Journal of Alzheimer's Disease - Volume 54, issue 3

Authors: McGeer, Patrick L. | Rogers, Joseph | McGeer, Edith G.

Article Type: Review Article

Abstract: Two basic discoveries spurred research into inflammation as a driving force in the pathogenesis of Alzheimer’s disease (AD). The first was the identification of activated microglia in association with the lesions. The second was the discovery that rheumatoid arthritics, who regularly consume anti-inflammatory agents, were relatively spared from the disease. These findings led to an exploration of the inflammatory pathways that were involved in AD pathogenesis. A pivotal advance was the discovery that amyloid-β protein (Aβ) activated the complement system. This focused attention on anti-inflammatories as blockers of complement activation. More than 15 epidemiological studies have since showed a sparing …effect of non-steroidal anti-inflammatory drugs (NSAIDs) in AD. A consistent finding has been that the longer the NSAIDs were used prior to clinical diagnosis, the greater the sparing effect. The reason has since emerged from studies of biomarkers such as amyloid-β (Aβ) levels in the cerebrospinal fluid and Aβ deposits in brain. They have established that the onset of AD commences at least a decade before cognitive decline permits clinical diagnosis. Such biomarker studies have revealed that a huge window of opportunity exists when application of NSAIDs, other anti-inflammatory agents, or complement activation blockers, could arrest further progress of AD, thus eliminating its manifestation. It can be anticipated that this principle will apply to many other chronic neurodegenerative diseases. Neuroinflammation, discovered in AD more than 30 years ago, has now become a major field of brain research today. Inhibiting it may be the key to successful treatment of many chronic neurological disorders. Show more

Keywords: Biomarkers, complement, immunohistochemistry, membrane attack complex, NSAID, reactive microglia

DOI: 10.3233/JAD-160488

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 853-857, 2016

Authors: Bourgade, Karine | Dupuis, Gilles | Frost, Eric H. | Fülöp Jr., Tamàs

Article Type: Review Article

Abstract: Amyloid-β (Aβ) peptides generated by the amyloidogenic pathway of amyloid-β protein precursor processing contribute significantly to neurodegeneration characteristic of Alzheimer’s disease (AD). The involvement of Aβ peptides in the etiology of AD remains a subject of debate. Data published in the last 6 years by three different groups have added a new twist by revealing that Aβ peptides could act as antimicrobial peptides (AMP) in in vitro assays against some common and clinically relevant microorganisms, inhibit replication of seasonal and pandemic strains of influenza A and HSV-1 virus. These observations are of significance with respect to the notion that …pathogens may be important contributors to the development of AD, particularly in the case of herpes simplex virus (HSV) infection, which often resides in the same cerebral sites where AD arises. Here, we review the data that support the interpretation that Aβ peptides behave as AMP, with an emphasis on studies concerning HSV-1 and a putative molecular mechanism that suggests that interactions between Aβ peptides and the HSV-1 fusogenic protein gB lead to impairment of HSV-1 infectivity by preventing the virus from fusing with the plasma membrane. A number of avenues for future research are suggested. Show more

Keywords: Alzheimer’s disease, amyloid-beta peptides, antimicrobial peptides, antiviral activity, cocultures, glycoprotein B, herpes simplex virus, influenza virus, membrane proximal region

DOI: 10.3233/JAD-160517

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 859-878, 2016

Authors: Kang, Jae Myeong | Yeon, Byeong Kil | Cho, Seong-Jin | Suh, Yoo-Hun

Article Type: Review Article

Abstract: Stem cell therapy has been noted to be a disease-modifying treatment for Alzheimer’s disease (AD). After the failure to develop new drugs for AD, the number of studies on stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), has increased from the early 2000 s. Issues pertaining to stem cells have been investigated in many animal studies in terms of stem cell origin, differentiation potency, method of culture, tumor formation, injection route, and mobility. Since 2010, mainly in East Asia, researchers began clinical trials investigating the use of stem cells for AD. Two phase I trials on …moderate AD have been completed; though they revealed no severe acute or long-term side effects, no significant clinical efficacy was observed. Several studies, which involve more sophisticated study designs using different injection routes, well-established scales, and biomarkers such as amyloid positron emission tomography, are planned for mild to moderate AD patients. Here, we review the concept of stem cell therapy for AD and the progress of recent clinical trials. Show more

Keywords: Alzheimer’s disease, clinical trial, mesenchymal stem cell transplantation, stem cell

DOI: 10.3233/JAD-160406

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 879-889, 2016

Authors: Kuruppu, Sanjaya | Rajapakse, Niwanthi W. | Spicer, Alexander J. | Parkington, Helena C. | Smith, A. Ian

Article Type: Research Article

Abstract: Alzheimer’s disease is a debilitating neurological disease placing significant burden on health care budgets around the world. It is widely believed that accumulation of amyloid-beta (Aβ) in the brain is a key event that initiates neurodegeneration, thus the clearance of Aβ from brain could be a key therapeutic strategy. Aβ exists in an equilibrium in healthy individuals, and recent research would suggest that dysfunction in the clearance pathways is the driving force behind its accumulation. One mechanism of clearance is proteolytic degradation by enzymes, and increasing the expression of these enzymes in animal models of Alzheimer’s disease has indeed shown …promising results. This approach could be challenging to translate into the clinic given the likely need for genetic manipulation. We hypothesize that stimulating the activity of these enzymes (as opposed to increasing expression) through pharmacological agents will enhance degradation or at least prevent amyloid deposition, and is therefore another potentially novel avenue to manipulate Aβ levels for therapeutic purposes. We discuss the recent research supporting this hypothesis as well as possible drawbacks to this approach. Show more

Keywords: Alzheimer’s disease, amyloid-beta, enzymes, peptides

DOI: 10.3233/JAD-160492

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 891-895, 2016

Authors: Villarreal, Alcibiades E. | Grajales, Shantal | O’Bryant, Sid E. | Edwards, Melissa | López, Lineth | Montalván, Astevia | Britton, Gabrielle B. | for the Panama Aging Research Initiative (PARI)

Article Type: Short Communication

Abstract: Research on age-related cognitive impairment is scarce in Central America. We report factors associated with cognitive impairment among a sample of older adults in Panama diagnosed with Alzheimer’s disease (AD, n  = 31), mild cognitive impairment (MCI, n  = 43), or no cognitive impairment (controls, n  = 185). Apolipoprotein E (ApoE) genotype was assessed in a subset of cases (n  = 135). Age (OR = 2.53, 95% CI = 1.03–6.17) and ApoE ɛ 4 (OR = 5.14, 95% CI = 2.11–12.52) were significantly related to cognitive impairment (AD/MCI combined). Results underscore the potential of genetic screening in Panama for identifying those at risk of dementia.

Keywords: Aging, Alzheimer’s disease, apolipoprotein E, cognition, dementia, Latin America, mild cognitive impairment

DOI: 10.3233/JAD-160402

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 897-901, 2016

Authors: Aso, Ester | Andrés-Benito, Pol | Ferrer, Isidro

Article Type: Research Article

Abstract: Previous reports have demonstrated that the combination of Δ9 -tetrahydrocannabinol (Δ9 -THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimer-like phenotype of AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in AβPP/PS1 mice at advanced stages of the disease but are not effective in modifying the Aβ processing or in reducing the glial reactivity associated with aberrant Aβ deposition as occurs when administered at early stages of the disease. The present study …also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice. The positive effects induced by Δ9 -THC and CBD in aged AβPP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Rα1 in cannabinoid-treated animals when compared with animals treated with vehicle alone. Show more

Keywords: Advanced stages, Alzheimer’s disease, cannabidiol, Δ9-tetrahydrocannabinol, dementia

DOI: 10.3233/JAD-160533

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 903-912, 2016

Authors: De Beaumont, Louis | Pelleieux, Sandra | Lamarre-Théroux, Louise | Dea, Doris | Poirier, Judes | the Alzheimer’s Disease Cooperative Study

Article Type: Research Article

Abstract: Background: Genetic heterogeneity in amnestic mild cognitively impaired (aMCI) subjects could lead to variations in progression rates and response to cholinomimetic agents. Together with the apolipoprotein E4 (APOE -ɛ4) gene, butyrylcholinesterase (BCHE ) has become recently one of the few Alzheimer’s disease (AD) susceptibility genes with distinct pharmacogenomic properties. Objective: To validate candidate genes (APOE/BCHE ) which display associations with age of onset of AD and donepezil efficacy in aMCI subjects. Methods: Using the Petersen et al. (2005) study on vitamin E and donepezil efficacy in aMCI, we contrasted the effects of BCHE and …APOE variants on donepezil drug response using the Alzheimer’s Disease Assessment Score-Cognition (ADAS-Cog) scale. Independently, we assessed the effects of APOE/BCHE genotypes on age of onset and cortical choline acetyltransferase activity in autopsy-confirmed AD and age-matched control subjects. Results: Statistical analyses revealed a significant earlier age of onset in AD for APOE- ɛ4, BCHE -K* , and APOE- ɛ4/BCHE-K* carriers. Among the carriers of APOE- ɛ4 and BCHE -K* , the benefit of donepezil was evident at the end of the three-year follow-up. The responder’s pharmacogenomic profile is consistent with reduced brain cholinergic activity measured in APOE- ɛ4 and BCHE -K* positive subjects. Conclusions: APOE- ɛ4 and BCHE -K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, butyrylcholinesterase variant, choline acetyltransferase activity, mild cognitive impairment, pharmacogenomics∥

DOI: 10.3233/JAD-160373

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 913-922, 2016

Authors: Heath, Matthew | Weiler, Jeffrey | Gregory, Michael A. | Gill, Dawn P. | Petrella, Robert J.

Article Type: Research Article

Abstract: Persons with an objective cognitive impairment (OCI) are at increased risk for progression to Alzheimer’s disease and related dementias. The present pilot project sought to examine whether participation in a long-term exercise program involving cognitive-motor (CM) dual-task gait training and aerobic exercise training improves executive function in persons with an OCI. To accomplish our objective, individuals with an OCI (n  = 12) as determined by a Montreal Cognitive Assessment (MoCA) score of less than 26 and older adults (n  = 11) deemed to be cognitively healthy (i.e., control group: MoCA score ≥26) completed a six-month moderate-to-high intensity (65–85% maximum heart rate) …treadmill-based CM and aerobic exercise training program wherein pre- and post-intervention executive control was examined via the antisaccade task. Notably, antisaccades require a goal-directed eye-movement mirror-symmetrical to a target and represent an ideal tool for the study of executive deficits because of its hands- and language-free nature. As well, the cortical networks mediating antisaccades represent regions associated with neuropathology in cognitive decline and dementia (e.g., dorsolateral prefrontal cortex). Results showed that antisaccade reaction times for the OCI group reliably decreased by 30 ms from pre- to post-intervention, whereas the control group did not produce a reliable pre- to post-intervention change in reaction time (i.e., 6 ms). Thus, we propose that in persons with OCI long-term CM and aerobic training improves the efficiency and effectiveness of the executive mechanisms mediating high-level oculomotor control. Show more

Keywords: Aerobic exercise, antisaccade, cognitive decline, cognitive-motor training, executive control, objective cognitive impairment

DOI: 10.3233/JAD-160288

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 923-931, 2016

Authors: Seo, Eun Hyun | Kim, Hoowon | Lee, Kun Ho | Choo, IL Han

Article Type: Research Article

Abstract: Background: For the early detection of Alzheimer’s disease (AD), there is increasing interest in pre-mild cognitive impairment (pre-MCI). Objective: We explored the neuropsychological characteristics in a group of pre-MCI and cognitively normal (CN) elderly individuals, with the aim of providing measures sensitive to cognitive change in pre-MCI. Methods: We included 188 CN elderly and 77 individuals with pre-MCI. All participants underwent comprehensive clinical and neuropsychological assessment. We compared 17 cognitive tests between the CN and pre-MCI groups by using one-way ANOVAs with false discovery rate correction for multiple comparisons. Pearson’s correlations were also obtained between …episodic memory and executive function tests in the pre-MCI group. Results: The pre-MCI group showed significantly lower scores for visual immediate recall, fluency tests, and Stroop color naming in the color-word incongruent condition than the CN group (p  < 0.05). Most of these executive function measures were significantly correlated with episodic memory (p  < 0.05). There were no significant group-differences in other tests assessing attention, verbal memory, visuospatial ability, and language. Conclusion: Our findings indicate that poor executive function especially demanding inhibition and goal-directed behaviors within time limit could be the characteristics of the very early cognitive sign in the course of AD. Show more

Keywords: Alzheimer’s disease, early detection, executive function, mild cognitive impairment

DOI: 10.3233/JAD-160052

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 933-940, 2016

Authors: Chapleau, Marianne | Aldebert, Joséphine | Montembeault, Maxime | Brambati, Simona M.

Article Type: Research Article

Abstract: Background/Objectives: Alzheimer’s disease (AD) and semantic dementia (SD) have distinct episodic memory profiles despite the hippocampal atrophy that characterizes both diseases. The aim of this study was to delineate the pattern of gray matter (GM) atrophy associated with AD and SD as well as any differences in these patterns by pooling together the results of previous voxel-based morphometry (VBM) studies. Methods/Overview: We conducted a meta-analysis of VBM studies that investigated GM atrophy in AD patients versus controls (CTRLs) and in SD patients versus CTRLs using the activation likelihood estimation (ALE) approach. Our systematic review allowed us to …identify 63 VBM studies. Results: The results confirmed that in addition to the classical cortical pattern of atrophy involving posterior medial and lateral regions in AD and the anterior lateral temporal lobes in SD, both AD and SD patients are characterized by bilateral atrophy of the hippocampus. Furthermore, in SD, the hippocampal atrophy was limited to the anterior portion of the hippocampus, while in AD, both the anterior and posterior parts of the hippocampus exhibited atrophy. When we compared the foci identified in the studies that compared AD patients versus CTRLs with those identified in the studies that compared SD patients versus CTRLs, we observed that the atrophy in the posterior hippocampus and precuneus was more severe in AD. Conclusion: These results support theories that propose that the deficits observed in AD result from damage to the episodic memory network, which involves the posterior hippocampus and posterior medial brain regions. However, sparing of the posterior hippocampus in SD could explain the absence of episodic memory deficits in this population. Show more

Keywords: Alzheimer’s disease, episodic memory, gray matter, meta-analysis, semantic dementia, semantic memory, semantic variant of primary progressive aphasia, voxel-based morphometry

DOI: 10.3233/JAD-160382

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 941-955, 2016