Volume 54, Number 3, 2016

Pages 853-857

Patrick L. McGeer, Joseph Rogers, Edith G. McGeer
Inflammation, Antiinflammatory Agents, and Alzheimer’s Disease: The Last 22 Years
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.

Pages 859-878

Karine Bourgade, Gilles Dupuis, Eric H. Frost, Tamàs Fülöp Jr.
Anti-Viral Properties of Amyloid-β PeptidesAbstract: 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.

Pages 879-889

Jae Myeong Kang, Byeong Kil Yeon, Seong-Jin Cho, Yoo-Hun Suh
Stem Cell Therapy for Alzheimer’s Disease: A Review of Recent Clinical Trials
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 2000s. 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.

Pages 891-895

Sanjaya Kuruppu, Niwanthi W. Rajapakse, Alexander J. Spicer, Helena C. Parkington, A. Ian Smith
Stimulating the Activity of Amyloid-Beta Degrading Enzymes: A Novel Approach for the Therapeutic Manipulation of Amyloid-Beta Levels
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.

Pages 897-901
Short Communication

Alcibiades E. Villarreal, Shantal Grajales, Sid E. O’Bryant, Melissa Edwards, Lineth López, Astevia Montalván, Gabrielle B. Britton for the Panama Aging Research Initiative (PARI)
Characterization of Alzheimer’s Disease and Mild Cognitive Impairment in Older Adults in Panama
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 ε4 (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.

Pages 903-912
Ester Aso, Pol Andrés-Benito, Isidro Ferrer (Handling Associate Editor: Tommaso Cassano)
Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model
Abstract: Previous reports have demonstrated that the combination of D9-tetrahydrocannabinol (D9-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 D9-THC and CBD in aged AβPP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A RA1 in cannabinoid-treated animals when compared with animals treated with vehicle alone.

Pages 913-922
Louis De Beaumont, Sandra Pelleieux, Louise Lamarre-Théroux, Doris Dea, the Alzheimer's Disease Cooperative Study, Judes Poirier
Butyrylcholinesterase K and Apolipoprotein E-ε4 Reduce the Age of Onset of Alzheimer’s Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects
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-ε4) 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-ε4, BCHE-K*, and APOE-ε4/BCHE-K* carriers. Among the carriers of APOE-ε4 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-ε4 and BCHE-K* positive subjects. Conclusions: APOE-ε4 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.

Pages 923-931
Matthew Heath, Jeffrey Weiler, Michael A. Gregory, Dawn P. Gill, Robert J. Petrella (Handling Associate Editor: Krista Lanctôt)
A Six-Month Cognitive-Motor and Aerobic Exercise Program Improves Executive Function in Persons with an Objective Cognitive Impairment: A Pilot Investigation Using the Antisaccade Task
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 a cognitive-motor (CM) dual-task gait training component and an aerobic exercise training component 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.

Pages 933-940
Eun Hyun Seo, Hoowon Kim, Kun Ho Lee, IL Han Choo (Handling Associate Editor: Sang Won Seo)
Altered Executive Function in Pre-Mild Cognitive Impairment
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.

Pages 941-955
Marianne Chapleau, Joséphine Aldebert, Maxime Montembeault, Simona M. Brambati
Atrophy in Alzheimer’s Disease and Semantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies
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.

Pages 957-970
Hernando Santamaría-García, Pablo Reyes, Adolfo García, Sandra Baéz, Angela Martinez, Jose Manuel Santacruz, Andrea Slachevsky, Mariano Sigman, Diana Matallana, Agustín Ibañez
First Symptoms and Neurocognitive Correlates of Behavioral Variant Frontotemporal Dementia
Abstract: Background: Previous works highlight the neurocognitive differences between apathetic and disinhibited clinical presentations of the behavioral variant frontotemporal dementia (bvFTD). However, little is known regarding how the early presentation (i.e., first symptom) is associated to the neurocognitive correlates of the disease’s clinical presentation at future stages of disease. Objectives: We analyzed the neurocognitive correlates of patients with bvFTD who debuted with apathy or disinhibition as first symptom of disease. Methods: We evaluated the neuropsychological, clinical, and neuroanatomical (3T structural images) correlates in a group of healthy controls (n=30) and two groups of bvFTD patients (presented with apathy [AbvFTD, n=18] or disinhibition [DbvFTD, n=16]). To differentiate groups according to first symptoms, we used multivariate analyses. Results: The first symptom in patients described the evolution of the disease. AbvFTD and DbvFTD patients showed increased brain atrophy and increased levels of disinhibition and apathy, respectively. Whole brain analyzes in AbvFTD revealed atrophy in the frontal, insular, and temporal areas. DbvFTD, in turn, presented atrophy in the prefrontal regions, temporoparietal junction, insula, and temporoparietal region. Increased atrophy in DbvFTD patients (compared to AbvFTD) was observed in frontotemporal regions. Multivariate analyses confirmed that a set of brain areas including right orbitofrontal, right dorsolateral prefrontal, and left caudate were enough to distinguish the patients’ subgroups. Conclusion: First symptom in bvFTD patients described the neurocognitive impairments after around three years of disease, playing an important role in the early detection, disease tracking, and neuroanatomical specification of bvFTD, as well as in future research on potential disease-modifying treatments.

Pages 971-982
Ann Tiiman, Jinghui Luo, Cecilia Wallin, Lisa Olsson, Joel Lindgren, Jüri Jarvet, Per Roos, Sabrina B. Sholts, Shai Rahimipour, Jan Pieter Abrahams, Amelie Eriksson Karlström, Astrid Gräslund, Sebastian K.T.S. Wärmländer
Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species
Abstract: Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer’s disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, Aβ is found in various cellular locations including membranes. So far, Cu(II)/Aβ interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with Aβ bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the ZAβ3(12–58)Y18L Affibody molecule). In all studied systems the Aβ N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, Aβ was found to bind Cu(II) and Zn(II) with the same ligands and the same KD as in aqueous solution. ROS was generated in all Cu(II)/Aβ complexes. These results indicate that binding of Aβ to membranes, drugs, and other entities that do not interact with the Aβ N-terminal part, appears not to compromise the N-terminal segment’s ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.

Pages 983-993
Guangyu Chen*, Hao Shu*, Gang Chen, B. Douglas Ward, Piero G. Antuono, Zhijun Zhang, Shi Jiang Li, Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Staging Alzheimer’s Disease Risk by Sequencing Brain Function and Structure, Cerebrospinal Fluid, and Cognition Biomarkers
Abstract: This study aims to develop a composite biomarker that can accurately measure the sequential biological stages of Alzheimer’s disease (AD) on an individual level. We selected 144 subjects from the Alzheimer’s Disease Neuroimaging Initiative 2 datasets. Ten biomarkers, from brain function and structure, cerebrospinal fluid, and cognitive performance, were integrated using the event-based probabilistic model to estimate their optimal temporal sequence (Soptimal). We identified the numerical order of the Soptimal as the characterizing Alzheimer’s disease risk events (CARE) index to measure disease stage. The results show that, in the Soptimal, hippocampal and posterior cingulate cortex network biomarkers occur first, followed by aberrant cerebrospinal fluid amyloid-β and p-tau levels, then cognitive deficit, and finally regional gray matter loss and fusiform network abnormality. The CARE index significantly correlates with disease severity and exhibits high reliability. Our findings demonstrate that use of the CARE index would advance AD stage measurement across the whole AD continuum and facilitate personalized treatment of AD.

Pages 995-1004
Douglas W. Scharre, Shu-Ing Chang, Haikady N. Nagaraja, Ariane Park, Anahita Adeli, Punit Agrawal, Anne Kloos, Deb Kegelmeyer, Shannon Linder, Nora Fritz, Sandra K. Kostyk, Maria Kataki
Paired Studies Comparing Clinical Profiles of Lewy Body Dementia with Alzheimer’s and Parkinson’s Diseases
Abstract: Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer's disease (AD) and Parkinson’s disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

Pages 1005-1014
Maxime Bertoux*, Siddharth Ramanan*, Andrea Slachevsky, Stephanie Wong, Fernando Henriquez, Gada Musa, Carolina Delgado, Emma Flanagan, Michel Bottlaender, Marie Sarazin, Michael Hornberger, Bruno Dubois *These authors contributed equally to this work.
So Close Yet So Far: Executive Contribution to Memory Processing in Behavioral Variant Frontotemporal Dementia
Abstract: Background. Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties. Objective. This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach. Method. Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls (among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n=33) and non-amnestic (n=38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling. Results. Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4%-12.7%) predicted by EF. Discussion. These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD.

Pages 1015-1026
Young Noh, Sang Won Seo, Seun Jeon, Jong Min Lee, Jae Seung Kim, Jae-Hong Lee, Jung-Hyun Kim, Geon Ha Kim, Byoung Seok Ye, Hanna Cho, Hee Jin Kim, Cindy W Yoon, Yearn Seong Choe, Kyung-Han Lee, Michael W. Weiner, Duk L. Na
The Role of Cerebrovascular Disease in Amyloid Deposition
Abstract: Background: Some patients clinically diagnosed with subcortical vascular cognitive impairment (SVCI) have co-morbidity with AD pathology. Objective: We investigated topographical differences in amyloid burden between SVCI and Alzheimer’s disease type cognitive impairment (ADCI) using [11C] Pittsburgh compound B (PiB) positron emission tomography (PET). The purpose of this study was to investigate the role of cerebrovascular disease (CVD) in the amyloid deposition. Methods We recruited 44 patients with SVCI and 44 patients with ADCI (amnestic mild cognitive impairment or Alzheimer’s disease) with absent or minimal white matter hyperintensities, all with PiB-positive PET scans [PiB+]. As controls, we included 13 participants with normal cognition and PiB-negative scans. We divided the SVCI and ADCI patients into three groups according to global PiB retention ratio of SVCI, and then compared the tertiles in terms of the distribution of PiB retention using statistical parametric mapping analyses. Lobar to global PiB retention ratio and asymmetry indices were also compared between SVCI and ADCI groups. Results Compared to PiB+ ADCI patients, PiB+ SVCI patients exhibited: 1) increased left-right asymmetry, and increased anterior-posterior difference; and 2) increased PiB retention in the parietal cortex, the occipital cortex and the precuneus-posterior cingulate cortex. In contrast, ADCI patients showed increased PiB retention in the striatum. When stratified by level of PiB retention, each group showed different characteristics. Conclusion Our results showed that the distribution of amyloid deposition differed between patients with PiB+ SVCI and ADCI. These suggest that CVD contribute to and alter the known progression pattern in amyloid deposition in Alzheimer's disease.

Pages 1027-1037
Eske Christiane Gertje, John Pluta, Sandhitsu Das, Lauren Mancuso, Dasha Kliot, Paul Yushkevich, David Wolk
Clinical Application of Automatic Segmentation of Medial Temporal Lobe Subregions in Prodromal and Dementia-Level Alzheimer’s Disease
Abstract: Background: Volumetry of medial temporal lobe (MTL) structures to diagnose Alzheimer’s disease (AD) in its earliest symptomatic stage could be of great importance for interventions or disease modifying pharmacotherapy. Objective: This study aimed to demonstrate the first application of an automatic segmentation method of MTL subregions in a clinical population. Automatic segmentation of magnetic resonance images (MRIs) in a research population has previously been shown to detect evidence of neurodegeneration in MTL subregions and to help discriminate AD and mild cognitive impairment (MCI) from a healthy comparison group. Methods: Clinical patients were selected and T2-weighted MRI scan quality was checked. An automatic segmentation method of hippocampal subfields (ASHS) was applied to scans of 67 AD patients, 38 amnestic MCI patients, and 57 healthy controls. Hippocampal subfields, entorhinal cortex (ERC), and perirhinal cortex were automatically labeled and subregion volumes were compared between groups. Results: One fourth of all scans were excluded due to bad scan quality. There were significant volume reductions in all subregions, except BA36, in aMCIs (p<0.001), most prominently in Cornu Ammonis 1 (CA1) and ERC, and in all subregions in AD. However, sensitivity of CA1 and ERC hardly differed from sensitivity of WH in aMCI and AD. Conclusion: Applying automatic segmentation of MTL subregions in a clinical setting as a potential biomarker for prodromal AD is feasible, but issues of image quality due to motion remain to be addressed. CA1 and ERC provided strongest group discrimination in differentiating aMCIs from controls, but discriminatory power of different subfields was low overall.

Pages 1039-1045
Alessandro Trebbastoni, Fabrizia D’Antonio, Carlo de Lena, Emanuela Onesti, Bev John, Maurizio Inghilleri (Handling Associate Editor: Jin-Tai Yu)
Primary Progressive Orofacial Apraxia: A Ten-Year Long Follow-Up Case Report
Abstract: Orofacial apraxia (OA) as the main symptom in neurodegenerative disorders has not been yet reported. We present the case of a woman with a 22-month long history of isolated OA, studied with cerebrospinal fluid biomarkers and repeated clinical, neuropsychological, and morpho-functional evaluations. Baseline morpho-functional neuroimages revealed a left frontal operculum hypoperfusion with a widespread fronto-temporal involvement at follow-up. Cerebrospinal fluid concentrations of tau and amyloid-β were normal. The ten-year long clinical observation disclosed progressive OA worsening and the late onset of frontal functions impairment and extrapyramidal signs. The early and late stages of a neurodegenerative syndrome with OA as the main clinical feature were characterized.

Pages 1047-1059
Hideo Hara, Fumiko Ono, Shinichiro Nakamura, Shin-ei Matsumoto, Haifeng Jin, Nobutaka Hattori, Takeshi Tabira (Handling Associate Editor: Robert Friedland)
An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers
Abstract: With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys’ conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aβ without inflammatory or hemorrhagic changes in the brain. However, soluble Aβ and some Aβ oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aβ oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer’s disease when little amyloid is deposited.

Pages 1061-1072
Saeid Taheri, Jin Yu, Hong Zhu, Mark S. Kindy (Handling Associate Editor: Jurgen Claassen)
High-Sodium Diet Has Opposing Effects on Mean Arterial Blood Pressure and Cerebral Perfusion in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Background: Cerebral ionic homeostasis impairment, especially Ca2+, has been observed in Alzheimer’s disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment in AD and hypertension and cerebral blood flow (CBF) autoregulation is not clear. Objective: To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-β (Aβ), exacerbates cognitive decline, and increases the propensity to AD. Methods: Double transgenic mice harboring the amyloid-β protein precursor (APPswe), and presenilin-1 (PSEN1) along with control littermates, 2 months of age at initiation of special diet, were divided into 4 groups: Group A, APP/PS1 and Group B, controls fed a high-sodium (4.00%) chow diet for 3 months; Group C, APP/PS1 and Group D, controls fed a low-sodium (0.08%) regular chow diet for 3 months. Mean arterial blood pressure (MAP) and CBF were measured noninvasively using the tail MAP measurement device and magnetic resonance imaging, respectively. Aβ plaques numbers in the cortex and hippocampus of APP/PS1 were quantified. Results: In contrary to controls, APP/PS1 mice fed a high-salt diet did not show markedly elevated mean systolic and diastolic blood pressure (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg, p<0.0001). However, a high-salt diet increased CBF in both APP/PS1 and controls and did not alter the cerebral tissue integrity. Aβ plaques were significantly reduced in the cortex and hippocampus of mice fed a high-salt diet. Conclusion: These data suggest that a high-salt diet differently affects MAP/CBF in APP/PS1 mice and controls.

Pages 1073-1084
William R. Shankle, Junko Hara, Lori W. Barrentine, Melanie V. Curole
CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer’s Disease and Cerebrovascular Disease
Abstract: We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer’s disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ±σ] = 18.6 ± 16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ±σ] = 12.6 ± 5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ±σ] = 13.3 ± 17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group’s hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group’s forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy, and should be further validated.

Pages 1085-1094
Xabier Bengoetxea, Adela López de Cerain, Amaya Azqueta, Maria J. Ramirez (Handling Associate Editor: Eva Carro)
Purported Interactions of Amyloid-β and Glucocorticoids in Cytotoxicity and Genotoxicity: Implications in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the presence of aggregates of the amyloid-β peptide (Aβ) that are believed to be neurotoxic. One of the purposed damaging mechanisms of Aβ is oxidative insult, which eventually could damage the cellular genome. Stress and associated increases in glucocorticoids (GCs) have been described as a risk factor for the development of AD, although the purported genotoxic effects of GCs have not been fully characterized. Therefore, it is possible to speculate about purported synergistic effects of GCs on the Aβ-driven genotoxic damage. This in vitro study addresses the single and combined cyto/genotoxic effects of Aβ and GCs in SH-SY5Y cells. Cytotoxicity was determined by the MTT assay, and the genotoxic effects were studied using the comet assay. A comet assay derivation allows for measuring the presence of the FPG-sensitive sites (mainly 8-oxoguanines) in the DNA, apart from the DNA strand breaks. Treatment with Aβ (10 µM, 72 h) induced cytotoxicity (35% decrease in cell viability) and DNA strand breaks, but had no significant effect on oxidative DNA damage (FPG sites). Corticosterone showed no effect on cell viability, genotoxicity, or reparation processes. Corticosterone was unable to neither reverse nor potentiate Aβ driven effects. The present results suggest the existence of alternative mechanisms for the Aβ driven damage, not involving oxidative damage of DNA. In addition, could be suggested that the interaction between Aβ and GCs in AD does not seem to involve DNA damage.

Pages 1095-1112
Han Zhang, Xiaobo Chen, Feng Shi, Gang Li, Minjeong Kim, Panteleimon Giannakopoulos, Sven Haller, Dinggang Shen (Handling Associate Editor: Yong Liu)
Topographical Information-Based High-Order Functional Connectivity and Its Application in Abnormality Detection for Mild Cognitive Impairment
Abstract: Temporal synchronization-based functional connectivity (FC) has long been used by the neuroscience community. However, topographical FC information may provide additional information to characterize the advanced relationship between two brain regions. Accordingly, we proposed a novel method, namely high-order functional connectivity (HOFC), to capture this second-level relationship using inter-regional resemblance of the FC topographical profiles. Specifically, HOFC first calculates an FC profile for each brain region, notably between the given brain region and other brain regions. Based on these FC profiles, a second layer of correlations is computed between all pairs of brain regions (i.e., correlation’s correlation). On this basis, we generated an HOFC network, where “high-order” network properties were computed. We found that HOFC was discordant with the traditional FC in several links, indicating additional information being revealed by the new metrics. We applied HOFC to identify biomarkers for early detection of Alzheimer’s disease by comparing 77 mild cognitive impairment patients with 89 healthy individuals (control group). Sensitivity in detection of group difference was consistently improved by ~25% using HOFC compared to using FC. An HOFC network analysis also provided complementary information to an FC network analysis. For example, HOFC between olfactory and orbitofrontal cortices was found significantly reduced in patients, besides extensive alterations in HOFC network properties. In conclusion, our results showed promise in using HOFC to comprehensively map the human connectome.

Pages 1113-1121
Sara Lima, Miguel Gago, Carolina Garrett, M. Graça Pereira (Handling Associate Editor: Marcia Cristina Nascimento Dourado)
Predictors and Moderators of Quality of Life in Alzheimer’s Disease Patients
Abstract: Background: Alzheimer's disease (AD) is a chronic degenerative disease leading to global cognitive and functional decline. Quality of Life (QOL) is an important variable in the effectiveness of intervention programs in dementia. Objective: This study analyzed the relationship between gender, psychological variables and QOL, the predictors of QOL, and the role of spirituality as a moderator between functionality and QOL. Method: A cross-sectional study was conducted with 128 patients with mild AD. Results: Being a male, good social support, and high functionality were significant predictors of better QOL. Spirituality was a moderator of the relationship between functionality and QOL. Conclusion: These results reinforce the importance of gender, psychological morbidity, social support, and functionality, with special emphasis on the role of spirituality, regarding intervention programs that promote QOL, in patients with mild AD.

Pages 1123-1133
Petra Maresova, Blanka Klimova, Michal Novotny, Kamil Kuca
Alzheimer’s and Parkinson’s Diseases: Expected Economic Impact on Europe—A Call for a Uniform European Strategy
Abstract: The purpose of this study is to analyze the economic burden of persons with Alzheimer’s disease (AD) and Parkinson’s disease (PD) in Europe. On the basis of available data about the number of persons with dementia, their prevalence, and treatment and care costs, a mean cost burden is estimated for the year of 2030 and for the year of 2050 in Europe. The method of retrospective analysis of available sources was used; furthermore, analysis of database data such as WHO and Eurostat, which provide information about the number of older people and people with dementia; and specification of direct and indirect medical and nonmedical costs of patients with AD and PD from current studies was also used. The findings of this study confirm that the number of patients affected with AD and PD, as well as annual costs of the treatment and care of these patients, in the selected European countries are rapidly growing. The cost burden of both AD and PD in the selected European countries rises year by year, and by 2050, the cost burden of both diseases in fact will be almost two times higher in comparison with the year of 2010. In 2050, the overall mean cost burden is estimated to reach 357 billion Euros. The European Union calls for a joint initiative in the development of a uniformed strategic plan in the fight against dementia.

Pages 1135-1146
Steffen Wolfsgruber*, Luca Kleineidam*, Michael Wagner, Edelgard Mösch, Horst Bickel, Dagmar Lühmann, Annette Ernst, Birgitt Wiese, Susanne Steinmann, Hans-Helmut König, Christian Brettschneider, Tobias Luck, Janine Stein, Siegfried Weyerer, Jochen Werle, Michael Pentzek, Angela Fuchs, Wolfgang Maier, Martin Scherer, Steffi G. Riedel-Heller**, Frank Jessen** for the AgeCoDe Study Group (Handling Associate Editor: Andrea Tales) * These authors contributed equally to the manuscript; ** These last authors contributed equally to the manuscript.
Differential Risk of Incident Alzheimer’s Disease Dementia in Stable Versus Unstable Patterns of Subjective Cognitive Decline
Abstract: Background: It is unknown whether longitudinal stability versus instability in subjective cognitive decline (SCD) is a modifying factor of the association between SCD and risk of incident Alzheimer’s disease (AD) dementia. Objective: We tested the modifying role of temporal stability of the SCD report on AD dementia risk in cognitively normal elderly individuals. Methods: We analyzed data of 1,990 cognitively normal participants from the longitudinal AgeCoDe Study. We assessed SCD with/without associated worries both at baseline and first follow-up 18 months later. Participants were then classified either as (a) Controls (CO, with no SCD at both baseline and follow-up 1, n=613), (b) inconsistent SCD (with SCD reported only at baseline or at follow-up 1, n=637), (c) consistent SCD but without/ or with inconsistent worries (n=610) or (d) consistent SCD with worries (n=130). We estimated incident AD dementia risk over up to 6 years for each group with Cox-Proportional Hazard Regression analyses adjusted for age, gender, education, ApoE4 status, and depression. Results: Compared to CO, inconsistent SCD was not associated with increased risk of incident AD dementia. In contrast, risk was doubled in the group of consistent SCD without/ with inconsistent worries, and almost 4-fold in the group of consistent SCD with worries. These results could be replicated when using follow-up 1 to follow-up 2 response patterns for group definition. Conclusion: These findings suggest that longitudinal stability versus instability is an important modifying factor of the association between SCD and AD dementia risk. Worrisome SCD that is also consistently reported over time is associated with greatly increased risk of AD dementia.

Pages 1147-1155
Nitish Rai, Rahul Kumar, Gaurav Rajesh Desai, G. Venugopalan, Shashank Shekhar, Prasun Chatterjee, Manjari Tripathi, Ashish Datt Upadhyay, Sadanand Dwivedi, Aparajit B. Dey, Sharmistha Dey
Relative Alterations in Blood-Based Levels of Sestrin in Alzheimer’s Disease and Mild Cognitive Impairment Patients
Abstract: Sestrins (sesn) are highly conserved proteins that play an important neuroprotective role, in part as a consequence of their antioxidative capacity, which prevents reactive oxygen species formation. In this study, we evaluated the concentrations of sesn1 and sesn2 in the serum of 41 Alzheimer’s disease (AD) patients, 27 mild cognitive impairment (MCI), and 60 elderly controls, by surface plasmon resonance, which was validated by using western blot. Moreover, the mRNA level of sestrins in all the study groups was determined by real time polymerase chain reaction. The results showed significant overexpression of serum sesn2 protein and mRNA levels in the AD group compared to MCI and elderly control groups. A difference in serum sesn2 concentration between MCI and the control group was also evident. ROC analysis showed highly sensitive, selective cutoff values for sens2 in the differentiation of AD, MCI, and controls. No significant difference in sesn1 level was observed among the study groups. This study highlights the important role of sesn2 in the progression of the AD, indicating its potential utility as a protein marker in this devastating disease.

Pages 1157-1167
Ling Guo*, Aras Rezvanian*, Lokesh Kukreja, Ramez Hoveydai, Eileen H. Bigio, M.-Marsel Mesulam, Joseph El Khoury, Changiz Geula *These authors contributed equally to this work.
Postmortem Adult Human Microglia Proliferate in Culture to High Passage and Maintain Their Response to Amyloid-β
Abstract: Microglia are immune cells of the brain that display a range of functions. Most of our knowledge about microglia biology and function is based on cells from the rodent brain. Species variation in the complexity of the brain and differences in microglia response in the primate when compared with the rodent, require use of adult human microglia in studies of microglia biology. While methods exist for isolation of microglia from postmortem human brains, none allow culturing cells to high passage. Thus cells from the same case could not be used in parallel studies and multiple conditions. Here we report a method, which includes use of growth factors such as granulocyte macrophage colony stimulating factor, for successful culturing of adult human microglia from postmortem human brains up to 28 passages without significant loss of proliferation. Such cultures maintained their phenotype, including uptake of the scavenger receptor ligand acetylated low density lipoprotein and response to the amyloid-β peptide, and were used to extend in vivo studies in the primate brain demonstrating that inhibition of microglia activation protects neurons from amyloid-β toxicity. Significantly, microglia cultured from brains with pathologically confirmed Alzheimer’s disease displayed the same characteristics as microglia cultured from normal aged brains. The method described here provides the scientific community with a new and reliable tool for mechanistic studies of human microglia function in health from childhood to old age, and in disease, enhancing the relevance of the findings to the human brain and neurodegenerative conditions.

Pages 1169-1182
Amy Jenkins, Stephen Lindsay, Parisa Eslambolchilar, Ian Michael Thornton, Andrea Tales
Administering Cognitive Tests Through Touch Screen Tablet Devices: Potential Issues
Abstract: Mobile technologies, such as tablet devices, open up new possibilities for health-related diagnosis, monitoring, and intervention for older adults and healthcare practitioners. Current evaluations of cognitive integrity typically occur within clinical settings, such as memory clinics, using pen and paper or computer-based tests. In the present study, we investigate the challenges associated with transferring such tests to touch-based, mobile technology platforms from an older adult perspective. Problems may include individual variability in technical familiarity and acceptance; various factors influencing usability; acceptability; response characteristics and thus validity per se of a given test. For the results of mobile technology-based tests of reaction time to be valid and related to disease status rather than extraneous variables, it is imperative the whole test process is investigated in order to determine potential effects before the test is fully developed. Researchers have emphasized the importance of including the ‘user’ in the evaluation of such devices; thus we performed a focus group-based qualitative assessment of the processes involved in the administration and performance of a tablet-based version of a typical test of attention and information processing speed (a multi-item localization task), to younger and older adults. We report that although the test was regarded positively, indicating that using a tablet for the delivery of such tests is feasible, it is important for developers to consider factors surrounding user expectations, performance feedback, and physical response requirements and to use this information to inform further research into such applications.

Pages 1183-1192
Johanne Købstrup Zakarias, Christina Jensen-Dahm, Ane Nørgaard, Lea Stevnsborg, Christiane Gasse, Bodil Gramkow Andersen, Søren Jakobsen, Frans Boch Waldorff, Torben Moos, Gunhild Waldemar
Geographical Variation in Antipsychotic Drug Use in Elderly Patients with Dementia: A Nationwide Study
Abstract: Background: Use of antipsychotics in elderly patients with dementia has decreased in the past decade due to safety regulations; however use is still high. Geographical variation may indicate discrepancies in clinical practice and lack of adherence to evidence-based guidelines for the management of behavioral symptoms. Objective: To investigate potential geographical variances in use of antipsychotic drugs in dementia care. Methods: A registry-based cross-sectional study in the entire elderly population of Denmark (≥65 years) conducted in 2012. Data included place of residence, prescriptions filled, and hospital discharge diagnoses. Antipsychotic drug use among elderly with (n=34,536) and without (n=931,203) a dementia diagnosis was compared across the five regions and 98 municipalities in Denmark, adjusted for age and sex. Results: In 2012, the national prevalence of antipsychotic drug use was 20.7% for elderly patients with dementia, with a national incidence of 3.9%. The prevalence ranged from 17.0% to 23.3% in the five regions and from 7.5% to 33.1% in the 98 municipalities, demonstrating an over four-fold difference. Conclusion: The observed geographical variation was more pronounced at municipal level as compared to regional level, suggesting that the variation may be related to variances in clinical practice in primary care. This study highlights an urgent need for further educating professional carers and physicians to guide non-pharmacological as well as pharmacological management of neuropsychiatric symptoms in elderly patients with dementia.

Pages 1193-1205
Lisbell D. Estrada, David Chamorro, María José Yañez, Marcelo Gonzalez, Nancy Leal, Rommy von Bernhardi, Andrés E. Dulcey, Juan Marugan, Marc Ferrer, Claudio Soto, Silvana Zanlungo, Nibaldo C. Inestrosa, Alejandra R. Alvarez
Reduction of Blood Amyloid-β Oligomers in Alzheimer’s Disease Transgenic Mice by c-Abl Kinase Inhibition
Abstract: One of the pathological hallmarks of Alzheimer’s disease (AD) is the presence of amyloid plaques, which are deposits of misfolded and aggregated amyloid-beta peptide (Aβ). The role of the c-Abl tyrosine kinase in Aβ-mediated neurodegeneration has been previously reported. Here, we investigated the therapeutic potential of inhibiting c-Abl using imatinib. We developed a novel method, based on a technique used to detect prions (PMCA), to measure minute amounts of misfolded-Aβ in the blood of AD transgenic mice. We found that imatinib reduces Aβ-oligomers in plasma, which correlates with a reduction of AD brain features such as plaques and oligomers accumulation, neuroinflammation, and cognitive deficits. Cells exposed to imatinib and c-Abl KO mice display decreased levels of β-CTF fragments, suggesting that an altered processing of the amyloid-beta protein precursor is the most probable mechanism behind imatinib effects. Our findings support the role of c-Abl in Aβ accumulation and AD, and propose AD-PMCA as a new tool to evaluate AD progression and screening for drug candidates.

Pages 1207-1217
Siân Baker, Juan Carlos Polanco, Jürgen Götz (Handling Associate Editor: Illana Gozes)
Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice
Abstract: In Alzheimer’s disease, the distribution of neurofibrillary tangles, a histological hallmark comprised of phosphorylated forms of the protein tau, follows a distinct pattern through anatomically connected brain regions. The well-documented correlation between the severity of tau pathology and disease progression implies a prion-like seeding and spreading mechanism for tau. Experimentally, this has been addressed in transgenic mice by the injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, that were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. More specifically, in vivo data suggest that brain lysates from mice harboring the P301S mutation of tau can seed protein aggregation when injected into the hippocampi of human wild-type tau transgenic ALZ17 mice. Here, we compared the seeding potential of brain lysates and isolated extracellular vesicles from wild-type and human P301L tau transgenic rTg4510 mice. We show that transgenic extracellular vesicles cause increased tau phosphorylation and soluble oligomer formation in a manner comparable to that of freely available proteins in brain lysates, a prerequisite for the formation of mature protein aggregates.

Pages 1219-1233
Anat Boehm-Cagan, Roni Bar, Ori Liraz, John K. Bielicki, Jan O. Johansson, Daniel M. Michaelson (Handling Associate Editor: Rakez Kayed)
ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies
Abstract: The allele ε4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.

Pages 1235-1246
Micaela Sepe-Monti, Nicola Vanacore, Luisa Bartorelli, Alessandra Tognetti, Franco Giubilei and Savvy Caregiver Study Group
The Savvy Caregiver Program: A Probe Multicenter Randomized Controlled Pilot Trial in Caregivers of Patients Affected by Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is a major cause of disability in the elderly, leading to a considerable burden on caregivers and high costs to society. Psycho-education programs such as the Savvy Caregiver Program (SCP) are reported to be a successful means of reducing caregivers’ distress through various intervention strategies. The aim of the present study was to assess the efficacy of the SCP in reducing the burden and psychological symptoms in caregivers of AD patients and to analyze the coping strategies adopted by the caregivers. The study was designed as a multicenter, randomized, controlled, pilot clinical trial. One hundred and sixty-four caregivers of patients with probable AD were randomized. The SCP was structured in six, weekly, two-hour sessions. All the clinical scales were administered before treatment, two weeks and six months after treatment. Caregivers in the SCP group displayed better coping strategies adopted to positive attitudes, and they tended to be less anxious and less depressed than those in the control group. However, caregiver burden levels were not reduced in SCP caregivers. The patients of SCP caregivers received a lower number of new prescriptions of neuroleptics during the 6 months of follow-up than the patients of control caregivers and apathy was the neuropsychiatric symptom that improved most as a result of the SCP. The results of this study suggest that the SCP may improve coping strategies of caregivers of people affected by AD, influencing their psychological symptoms and those of their patients.

Pages 1247-1248
Book Review

Alzheimer’s Disease: Life Course Perspectives on Risk Reduction, by Amy R. Bornstein and James A. Mortimer, Academic Press, 2016, 466 p., ISBN: 9780128045381. Reviewed by Dharma Singh Khalsa