Journal of Alzheimer's Disease - Volume 52, issue 2

Authors: Yang, Canhong | Huang, Xiaomin | Huang, Xiaoyu | Mai, Hantao | Li, Jie | Jiang, Tao | Wang, Xiaofeng | Lü, Tianming

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia. Although the pathogenesis of AD remains unclear, AD is thought to result from an imbalance in the production and clearance of amyloid-β protein (Aβ). Aquaporin-4 (AQP4) is the major aquaporin in the mammalian brain, is mostly expressed on astrocytic endfeet, and functions as a water transporter. However, the distribution and expression of AQP4 are altered in both AD clinical populations and animal models. Recent studies have revealed that AQP4 is important to the clearance of Aβ in brain via lymphatic clearance, transcytotic delivery, and glial degradation, as well as to …the synaptic function. Thus, AQP4 likely plays an important role in the pathogenesis of AD. Further studies would provide new targets for prevention, ultimately leading to improved treatment options for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, aquaporin-4, astrocyte, cerebral amyloid angiopathy, synaptic function

DOI: 10.3233/JAD-150949

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 391-402, 2016

Authors: Cuchillo-Ibañez, Inmaculada | Balmaceda, Valeria | Mata-Balaguer, Trinidad | Lopez-Font, Inmaculada | Sáez-Valero, Javier

Article Type: Review Article

Abstract: In the continuing search for proteins that play a role in Alzheimer’s disease (AD) and that are related to the pathological hallmarks, those that influence cognitive function and that constitute potential therapeutic targets deserve special interest. Reelin is a signaling protein that is involved in a cascade of cytoplasmic events that control tau phosphorylation and that regulate synaptic neurotransmission, plasticity, and memory. Both Reelin expression and glycosylation are modulated by amyloid-β (Aβ), suggesting that the activity of Reelin could be affected in AD and hence, its possible influence on this pathology should be taken into consideration. The levels of Reelin …in the brain of AD patients appear to be altered and interestingly, disrupted Reelin signaling is associated with increased tau phosphorylation as well as with amyloid-β protein precursor processing. We discuss here the somewhat contradictory data regarding Reelin levels in AD and we evaluate the processing of the Reelin receptor, ApoER2, and other downstream events, such as the phosphorylation of the intracellular adapter Dab1. Together with brain Reelin levels, these changes may represent a relevant read-out of Reelin signaling in the human brain. Show more

Keywords: AβPP, Alzheimer’s disease, amyloid-β, ApoER2, glycosylation, Reelin, P-tau

DOI: 10.3233/JAD-151193

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 403-416, 2016

Authors: Piazza, Fabrizio | Winblad, Bengt

Article Type: Short Communication

Abstract: At the 8th International Conference on Clinical Trials in Alzheimer’s Disease held November 5–7, 2015 in Barcelona, Spain, promising data were presented on two candidate Alzheimer’s disease immunotherapeutic agents, gantenerumab and aducanumab. Trial results demonstrated that the implementation of cerebrospinal fluid and Aβ-PET biomarkers improves trial enrichment and outcome, which has led to a change in targeting strategy as clinical trials would be conducted with earlier, even presymptomatic, stages of the disease. Promising findings of outcomes, as measured by Aβ-PET and cerebrospinal fluid tau and P-tau, were, nevertheless, associated with antibody dose-dependent increased risk of severe adverse effects, specifically amyloid-related …imaging abnormalities (ARIA). Aducanumab was associated with concomitant time-, dose-, and APOE -related incidence of ARIA in more than one-half of the patients within the high-dose arm. The future challenge will thus be to find biomarkers more favorably balanced between effective dosing of antibody to remove Aβ versus dosing to limit deleterious side effects. Interest was shown by Roche and Biogen, which promoted high-dose phase 3 trials. However, this generated some concerns related to a reasonable expected further increase in the incidence of severe side effects. What has been learned is challenging primary industry strategies for following-up and monitoring safety and effectiveness of anti-Aβ antibodies in clinical trials. Here, we debate the issue of what is an acceptable balance of treatment side effects, i.e., therapeutic-induced ARIA, versus the positive prospects. Indeed, implementation of biomarkers for ARIA might increase value and reduce waste in the design of immunotherapy trials of Alzheimer’s disease. Show more

Keywords: Aducanumab, adverse effects, Alzheimer’s disease, amyloid-related imaging abnormalities, anti-Aβ autoantibodies, cerebral amyloid angiopathy-related inflammation, clinical trial, drug safety biomarkers, gantenerumab, immunotherapy

DOI: 10.3233/JAD-160122

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 417-420, 2016

Authors: El Haj, Mohamad | Kapogiannis, Dimitrios | Antoine, Pascal

Article Type: Research Article

Abstract: Multiple studies have shown compromise of autobiographical memory and phenomenological reliving in Alzheimer’s disease (AD). We investigated various phenomenological features of autobiographical memory to determine their relative vulnerability in AD. To this aim, participants with early AD and cognitively normal older adult controls were asked to retrieve an autobiographical event and rate on a five-point scale metacognitive judgments (i.e., reliving, back in time, remembering, and realness), component processes (i.e., visual imagery, auditory imagery, language, and emotion), narrative properties (i.e., rehearsal and importance), and spatiotemporal specificity (i.e., spatial details and temporal details). AD participants showed lower general autobiographical recall than controls, …and poorer reliving, travel in time, remembering, realness, visual imagery, auditory imagery, language, rehearsal, and spatial detail—a decrease that was especially pronounced for visual imagery. Yet, AD participants showed high rating for emotion and importance. Early AD seems to compromise many phenomenological features, especially visual imagery, but also seems to preserve some other features. Show more

Keywords: Alzheimer’s disease, autobiographical memory, autonoetic consciousness, phenomenological reliving, visual imagery

DOI: 10.3233/JAD-151122

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 421-431, 2016

Authors: Schütt, Trine | Helboe, Lone | Pedersen, Lars Østergaard | Waldemar, Gunhild | Berendt, Mette | Pedersen, Jan Torleif

Article Type: Research Article

Abstract: Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer’s disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-β (Aβ) plaque …deposition (N-terminally truncated and pyroglutamyl-modified Aβ included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aβ deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aβ deposition followed a progressive pattern in four maturation stages. Accumulation of the Aβ peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aβ pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aβ-related pathology. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β, animal model, canine, dog, neurodegeneration

DOI: 10.3233/JAD-151085

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 433-449, 2016

Authors: Callahan, Brandy L. | Simard, Martine | Mouiha, Abderazzak | Rousseau, François | Laforce Jr., Robert | Hudon, Carol

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) and late-life depression (LLD) are associated with increased risk of Alzheimer’s disease (AD). This is also true for aMCI with concomitant depressive symptoms (aMCI/D+), but few studies have investigated this syndrome. Objectives: We aimed to clarify the association between cognitive and depressive symptoms in individuals at risk for AD by examining episodic memory for emotional stimuli in aMCI, aMCI/D+, and LLD. Methods: Participants were 34 patients with aMCI, 20 patients with aMCI/D+, 19 patients with LLD, and 28 healthy elderly adults. In an implicit encoding task, participants rated the …emotional valence of 12 positive, 12 negative, and 12 neutral words. Immediately and 20 minutes later, participants recalled as many words as possible. They were also asked to identify previously presented words during a yes/no recognition trial. Results: At immediate recall, aMCI participants displayed better recall of emotional words, particularly positive words. aMCI/D+ and control participants displayed better recall of positive and negative words compared to neutral words. LLD participants recalled more negative than neutral words. At delayed recall, emotional words were generally better-remembered than neutral words by all groups. At recognition, all subjects responded more liberally to emotional than to neutral words. Conclusion: We find that the type of emotional information remembered by aMCI patients at immediate recall depends on the presence or absence of depressive symptoms. These findings contribute to identifying sources of heterogeneity in individuals at risk for AD, and suggest that the cognitive profile of aMCI/D+ is different from that of aMCI and LLD. Future studies should systematically consider the presence of depressive symptoms in elderly at-risk individuals. Show more

Keywords: Aging, Alzheimer’s disease, dementia, depression, emotion, episodic memory

DOI: 10.3233/JAD-150585

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 451-462, 2016

Authors: Torres-Cruz, Francisco M. | Rodríguez-Cruz, Fanny | Escobar-Herrera, Jaime | Barragán-Andrade, Norma | Basurto-Islas, Gustavo | Ripova, Daniela | Ávila, Jesús | Garcia-Sierra, Francisco

Article Type: Research Article

Abstract: Abnormal aggregation of Tau in glial cells has been reported in Alzheimer’s disease (AD) and other tauopathies; however, the pathological significance of these aggregates remains unsolved to date. In this study, we evaluated whether full-length Tau (Tau441) and its aspartic acid421 -truncated Tau variant (Tau421) produce alterations in the normal organization of the cytoskeleton and plasma membrane (PM) when transiently expressed in cultured C6-glial cells. Forty-eight hours post-transfection, abnormal microtubule bundling was observed in the majority of the cells, which expressed either Tau441 or Tau421. Moreover, both variants of Tau produced extensive PM blebbing associated with cortical redistribution of filamentous …actin (F-Actin). These effects were reverted when Tau-expressing cells were incubated with drugs that depolymerize F-Actin. In addition, when glial cells showing Tau-induced PM blebbing were incubated with inhibitors of the Rho-associated protein kinase (ROCK) signaling pathway, both formation of abnormal PM blebs and F-Actin remodeling were avoided. All of these effects were initiated upstream by abnormal Tau-induced microtubule bundling, which may release the microtubule-bound guanine nucleotide exchange factor-H1 (GEF-H1) into the cytoplasm in order to activate its major effector RhoA-GTPase. These results may represent a new mechanism of Tau toxicity in which Tau-induced microtubule bundling produces activation of the Rho-GTPase-ROCK pathway that in turn mediates the remodeling of cortical Actin and PM blebbing. In AD and other tauopathies, these Tau-induced abnormalities may occur and contribute to the impairment of glial activity. Show more

Keywords: F-Actin remodeling, glial degeneration, membrane blebbing, Rho associated protein kinase, RhoGTPases, Tau, tauopathies

DOI: 10.3233/JAD-150396

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 463-482, 2016

Authors: Zhu, Dan | Yang, Nan | Liu, Yan-Yong | Zheng, Ji | Ji, Chao | Zuo, Ping-Ping

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly population. Neuroinflammation induced by amyloid-β (Aβ) aggregation is considered to be the critical factor underlying AD pathological mechanisms. Alternatively activated (M2) macrophages/microglia have been reported to have neuroprotective effects in neurodegenerative disease. In this study, we characterized the neuroprotective effects of M2 macrophage transplantation in AD model rats and investigated the underlying mechanisms. Intracerebroventricular injection of Aβ1 - 42 to rats was used to model AD and resulted in cognitive impairment, neuronal damage, and inflammatory changes in the brain microenvironment. We observed an increased interferon regulatory factor (IRF) 5/IRF4 …ratio, resulting in greater production of classically activated (M1) versus M2 microglia. M2 macrophage transplantation attenuated inflammation in the brain, reversed Aβ1 - 42 -induced changes in the IRF4-IRF5 ratio, drove endogenous microglial polarization toward the M2 phenotype, and ameliorated cognitive impairment. Nerve growth factor (NGF) treatment reduced the IRF5/IRF4 ratio and induced primary microglial polarization to the M2 phenotype in vitro ; these effects were prevented by tyrosine Kinase Receptor A (TrkA) inhibition. M2 macrophage transplantation restored the balance of IRF4-IRF5 by affecting the expression of NGF and inflammatory cytokines in the brains of AD model rats. This drove microglial polarization to the M2 phenotype, promoted termination of neuroinflammation, and resulted in improved cognitive abilities. Show more

Keywords: Alzheimer’s disease, M2 macrophage, microglial polarization, nerve growth factor, neuroinflammation

DOI: 10.3233/JAD-151090

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 483-495, 2016

Authors: Koivisto, Anne M. | Kurki, Mitja I. | Alafuzoff, Irina | Sutela, Anna | Rummukainen, Jaana | Savolainen, Sakari | Vanninen, Ritva | Jääskeläinen, Juha E. | Soininen, Hilkka | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known. Objectives: We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH. Methods: A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years. Results: Altogether, 232 patients (50%) …with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n  = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer’s disease (n  = 94, 36%), followed by vascular dementia (n  = 68, 26%). Conclusions: One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized. Show more

Keywords: Alzheimer’s disease, cognition, dementia, memory, normal pressure hydrocephalus, prognosis, vascular dementia, ventricular enlargement

DOI: 10.3233/JAD-150909

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 497-507, 2016

Authors: Jekel, Katrin | Damian, Marinella | Storf, Holger | Hausner, Lucrezia | Frölich, Lutz

Article Type: Research Article

Abstract: Background: The assessment of activities of daily living (ADL) is essential for dementia diagnostics. Even in mild cognitive impairment (MCI), subtle deficits in instrumental ADL (IADL) may occur and signal a higher risk of conversion to dementia. Thus, sensitive and reliable ADL assessment tools are important. Smart homes equipped with sensor technology and video cameras may provide a proxy-free assessment tool for the detection of IADL deficits. Objective: The aim of this paper is to investigate the potential of a smart home environment for the assessment of IADL in MCI. Method: The smart home consisted of …a two-room flat equipped with activity sensors and video cameras. Participants with either MCI or healthy controls (HC) had to solve a standardized set of six tasks, e.g., meal preparation, telephone use, and finding objects in the flat. Results: MCI participants needed more time (1384 versus 938 seconds, p  <  0.001) and scored less total points (48 versus 57 points, p  <  0.001) while solving the tasks than HC. Analyzing the subtasks, intergroup differences were observed for making a phone call, operating the television, and retrieving objects. MCI participants showed more searching and task-irrelevant behavior than HC. Task performance was correlated with cognitive status and IADL questionnaires but not with participants’ age. Conclusion: This pilot study showed that smart home technologies offer the chance for an objective and ecologically valid assessment of IADL. It can be analyzed not only whether a task is successfully completed but also how it is completed. Future studies should concentrate on the development of automated detection of IADL deficits. Show more

Keywords: Instrumental activities of daily living, mild cognitive impairment, performance-based measures, smart homes

DOI: 10.3233/JAD-151054

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 509-517, 2016