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