Pages 701-707
Ethics Review
Nancy A. Pachana, Jacki Liddle, Nancye M. Peel, Elizabeth Beattie, Christine Juang, Bob G. Knight
Can We Do Better? Researchers’ Experiences with Ethical Review Boards on Projects with Later Life as a Focus
Abstract: The goal of this study was to describe researchers’ experiences in submitting ethical proposals focused on older adult populations, including studies with persons with dementia, to ethical review boards. Ethical approval was granted for an online survey. Researchers were recruited via listservs and snowballing techniques. Participants included 157 persons (73% female) from Australia and the United States, with a mean age of 46 (±13). Six main issues were encountered by researchers who participated in this survey. In descending order, these included questions regarding: informed consent and information requirements (61.1%), participants’ vulnerability, particularly for those with cognitive impairments (58.6%), participant burden (44.6%), data access (29.3%), adverse effects of data collection/intervention (26.8%), and study methodology (25.5%). An inductive content analysis of responses revealed a range of encounters with ethical review panels spanning positive, negative, and neutral experiences. Concerns voiced about ethical review boards included committees being overly focused on legal risk, as well as not always hearing the voice of older research participants, both potential and actual. Respondents noted inability to move forward on studies, as well as loss of researchers and participant groups from gerontological and clinical research as a result of negative interactions with ethics committees. Positive interactions with the committees reinforced researchers’ need to carefully construct their research approaches with persons with dementia in particular. Suggested guidelines for committees when dealing with ethics applications involving older adults include self-reflecting on potential biases and stereotypes, and seeking further clarification and information from gerontological researchers before arriving at decisions.
Pages 709-710
Review Response
Jennifer H. Lingler
Investigators’ Perceptions of Research Oversight: Are Regulators Really Undermining Autonomy?
Pages 711-724
Review
Brandon P. Lucke-Wold, Ryan C. Turner, Aric F. Logsdon, James W. Simpkins, Daniel L. Alkon, Kelly E. Smith, Yi-Wen Chen, Zhenjun Tan, Jason D. Huber, Charles L. Rosen (Handling Associate Editor: Jose Abisambra)
Common Mechanisms of Alzheimer’s Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration
Abstract: Ischemic stroke and Alzheimer’s disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury.
Pages 725-738
Review
Deborah K. Shoemark and Shelley J. Allen (Handling Associate Editor: Carol Brayne)
The Microbiome and Disease: Reviewing the Links between the Oral Microbiome, Aging, and Alzheimer’s Disease
Abstract: This review, gathered from diverse sources, shows how our microbiome influences health and ultimately how well we age. Evidence linking oral bacteria to Alzheimer’s disease (AD) is discussed in the context of aging, drawing together data from epidemiological, experimental, genetic, and environmental studies. Immunosenescence results in increased bacterial load as cell-mediated and humoral immune responses wane. The innate immune system gradually takes over; contributing to the rise in circulating proinflammatory cytokines such as TNFα. Maintaining the integrity of the blood-brain barrier (BBB) against a backdrop of increasing bacterial load is important. Aging may favor the proliferation of anaerobes in the mouth eliciting a robust TNFα response from the oral epithelium. Prolonged exposure to high levels of circulating TNFα compromises the integrity of the BBB. Sensitive techniques now detect the “asymptomatic” presence of bacteria in areas previously thought to be sterile, providing new insights into the wider distribution of components of the microbiome. These “immune-tolerated” bacteria may slowly multiply elsewhere until they elicit a chronic inflammatory response; some are now considered causal in instances of atherosclerosis and back pain. Inflammatory processes have long been associated with AD. We propose for a subset of AD patients, aging favors the overgrowth of oral anaerobes established earlier in life provoking a pro-inflammatory innate response that weakens the BBB allowing bacteria to spread and quietly influence the pathogenesis of AD. Finally, we suggest that human polymorphisms considered alongside components of the microbiome may provide new avenues of research for the prevention and treatment of disease.
Pages 739-755
Review
Tim L. Emmerzaal, Amanda J. Kiliaan, Deborah R. Gustafson
2003-2013: A Decade of Body Mass Index, Alzheimer’s Disease, and Dementia
Abstract: The occurrence of obesity, commonly estimated using body mass index (BMI), and the most common late-onset dementia, Alzheimer’s disease (AD), are increasing globally. The year 2013 marked a decade of epidemiologic observational reports on the association between BMI and late-onset dementias. In this review, we highlight epidemiological studies that measured both mid- and late-life BMI in association with dementia. Studies investigating the association between midlife BMI and risk for dementia demonstrated generally an increased risk among overweight and obese adults. When measured in late-life, elevated BMI has been associated with lower risk. In addition, being underweight and/or having a decrease in BMI in late-life are associated with higher dementia risk compared to BMI in the normal range or stable BMI. In this review, a decade (2003-2013) of epidemiologic observational studies on associations between BMI and AD is highlighted. These observations provide a strong base for addressing biological mechanisms underlying this complex association.
Pages 757-761
Short Communication
Maria Serpente, Chiara Fenoglio, Francesca Clerici, Rossana Bonsi, Beatrice Arosio, Sara M.G. Cioffi, Emanuela Rotondo, Massimo Franceschi, Filippo Martinelli Boneschi, Daniela Mari, Claudio Mariani, Elio Scarpini*, Daniela Galimberti* (Handling Associate Editor: Benedetta Nacmias) *These authors contributed equally to this work.
Transmembrane Protein 106B Gene (TMEM106B) Variability and Influence on Progranulin Plasma Levels in Patients with Alzheimer’s Disease
Abstract: We carried out an association study of transmembrane protein 106B gene (TMEM106B) rs1020004 A/G, rs6966915 C/T, and rs1990622 A/G in a population of 656 patients with Alzheimer’s disease (AD) and 619 controls, and tested whether the rs1990622 influences plasma progranulin levels. No differences in allele and genotype distribution were observed between cases and controls, even stratifying according to APOE status (p>0.05). No differences in progranulin plasma levels were found between carriers of the rs1990622 and non-carriers. TMEM106b variability does not influence AD risk or plasma levels. Replication, preferably in a population with pathological confirmation, is required to confirm these results.
Pages 763-774
Ioannis Sotiropoulos, Joana Silva, Tetsuya Kimura, Ana Joao Rodrigues, Patricio Costa, Osborne F.X. Almeida, Nuno Sousa, Akihiko Takashima
Female Hippocampus Vulnerability to Environmental Stress as Precipitating Factor in Tau Aggregation Pathology
Abstract: Tau-mediated neurodegeneration is a central event in Alzheimer’s disease (AD) and other tauopathies. Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD pathology, we previously showed that stress triggers tau hyperphosphorylation and accumulation; however, little is known about the etiopathogenic interaction of chronic stress with other AD risk factors, such as sex and aging. This study focused on how these various factors converge on the cellular mechanisms underlying tau aggregation in the hippocampus of chronically stressed male and female (middle-aged and old) mice expressing the most commonly found disease-associated Tau mutation in humans, P301L-Tau. We report that environmental stress triggers memory impairments in female, but not male, P301L-Tau transgenic mice. Furthermore, stress elevates levels of caspase-3-truncated tau and insoluble tau aggregates exclusively in the female hippocampus while it also alters the expression of the molecular chaperones Hsp90, Hsp70, and Hsp105, thus favoring accumulation of tau aggregates. Our findings provide new insights into the molecular mechanisms through which clinically-relevant precipitating factors contribute to the pathophysiology of AD. Our data point to the exquisite sensitivity of the female hippocampus to stress-triggered tau pathology.
Pages 775-784
Lai-Ling Du*, Da-Min Chai*, Li-Na Zhao, Xiao-Hong Li, Fu-Chi Zhang, Hai-Bo Zhang, Lv-Bin Liu, Kang Wu, Rong Liu, Jian-Zhi Wang, Xin-Wen Zhou *These authors contributed equally to this work
AMPK Activation Ameliorates Alzheimer’s Disease-Like Pathology and Spatial Memory Impairment in a Streptozotocin-Induced Alzheimer's Disease Model in Rats
Abstract: Collecting evidence has shown that type 2 diabetes mellitus is a high risk factor of late-onset Alzheimer’s disease (AD); the energy metabolic dysfunction is thought to be a convergent point of the two diseases. However, the underlying mechanisms of diabetes-associated AD are still unclear. In the current study, we investigated the roles of AMPK in diabetes-related AD-like pathologic features in models of intracerebroventricular-streptozotocin (ICV-STZ) animals. Rats infused with STZ (3 mg/kg, once) were followed by injection of AICAR (AMPK activator) or vehicle via ICV. We found that the level of p-AMPK (active type of AMPK) and SIRT1 activity were decreased and the level of phosphorylated tau was increased at Ser396 and Thr231 sites in ICV-STZ rats when compared with control rats. Mitochondria from ICV-STZ rats displayed a significant decrease in mitochondrial membrane potential, complex I activity, ATP level, and superoxide dismutase activity as well as an increase of reactive oxygen species production when compared with that from control rats. Meanwhile the number of apoptotic cell confirmed by cleaved caspase-3 (active type of caspase-3) staining was also stronger in ICV-STZ rats than control rats. All pathological changes including biochemistry and cognitive function could be mitigated through rescuing AMPK activity with its specific activator (AICAR) in ICV-STZ rats. Taken together, these results suggested that AMPK activation improves AD-like pathological changes via repairing mitochondrial functions in ICV-STZ rats.
Pages 785-796
Alicia A. McNeely*, Joel Ramirez*, Sean M. Nestor, Jiali Zhao, Fuqiang Gao, Alex Kiss, Donald T. Stuss, Sandra E. Black (Handling Associate Editor: Sang Won Seo) *These authors contributed equally to this work.
Cholinergic Subcortical Hyperintensities in Alzheimer's Disease Patients from the Sunnybrook Dementia Study: Relationships with Cognitive Dysfunction and Hippocampal Atrophy
Abstract: Background: Subcortical hyperintensities within the cholinergic fiber projections (chSH) on MRI are believed to reflect cerebral small vessel disease (SVD) which may adversely impact cognition. Additionally, hippocampal atrophy represents a commonly used biomarker to support the diagnosis of Alzheimer’s disease (AD). Objective: To examine potential differences in neuropsychological test performance between AD patients (n=234) with high and low chSH volumes and whether these differences corresponded to hippocampal atrophy. Methods: A modified version of Lesion Explorer was used to volumetrically quantify chSH severity. The Sunnybrook Hippocampal Volumetry Tool was applied to obtain hippocampal volumes. Composite z-scores to assess executive, memory, and visuospatial functioning were generated from standardized neuropsychological test performance scores. Results: Inter-method technique validation demonstrated a high degree of correspondence with the Cholinergic Pathways Hyperintensities Scale (n=40, ρ=0.84, p<0.001). After adjusting for brain atrophy, disease severity, global SH volumes, and demographic variables, multivariate analyses revealed a significant group difference, with the high chSH group demonstrating poorer memory function compared to the low chSH group (p=0.03). A significant difference was found between low and high chSH groups in total (p<0.05) and left (p<0.01) hippocampal volume. Conclusion: These results suggest degradation of the cholinergic projections due to strategic SVD may independently contribute to memory dysfunction and hippocampal atrophy. Future studies examining subcortical vasculopathy in the cholinergic pathways may have implications on the development of therapeutic strategies for dementia and SVD.
Pages 797-808
Hyundong Song*, Yu Jin Chang*, Minho Moon, Sarah Kyua Park, Phuong-Thao Tran, Van-Hai Hoang, Jeewoo Lee, Inhee Mook-Jung (Handling Associate Editor: Bhumsoo Kim) *These authors contributed equally to this work.
Inhibition of Glutaminyl Cyclase Ameliorates Amyloid Pathology in an Animal Model of Alzheimer’s Disease via the Modulation of γ-Secretase Activity
Abstract: Alzheimer’s disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid-β peptides (Aβ) are generated from amyloid-β precursor protein by consecutive catalysis by β- and γ-secretases. Diversely modified forms of Aβ have been discovered, including pyroglutamate Aβ (N3pE-42 Aβ). N3pE-42 Aβ has received considerable attention as one of the major constituents of the senile plaques of AD brains due to its higher aggregation velocity, stability, and hydrophobicity compared to the full-length Aβ. A previous study suggested that N3pE-42 Aβ formation is catalyzed by glutaminyl cyclase (QC) following limited proteolysis of Aβ at the N-terminus. Here, we reveal that decreasing the QC activity via application of a QC inhibitor modulates γ-secretase activity, resulting in diminished plaque formation as well as reduced N3pE-42 Aβ aggregates in the subiculum of the 5XFAD mouse model of AD. This study suggests a possible novel mechanism by which QC regulates Aβ formation, namely modulation of γ-secretase activity.
Pages 809-821
Volha Tryputsen, Allitia DiBernardo, Mahesh Samtani, Gerald P. Novak, Vaibhav A. Narayan, Nandini Raghavan and the Alzheimer`s Disease Neuroimaging Initiative (Handling Associate Editor: Tim Schultz)
Optimizing Regions-of-Interest Composites for Capturing Treatment Effects on Brain Amyloid in Clinical Trials
Abstract: Background: Pittsburgh Compound B (PiB) positron emission tomography (PET) neuroimaging is a powerful research tool to characterize amyloid evolution in the brain. Quantification of amyloid load critically depends on (i) the choice of a reference region (RR) and (ii) on the selection of regions of interest (ROIs) to derive the standard uptake value ratios (SUVRs). Objective: To evaluate the stability, i.e., negligible amyloid accumulation over time, of different RRs, and the performance of different PiB summary measures defined by selected ROIs and RRs for their sensitivity to detecting longitudinal change in amyloid burden. Methods: To evaluate RRs, cross-sectional and longitudinal analyses of focal regional and composite measures of amyloid accumulation were carried out on the standardized PiB-PET regional data for cerebellar grey matter (CER), subcortical white matter (SWM), and pons (PON). RRs and candidate composite SUVR measures were further evaluated to select regions and develop novel composites, using standardized 2-year change from baseline. Results: Longitudinal trajectories of PiB4—average of anterior cingulate (ACG), frontal cortex (FRC), parietal cortex, and precuneus—demonstrated marked variability and small change from baseline when normalized to CER, larger changes and less variability when normalized to SWM, which was further enhanced for the composite in PON-normalized settings. Novel composite PiB3, comprised of the average SUVRs of lateral temporal cortex, ACG, and FRC was created. Conclusion: PON and SWM appeared to be more stable RRs than the CER. PiB3 showed compelling sample size reduction and gains in power calculations for clinical trials over conventional PiB4 composite.
Pages 823-834
John J. Graybeal*, P. Lorenzo Bozzelli*, Lacey L. Graybeal, Caitlin M. Groeber, Patrick E. McKnight, Daniel N. Cox, Jane M. Flinn (Handling Associate Editor: Hemachandra Reddy)
Human ApoE ε4 Alters Circadian Rhythm Activity, IL-1β, and GFAP in CRND8 mice
Abstract: Disruptions to daily living, inflammation, and astrogliosis are characteristics of Alzheimer’s disease. Thus, circadian rhythms, nest construction, IL-1β and TNF-α, and glial fibrillary acidic protein (GFAP) were examined in a mouse model developed to model late-onset Alzheimer’s disease—the most common form of the disease. Mice carrying both the mutated human AβPP transgene found in the CRND8 mouse and the human apolipoprotein E ε4 allele (CRND8/E4) were compared with CRND8 mice and wildtype (WT) mice. Circadian rhythms were evaluated by wheel-running behavior. Activity of daily living was measured by nest construction. This study then examined mRNA levels of the inflammatory cytokines IL-1β and TNF-α as well as protein levels of GFAP. Behavioral outcomes were then correlated with cytokines and GFAP. Compared to WT controls, both CRND8 and CRND8/E4 mice showed significantly more frequent, but shorter, bouts of activity. In the three groups, the CRND8/E4 mice had intermediate disruptions in circadian rhythms. Both CRND8/E4 mice and CRND8 mice showed significant impairments in nesting behavior compared to WTs. While CRND8 mice expressed significantly increased IL-1β and GFAP expression compared to WT controls, CRND8/E4 mice expressed intermediate IL-1β and GFAP levels. Significant correlations between IL-1β, GFAP, and behavior were observed. These data are congruent with other studies showing that human ApoE ε4 is protective early in life in transgenic mice modeling Alzheimer’s disease.
Pages 835-847
Adrian Ivanoiu, Laurence Dricot, Nathalie Gilis, Cécile Grandin, Renaud Lhommel, Lisa Quenon, Bernard Hanseeuw (Handling Associate Editor: Sebastiaan Engelborghs)
Classification of Non-Demented Patients Attending a Memory Clinic using the New Diagnostic Criteria for Alzheimer’s Disease with Disease-Related Biomarkers
Abstract: Background: New diagnostic criteria for predemential Alzheimer’s disease (AD) advocate the use of biomarkers. However, the benefit of using biomarkers has not been clearly demonstrated in clinical practice. Objective: To investigate whether a combination of biomarkers may be helpful in classifying a population of non-demented patients attending a Memory Clinic. Methods: Sixty non-demented patients were compared with 31 healthy elderly subjects. All subjects underwent a neuropsychological examination, brain 3T magnetic resonance imaging, and [F18]-fluorodeoxyglucose and [F18]-flutemetamol positron emission tomography. According to their performance on memory, language, executive, and visuo-spatial domains, the patients were classified as mild cognitive impairment (amnestic, non-amnestic, single, or multiple domain) or subjective cognitive impairment. Patients were then classified according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria, using the normalized mean hippocampal volume (Freesurfer), [F18]-FDG PALZAD, and [F18]-flutemetamol standard uptake value ratio (SUVr) (cut-off at the 10th percentile of controls). The standard of truth was the clinical status at study entry (patient versus control). Results: The sensitivity/specificity of the clinical classification was 65/84%. The NIA-AA criteria were applicable in 85% of patients and 87% of controls. For biomarkers the best sensitivity (72%) at a fixed specificity of 84% was achieved by a combination of the three biomarkers. The clinical diagnosis was reconsidered in more than one third of the patients (42%) as a result of including the biomarker results. Conclusions: Application of the new NIA-AA AD diagnostic criteria based on biomarkers in an unselected sample of non-demented patients attending a Memory Clinic was useful in allowing for a better classification of the subjects.
Pages 849-855
Dario Grossi, Natascia de Lucia, Luigi Trojano (Handling Associate Editor: Montse Alegret)
Closing-in is related to Apathy in Alzheimer’s Disease Patients
Abstract: Background: Apathy and depression are behavioral manifestations that may occur often in Alzheimer’s disease (AD) patients. AD patients may also show Closing-in (CI) phenomenon, in graphic copying tasks. Recent evidence would suggest that apathetic symptoms are related to frontal dysfunctions in AD patients, whereas the cognitive bases of depressive symptoms in AD are still unclear. Recent studies demonstrated that frontal dysfunctions are also involved in the genesis of CI in AD patients. Objective: Since frontal dysfunctions are thought to be more strongly related to apathetic than depressive symptoms, here we tested the hypothesis that CI is significantly associated with apathy in AD patients. Methods: Forty-four AD patients were enrolled for this study. All patients completed a neuropsychological evaluation of visuo-spatial, frontal/executive, visuo-constructional, and memory skills. Moreover, graphic copying tasks were employed to detect CI, and behavioral scales to assess apathetic and depressive symptoms. Results: CI and apathetic and depressed symptoms occurred in more than half of the present AD sample, but regression models revealed that the number of CI was significantly related to apathy only. The number of CI was also significantly correlated with severity of apathetic but not of depressive symptoms. Conclusion: The present study demonstrated that CI and apathy are correlated with each other in mild to moderate AD, likely because they share common pathogenic mechanisms related to frontal/executive dysfunctions.
Pages 857-869
YuHong Fu, Jen-Hsiang T. Hsiao, George Paxinos, Glenda M. Halliday, Woojin Scott Kim
ABCA5 Regulates Amyloid-β Peptide Production and is associated with Alzheimer’s Disease Neuropathology
Abstract: Brain cholesterol homeostasis is regulated by a group of proteins called ATP-binding cassette subfamily A (ABCA) transporters. Certain ABCA transporters regulate amyloid-β protein precursor (AβPP) processing to generate amyloid-β peptides (Aβ) and are associated with an increased risk for late-onset Alzheimer’s disease (AD). ABCA5 is a little-known member of the ABCA subfamily with no known function. In this study we undertook a comprehensive analysis of ABCA5 expression in the human and mouse brains. We explored the potential role of ABCA5 in AβPP processing associated with AD pathology. ABCA5 was differentially expressed in multiple regions of both human and mouse brains. It was strongly expressed in neurons with only weak expression in microglia, astrocytes, and oligodendrocytes. ABCA5 was able to stimulate cholesterol efflux in neurons. ABCA5 expression was specifically elevated in the hippocampus of AD brains. Using two in vitro cell systems we demonstrated that ABCA5 reduces Aβ production, both Aβ40 and Aβ42, without altering AβPP mRNA and protein levels, indicating that the decrease in the Aβ levels was due to changes in AβPP processing and not AβPP expression. This report represents the first extensive expression and functional study of ABCA5 in the human brain and our data suggest a plausible function of ABCA5 in the brain as a cholesterol transporter associated with Aβ generation, information that may offer a potential new target for controlling Aβ levels in the brain.
Pages 871-891
Alain D. Dekker, Antonia M.W. Coppus, Yannick Vermeiren, Tony Aerts, Cornelia M. van Duijn, Berry P. Kremer, Pieter J.W. Naudé, Debby Van Dam, Peter P. De Deyn
Serum MHPG Strongly Predicts Conversion to Alzheimer’s Disease in Behaviorally Characterized Subjects with Down Syndrome
Abstract: Background: Down syndrome (DS) is the most prevalent genetic cause of intellectual disability. Early-onset Alzheimer’s disease (AD) frequently develops in DS and is characterized by progressive memory loss and behavioral and psychological signs and symptoms of dementia (BPSD). Predicting and monitoring the progression of AD in DS is necessary to enable adaptive caretaking. Objective: Reliable blood biomarkers that aid the prediction of AD are necessary, since cerebrospinal fluid sampling is rather burdensome, particularly for people with DS. Here, we investigate serum levels of eight biogenic amines and their metabolites in relation to dementia staging and probable BPSD items.Methods: Using RP-HPLC with electrochemical detection, (nor)adrenergic (NA/A and MHPG), serotonergic (5-HT and 5-HIAA), and dopaminergic (DA, HVA, and DOPAC) compounds were quantified in the serum of DS subjects with established AD at baseline (n=51), DS subjects without AD (n=50), non-demented DS individuals that converted to AD over time (n=50), and, finally, healthy non-DS controls (n=22). Results: Serum MHPG levels were significantly lower in demented and converted DS subjects (p<0.0001) compared to non-demented DS individuals and healthy controls. Those subjects with MHPG levels below median had a more than tenfold increased risk of developing dementia. Furthermore, significant correlations were observed between monoaminergic serum values and various probable BPSD items within each DS group. Conclusion: Decreased serum MHPG levels show great potential as biomarker to monitor and predict conversion to AD in DS. Moreover, significant monoaminergic alterations related to probable BPSD items, suggesting that monoaminergic dysregulation is an underlying biological mechanism, and demonstrating the need to develop a validated rating scale for BPSD in DS.
Pages 893-903
Haley C. Dunn, Rahasson R. Ager, David Baglietto-Vargas, David Cheng, Masashi Kitazawa, David H. Cribbs, Rodrigo Medeiros
Restoration of Lipoxin A4 Signaling Reduces Alzheimer’s Disease-Like Pathology in the 3xTg-AD Mouse Model
Abstract: The initiation of an inflammatory response is critical to the survival of an organism. However, when inflammation fails to reach resolution, a chronic inflammatory state may occur, potentially leading to bystander tissue damage. Accumulating evidence suggests that chronic inflammation contributes to the progression of Alzheimer’s disease (AD), and identifying mechanisms to resolve the pro-inflammatory environment stimulated by AD pathology remains an area of active investigation. Previously, we found that treatment with the pro-resolving mediator aspirin-triggered lipoxin A4 (ATL), improved cognition, reduced Aβ levels, and enhanced microglia phagocytic activity in Tg2576 transgenic AD mice. Here, we evaluated the effect of aging on brain lipoxin A4 (LXA4) levels using non-transgenic and 3xTg-AD mice. Additionally, we investigated the effect of ATL treatment on tau pathology in 3xTg-AD mice. We found that LXA4 levels are reduced with age, a pattern significantly more impacted in 3xTg-AD mice. Moreover, ATL delivery enhanced the cognitive performance of 3xTg-AD mice and reduced Aβ levels, as well as decreased the levels of phosphorylated-tau (p-tau). The decrease in p-tau was due in part to an inhibition of the tau kinases GSK-3β and p38 MAPK. In addition, microglial and astrocyte reactivity was inhibited by ATL treatment. Our results suggest that the inability to resolve the immune response during aging might be an important feature that contributes to AD pathology and cognitive deficits. Furthermore, we demonstrate that activation of LXA4 signaling could serve as a potential therapeutic target for AD-related inflammation and cognitive dysfunction.
Pages 905-913
Maria Fernanda B. Sousa, Raquel L. Santos, Marcela L. Nogueira, Tatiana Belfort, Rachel Dias, Bianca Torres, Pedro Simões, Daniel C. Mograbi, Jerson Laks, Marcia C.N. Dourado
Awareness of Disease is Different for Cognitive and Functional Aspects in Mild Alzheimer’s Disease: A One-Year Observation Study
Abstract: Awareness of disease can be compromised to some degree in a proportion of people with dementia, with evident differences across domains. We designed this study to determine the factors associated with the impairment of awareness over a period of time. Using a longitudinal design, 69 people with mild Alzheimer’s disease and their family caregivers completed the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia, the Quality of Life in Alzheimer’s Disease Scale, the Mini-Mental State Examination, the Clinical Dementia Rating scale, the Cornell Scale for Depression in Dementia, the Pfeffer Functional Activities Questionnaire, the Neuropsychiatric Inventory, and the Zarit Burden Interview. Univariate and logistic regression analyses were conducted to examine the contribution of the various factors. The level of awareness of disease was significantly lower (p≤0.001) between baseline and at follow up. At follow up, there was no change in the level of awareness of disease in 61.8%, whereas 25.4% worsened. However, the level of awareness improved in 12.3%. Logistic regression demonstrated that functional deficits (OR = 1.12, 95% CI: (1.03–1.22), p≤0.01), and caregivers’ quality of life (OR = 0.83, 95% CI: (0.70–0.98), p≤0.05) were a significant predictor of impaired awareness of disease. The results confirmed that awareness and cognition are relatively independent, and showed that in people with mild dementia, unawareness is mainly manifested by poor recognition of changes in the activities of daily living, and decrease in quality of life.
Pages 915-926
Kristina Paholikova, Barbara Salingova, Alena Opattova, Rostislav Skrabana, Petra Majerova, Norbert Zilka, Branislav Kovacech, Monika Zilkova, Peter Barath, Michal Novak
N-terminal Truncation of Microtubule Associated Protein Tau Dysregulates Its Cellular Localization
Abstract: Tau protein is a member of microtubule-associated protein family. Under pathological conditions, tau undergoes multiple modifications that lead to the formation of insoluble deposits in neurons, resulting in neuronal dysfunction in several neurodegenerative disorders collectively called tauopathies, with Alzheimer’s disease being the most frequent example. This typical cytosolic protein has been shown to translocate into the nucleus and participate in DNA protection upon stress conditions. In our study, we demonstrate that truncated Tau151-391/4R changes its usual behavior and gains constitutive access into the nucleus of both primary rat neurons and human neuroblastoma cells. Our results show that partial/dysregulated nuclear localization of tau results from the removal of the N-terminal (1-150) residues of the protein. Data obtained by cell fractionation data were supported by confocal microscopy analysis of GFP-fused tau proteins. Furthermore, neither addition of the fusion protein, nor increased tau phosphorylation had any effect on the intracellular distribution of truncated tau. Our data further suggest that differential tau phospho-status between cytosolic and nuclear fractions is rather a consequence than a cause of truncated tau nuclear localization. Finally, truncated tau in the nucleus is engaged in interactions with subnuclear structure(s), since it exhibits reduced mobility. We conclude that N-terminal truncation of tau proteins leads to their nonphysiological subcellular distribution as a result of modified tau conformation.
Pages 927-938
Stephanie Hagl, Rekha Grewal, Ion Ciobanu, Amr Helal, Mohamed T. Khayyal, Walter E. Muller, Gunter P. Eckert
Rice Bran Extract Compensates Mitochondrial Dysfunction in a Cellular Model of Early Alzheimer’s Disease
Abstract: Mitochondrial dysfunction plays an important role in brain aging and has emerged to be an early event in Alzheimer’s disease (AD), contributing to neurodegeneration and the loss of physical abilities seen in patients suffering from this disease. We examined mitochondrial dysfunction in a cell culture model of AD (PC12APPsw cells) releasing very low amyloid-β (Aβ40) levels and thus mimicking early AD stages. Our data show that these cells have impaired energy metabolism, low ATP levels, and decreased endogenous mitochondrial respiration. Furthermore, protein levels of PGC1α as well as of Mitofusin 1 were decreased. PC12APPsw cells also showed an increased mitochondrial content, probably due to an attempt to compensate the impaired mitochondrial function. Recent data showed that stabilized rice bran extract (RBE) protects from mitochondrial dysfunction in vivo (Hagl et al., Pharmacol Res 76, 17-27, 2013). To assess the effect of a RBE on mitochondrial function, we treated PC12APPsw cells for 24 h with RBE. Key components of RBE are oryzanols, tocopherols, and tocotrienols, all substances that have been found to exert beneficial effects on mitochondrial function. RBE incubation elevated ATP production and respiratory rates as well as PGC1α protein levels in PC12APPsw cells, thus improving the impaired mitochondrial function assessed in our cell culture AD model. Therefore, RBE represents to be a promising nutraceutical for the prevention of AD.
Pages 939-947
Lidia Glodzik, Marc Sollberger, Achim Gass, Amit Gokhale, Henry Rusinek, James. S. Babb1 Jochen G. Hirsch, Michael Amann, Andreas U. Monsch, Oded Gonen (Handling Associate Editor: Piotr Lewczuk)
Global N Acetylaspartate in Normal Subjects, Mild Cognitive Impairment and Alzheimer’s Disease Patients
Abstract: Background: Mild cognitive impairment (MCI) is an intermediary state on the way to Alzheimer’s disease (AD). Little is known about whole brain concentration of the neuronal marker, N acetylaspartate (NAA) in MCI patients. Objective: To test the hypothesis that since MCI and AD are both neurodegenerative, quantification of the NAA in their whole brain (WBNAA) could differentiate them from cognitively-intact matched controls. Methods: Proton MR spectroscopy to quantify the WBNAA was applied to 197 subjects (86 females) 72.6±8.4 years old (mean±standard deviation). Of these, 102 were cognitively intact, 42 diagnosed as MCI, and 53 as probable AD. Their WBNAA amounts were converted into absolute concentration by dividing with the brain volume segmented from the MRI that also yielded the fractional brain volume (fBPV), an atrophy metric. Results: WBNAA concentration of MCI and AD patients (10.5±3.0 and 10.1±2.9mM) were not significantly different (p=0.85). They were, however, highly significantly 25-29% lower than the 14.1±2.4mM of normal matched controls (p‹10-4). The fBPV of MCI and AD patients (72.9±4.9 and 69.9±4.7%) differed significantly from each other (4%, p=0.02) and both were significantly lower than the 74.6±4.4% of normal elderly (2%, p=0.003 for MCI; 6%, p‹10-4 for AD). ROC curve analysis has shown WBNAA to have 70.5% sensitivity and 84.3% specificity to differentiate MCI or AD patients from normal elderly versus just 68.4 and 65.7% for fBPV. Conclusion: Low WBNAA in MCI patients compared with cognitively normal contemporaries may indicate early neuronal damage accumulation and supports the notion of MCI as an early stage of AD. It also suggests WBNAA as a potential marker of early AD pathology.
Pages 949-955
Hong Liu-Seifert, Eric Siemers, Karen Sundell, Karen Price, Baoguang Han, Katherine Selzler, Paul Aisen, Jeffrey Cummings, Joel Raskin, Richard Mohs
Cognitive and Functional Decline and Their Relationship in Patients with Mild Alzheimer’s Dementia
Abstract: Background: In patients with Alzheimer’s disease (AD), the relationship between cognitive and functional progression is not fully understood; however, functional decline has been postulated to follow cognitive decline. Objective: To assess the relationship between cognitive and functional treatment effects in mild AD dementia patients. Methods: Data of patients with mild AD were pooled from two multicenter, double-blind, Phase 3 studies. Patients were randomized to infusions of 400-mg solanezumab (n=654), or placebo (n=660) every 4 weeks for 18 months. Cognitive and functional outcome measures were assessed using the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL), respectively. Analyses included comparisons among normalized scales, correlations between outcome measures, and path analyses to model the relationship of treatment effect on cognition and function. Results: Normalized ADAS-Cog and ADCS-ADL scales showed cognitive impairment was more evident than functional impairment in mild AD. The correlation between cognition and function increased over time. Path analyses demonstrated that 87% of the treatment effect on function was driven by the treatment effect on cognition, with the remaining 13% due to direct treatment effect. Conclusion: Findings from this study are consistent with the hypothesis that functional impairment is primarily driven by and follows cognitive decline in mild AD dementia. The cognitive treatment effect appeared to explain the majority of the functional treatment effect. It is possible that a cognitive treatment effect may be considered as a leading indicator for functional outcomes in an 18-month clinical trial for milder stages of AD.
Pages 957-966
Priya Maheshwari, Guy D. Eslick
Bacterial Infection and Alzheimer’s Disease: A Meta-Analysis
Abstract: The possibility of an infectious etiology for Alzheimer’s disease (AD) has been repeatedly postulated over the past three decades. We provide the first meta-analysis to address the relationship between bacterial infection and AD. Studies examining the association between AD and spirochetal bacteria or Chlamydophila pneumoniae (Cpn) were identified through a systematic search of the databases MEDLINE, EMBASE, PubMed, and Google Scholar. Data combined from 25 relevant, primarily case-control studies demonstrated a statistically significant association between AD and detectable evidence of infection of either bacterial group. We found over a ten-fold increased occurrence of AD when there is detectable evidence of spirochetal infection (OR: 10.61; 95% CI: 3.38-33.29) and over a four-fold increased occurrence of AD in a conservative risk estimate (OR 4.45; 95% CI: 2.33-8.52). We found over a five-fold increased occurrence of AD with Cpn infection (OR 5.66; 95% CI: 1.83-17.51). This study shows a strongly positive association between bacterial infection and AD. Further detailed investigation of the role of bacterial infection is warranted.
Pages 967-976
Shannon N. Campbell, Cheng Zheng, Louise Monte, Allyson D. Roe, Kenner C. Rice, Yvette Taché, Eliezer Masliah, Robert A. Rissman (Handling Associate Editor: Peter Davies)
Increased Tau Phosphorylation and Aggregation in Mice Overexpressing Corticotropin-Releasing Factor
Abstract: Clinical and basic science research suggests that stress and/or changes in central stress signaling intermediates may be involved in Alzheimer’s disease (AD) pathogenesis. Although the links between stress and AD remain unsettled, data from our group and others have established that stress exposure in rodents may confer susceptibility to AD pathology by inducing hippocampal tau phosphorylation (tau-P). Work in our lab has shown that stress-induced tau-P requires activation of the type-1 corticotropin-releasing factor receptor (CRFR1). CRF overexpressing (CRF-OE) mice are a model of chronic stress that display cognitive impairment at 9-10 month of age. In this study we used 6–7 month old CRF-OE mice to examine whether sustained exposure to CRF and stress steroids would impact hippocampal tau-P and kinase activity in the presence or absence of the CRFR1-specific antagonist, R121919, given daily for 30 days. CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK). Examination of hippocampal extracts from CRF-OE mice at the ultrastructural level revealed negatively stained round/globular aggregates that were positively labeled by PHF-1. These data suggest critical roles for CRF and CRFR1 in tau-P and aggregation and may have implications for the development of AD cognitive decline.
Pages 977-991
Ester Aso, Alexandre Sánchez-Pla, Esteban Vegas-Lozano, Rafael Maldonado, Isidro Ferrer (Handling Associate Editor: Tommaso Cassano)
Cannabis-Based Medicine Reduces Multiple Pathological Processes in AβPP/PS1 Mice
Abstract: Several recent findings suggest that targeting the endogenous cannabinoid system can be considered as a potential therapeutic approach to treat Alzheimer’s disease (AD). The present study supports this hypothesis demonstrating that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Moreover, THC+CBD reduced learning impairment in AβPP/PS1 mice. A significant decrease in soluble Aβ42 peptide levels and a change in plaques composition were also observed in THC+CBD-treated AβPP/PS1 mice, suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide. Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role. Here we observed reduced astrogliosis, microgliosis, and inflammatory-related molecules in treated AβPP/PS1 mice, which were more marked after treatment with THC+CBD than with either THC or CBD. Moreover, other cannabinoid-induced effects were uncovered by a genome-wide gene expression study. Thus, we have identified the redox protein thioredoxin 2 and the signaling protein Wnt16 as significant substrates for the THC+CBD-induced effects in our AD model. In summary, the present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD.
Pages 993-1006
Yaara Saad, Daniel Segal, Amir Ayali (Handling Associate Editor: Karen Mearow)
Enhanced Neurite Outgrowth and Branching Precede Increased Amyloid-β-Induced Neuronal Apoptosis in a Novel Alzheimer’s Disease Model
Abstract: Though it is widely accepted that amyloid-β (Aβ) is a key factor in Alzheimer's disease (AD) pathology, its underling mechanism remains unclear. In order to study the association between Aβ and neural circuitry dysfunction, we developed a primary culture preparation derived from the nervous system of transgenic Drosophila melanogaster larvae expressing human Aβ1-42 (Aβ42). Cultured neurons undergo a consistent developmental process, culminating in an elaborate neuronal network with distinct functional and morphological characteristics. Throughout this development, a time-dependent increase in intracellular expression levels of Aβ42 was detected, followed by extracellular staining at a later time point. When compared to controls, Aβ42 cultures exhibited enhanced levels of apoptosis, resulting in reduced cell viability. Moreover, as primary culture preparations enable high resolution monitoring of neuronal phenotypes, we were able to detect subtle morphological changes in neurons expressing Aβ42, namely an enhancement in neurite outgrowth and arborization, which preceded the effect of neurodegeneration. Our results establish D. melanogaster primary neuronal cultures as a rapid, accessible and cost-effective platform for AD molecular studies and drug screening, and suggest a possible role for Aβ42 in the organization of neuronal processes.
Pages 1007-1016
R. Scott Mackin, Philip Insel, Jing Zhang, Brian Mohlenhoff, Douglas Galasko, Michael Weiner, Niklas Mattsson, for the Alzheimer’s Disease Neuroimaging Initiative*
Cerebrospinal Fluid α-Synuclein and Lewy Body-Like Symptoms in Normal Controls, Mild Cognitive Impairment, and Alzheimer’s Disease
Abstract: Background: Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer’s disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD. Objective: Determine associations between CSF α-synuclein and Lewy body-like symptomatology. Methods: We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6-7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration. Results: Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI). Conclusion: The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.
Pages 1017-1030
Hua Zhao, Hongyun Li, Kalani Ruberu, Brett Garner (Handling Associate Editor: Ralph Martins)
Impaired Lysosomal Cobalamin Transport in Alzheimer’s Disease
Abstract: Cobalamin (vitamin B12) is required for erythrocyte formation and DNA synthesis and it plays a crucial role in maintaining neurological function. As a coenzyme for methionine synthase and methylmalonyl-CoA mutase, cobalamin utilization depends on its efficient transit through the intracellular lysosomal compartment and subsequent delivery to the cytosol and mitochondria. Lysosomal function deteriorates in Alzheimer’s disease (AD). Lysosomal acidification is defective in AD and lysosomal proteolysis is disrupted by AD-related presenilin 1 mutation. In this study, we propose that AD related lysosomal dysfunction may impair lysosomal cobalamin transport. The experiments use in vitro and in vivo models of AD to define how lysosomal dysfunction directly affects cobalamin utilization. SH-SY5Y-AβPP mutant cells were treated with a proteasome inhibitor to induce lysosomal amyloid-β accumulation. We metabolically labeled these cells with [57Co] cobalamin and isolated purified lysosomes, mitochondria, and cytosol fractions. The results indicated that proteasome inhibition was associated with lysosomal amyloid-β accumulation and a doubling of lysosomal [57Co] cobalamin levels. We also used AβPPxPS1 transgenic AD mice that were intraperitoneally injected with [57Co] cobalamin. The amount of [57Co] cobalamin in the major organs of these mice was measured and the subcellular [57Co] cobalamin distribution in the brain was assessed. The results demonstrated that lysosomal [57Co] cobalamin level was significantly increased by 56% in the AβPPxPS1 AD mouse brains as compared to wild type control mice. Together these data provide evidence that lysosomal cobalamin may be impaired in AD in association with amyloid-β accumulation.
Pages 1031-1037
Barbara Mroczko, Magdalena Groblewska, Marzena Zboch, Paweł Muszyński, Agata Zajkowska, Renata Borawska, Maciej Szmitkowski, Johannes Kornhuber, Piotr Lewczuk (Handling Associate Editor: Henrik Zetterberg)
Evaluation of Visinin-Like Protein 1 Concentrations in the Cerebrospinal Fluid of Patients with Mild Cognitive Impairment as a Dynamic Biomarker of Alzheimer’s Disease
Abstract: Background: The correlations between pathology of neurodegenerative diseases, especially Alzheimer’s disease (AD), and concentrations of neuronal calcium sensor proteins, such as visinin-like protein 1 (VILIP-1), in cerebrospinal fluid (CSF) have been discussed in the literature but its utility as biomarker of AD in comparison with mild cognitive impairment (MCI) has not been studied yet. Objective: Therefore, the aim of our study was to assess the clinical utility of the measurement of CSF concentrations of VILIP-1 in patients with AD, MCI subjects, and non-demented controls. The clinical and neuropsychological diagnoses were supported by CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio and increased concentrations of Tau and pTau181 proteins. Methods: The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of biomarkers tested were determined using ELISA method. Results: Concentrations of VILIP-1 in CSF were significantly higher in AD patients compared to the MCI subjects and elderly individuals without cognitive impairment. Increased concentrations of VILIP-1 correlated significantly with reduced Aβ42/40 ratio and higher pTau181 in AD group. Conclusion: Our findings suggest that VILIP-1 may play a role in the AD pathophysiology and is a good candidate for dynamic biomarker of AD, although this issue requires further investigation.
Pages 1039-1058
Lilian Calderón-Garcidueñas, Aristo Vojdani, Eleonore Blaurock-Busch, Yvette Busch, Albrecht Friedle, Maricela Franco-Lira, Partha Sarathi-Mukherjee, Su-Bin Park, Ricardo Torres-Jardón, Amedeo D’Angiulli
Air Pollution and Children: Neural and Tight Junction Antibodies and Combustion Metals, the Role of Barrier Breakdown and Brain Immunity in Neurodegeneration
Abstract: Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5), above safety standards. Mexico City Metropolitan Area (MCMA) megacity children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91±4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin oligodendrocyte glycoprotein IgG and IgM (p<0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p<0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p<0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p=0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic 'self' tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson’s pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children’s brains ought to be of pressing importance for public health.
Pages 1059-1072
Daniel Ferreira, Eric Westman, Helga Eyjolfsdottir, Per Almqvist, Göran Lind, Bengt Linderoth, Åke Seiger, Kaj Blennow, Azadeh Karami , Taher Darreh-Shori, Maria Wiberg, Andrew Simmons, Lars-Olof Wahlund, Lars Wahlberg, Maria Eriksdotter, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Patrizia Mecocci)
Brain Changes in Alzheimer’s Disease Patients with Implanted Encapsulated Cells Releasing Nerve Growth Factor
Abstract: New therapies with disease-modifying effects are urgently needed for treating Alzheimer’s disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age- and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42. However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects.
Pages 1073-1090
Stephen W. Scheff, Douglas A. Price, Mubeen A. Ansari, Kelly N. Roberts, Frederick A. Schmitt, Milos D. Ikonomovic, Elliott J. Mufson
Synaptic Change in the Posterior Cingulate Gyrus in the Progression of Alzheimer’s Disease
Abstract: Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer’s disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD.
Pages 1091-1092
Book Review: Proteomics and Metabolomics in Psychiatry, Advances in Biological Psychiatry, Volume 29, by D. Martins-de-Souza, editor, S. Karger AG, Basel, 2014, 142 p. Reviewed by Stephan B. H. Bach
