training phase than in the baseline phase, suggesting a positive …effect of Google Calendar. This case report offers a unique view into how smartphone calendars may alleviate prospective memory compromise in patients with mild Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, Google Calendar, prospective memory: rehabilitation, smartphones

DOI: 10.3233/JAD-161283

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 285-291, 2017

Authors: Lindemer, Emily R. | Greve, Douglas N. | Fischl, Bruce | Augustinack, Jean C. | Salat, David H. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: White matter signal abnormalities (WMSA) (also known as ‘hyperintensities’) on MRI are commonly seen in normal aging and increases have been noted in Alzheimer’s disease (AD), but whether there is a spatial specificity to these increases is unknown. Objective: To discern whether or not there is a spatial pattern of WMSA in the brains of individuals with AD that differs from those who exhibit cognitively healthy aging. Method: Structural MRI data from the Alzheimer’s Disease Neuroimaging Initiative public database were used to quantify WMSA in 35 regions of interest (ROIs). Regional measures were compared …between cognitively healthy older controls (OC; n  = 107) and individuals with a clinical diagnosis of AD (n  = 127). Regional WMSA volume was also assessed in individuals with mild cognitive impairment (MCI; n  = 74) who were 6, 12, and 24 months away from AD conversion. Results: WMSA volume was significantly greater in AD compared to OC in 24 out of 35 ROIs after controlling for age, and nine were significantly higher after normalizing for total WMSA. Regions with greater WMSA volume in AD included rostral frontal, inferior temporal, and inferior parietal WM. In MCI, frontal and temporal regions demonstrated significantly greater WMSA volume with decreasing time-to-AD-conversion. Discussion: Individuals with AD have greater regional volume of WMSA compared to OC regardless of age or total WMSA volume. Accumulation of regional WMSA is linked to time to AD conversion in individuals with MCI. These findings indicate WMSA is an important pathological component of AD development. Show more

Keywords: Aging, Alzheimer’s disease, cerebrovascular, hyperintensities, magnetic resonance imaging, mild cognitive impairment, white matter

DOI: 10.3233/JAD-161057

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 293-303, 2017

Authors: Zhu, Carolyn W. | Cosentino, Stephanie | Ornstein, Katherine A. | Gu, Yian | Andrews, Howard | Stern, Yaakov

Article Type: Research Article

Abstract: Background: Few studies have examined how dementia and comorbidities may interact to affect healthcare expenditures. Objective: To examine whether effects of dementia severity on Medicare expenditures differed for individuals with different levels of comorbidities. Methods: Data are drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP). Comprehensive clinical assessments of dementia severity were systematically carried out at ∼18 month intervals. Dementia severity was measured by Clinical Dementia Rating (CDR). Comorbidities were measured by a modified Elixhauser comorbidities index. Generalized linear models examined effects of dementia severity, comorbidities, and their interactions on Medicare expenditures (1999–2010). …Results: At baseline, 1,280 subjects were dementia free (CDR = 0, 66.4%), 490 had very mild dementia (CDR = 0.5, 25.4%), 108 had mild dementia (CDR = 1, 5.6%), and 49 had moderate/severe dementia (CDR = 2/3, 2.5%). Average annual Medicare expenditures for individuals with moderate/severe dementia were more than twice as high as those who were dementia free (CDR = 0: $9,108, CDR = 0.5/1: $11,664, CDR≥2: $19,604, p  < 0.01). Expenditures were approximately 10 times higher among those with≥3 comorbidities than among those with no comorbidities ($2,612 for those with no comorbidities, to $6,109 for those with 1, $10,656 for those with 2, and $30,244 for those with≥3 comorbidities, p  < 0.001). Dementia severity was associated with higher expenditures, but comorbidities were the most important predictor of expenditures. We did not find strong interaction effects between number of comorbidities and dementia severity. Conclusions: Increasing dementia severity and higher comorbidities are associated with higher Medicare expenditures. Care of individuals with dementia should focus on management of comorbidities. Show more

Keywords: Health expenditure, Medicare, economics, comorbidities, longitudinal analysis

DOI: 10.3233/JAD-161077

Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 305-315, 2017