Mark Anthony Smith (1965–2010): Visionary, Alzheimer Researcher, and Editor-in-Chief of the Journal of Alzheimer's Disease
Authors: Perry, George | Zhu, Xiongwei
Citation: Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 1-2, 2011
Scientific Truth or False Hope? Understanding Alzheimer's Disease from an Aging Perspective
Authors: Chen, Ming | Maleski, Jerome J. | Sawmiller, Darrell R.
Abstract: In this paper, we argue that the current official definition for Alzheimer's disease is misleading, since it defines senile dementia (SD), a long-known incurable senile/geriatric condition, as a discrete/curable disease. This overly optimistic definition was incepted in the 1970s amid the public's fear of the upcoming SD crisis and desperate hope for a cure. Scientifically, however, it has overturned Alois Alzheimer's age-based concept for disease classification—the essence of modern Geriatric Medicine and the National Institute of Aging. Thus, the current definition for SD, though socially and politically appealing, would be scientifically flawed. As an authoritative study guideline, it has caused …profound and far-reaching confusions in research by misleading attention to the presumptive pathogenic/erroneous factors as drug targets for "silver bullets". Such well-intentioned studies would generate numerous data, but render SD a scientific and logical enigma. In this context we discuss: 1) why and how senile conditions including SD differ from discrete diseases by origin, thus also by study paradigm and intervention strategy; 2) why senile conditions may not be explained by abnormal/pathogenic factors, but logically should be explained by "normal" elements in life, perhaps advanced aging plus risk factors; and 3) why the "amyloid-β toxicity" controversy, a simple scientific issue, has lasted for so long. Finally, we ask: can scientific inquiry preserve its integrity and objectivity under social pressure? It appears that these fundamental questions warrant serious attention if the scientific nature of SD is to be eventually understood. Corresponding author: Ming Chen. E-mail: [email protected] Show more
Keywords: Alzheimer's disease, amyloid, aging, tau
Citation: Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 3-10, 2011
Describing the Dying Days of "Alzheimer's Disease"
Authors: Whitehouse, Peter J. | George, Daniel R. | D'Alton, Simon
Citation: Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 11-13, 2011
Homeostatic Disinhibition in the Aging Brain and Alzheimer's Disease
Authors: Gleichmann, Marc | Chow, Vivian W. | Mattson, Mark P.
Abstract: In this article, we propose that impaired efficiency of glutamatergic synaptic transmission and a compensatory reduction in inhibitory neurotransmission, a process called homeostatic dishinhibition, occurs in the aging brain and more dramatically in Alzheimer's disease (AD). Homeostatic disinhibition may help understand certain features of the aging brain and AD, including: 1) the increased risk for epileptic seizures, especially in the early phase of the disease; 2) the reduced ability to generate γ-oscillations; and 3) the increase in neuronal activity as measured by functional MRI. Homeostatic disinhibition may be the major mechanism that activates cognitive reserve. Modulating neuronal activity may therefore …be a viable therapeutic strategy in AD that can complement existing anti-amyloid strategies. Specifically, enhancing endogenous glutamatergic synaptic transmission through increased co-agonist signaling or through positive allosteric modulation of metabotropic glutamatergic receptors appears as an attractive strategy. Alternatively, further reduction of GABAergic signaling may work as well, although care has to be taken to prevent epileptic seizures. Show more
Keywords: Alzheimer's disease, cognitive reserve, disinhibition, GABA, interneuron, neuronal activity
Impaired Lipoprotein Receptor-Mediated Peripheral Binding of Plasma Amyloid-β is an Early Biomarker for Mild Cognitive Impairment Preceding Alzheimer's Disease
Authors: Sagare, Abhay P. | Deane, Rashid | Zetterberg, Henrik | Wallin, Anders | Blennow, Kaj | Zlokovic, Berislav V.
Abstract: Soluble circulating low density lipoprotein receptor-related protein-1 (sLRP) provides key plasma binding activity for Alzheimer's disease (AD) amyloid-β peptide (Aβ). sLRP normally binds 70–90% of plasma Aβ preventing free Aβ access to the brain. In AD, Aβ binding to sLRP is compromised by increased levels of oxidized sLRP which does not bind Aβ. Here, we determined plasma oxidized sLRP and Aβ40/42 sLRP-bound, other proteins-bound and free plasma fractions, cerebrospinal fluid (CSF) tau/Aβ42 ratios, and mini-mental state examination (MMSE) scores in patients with mild cognitive impairment (MCI) who progressed to AD (MCI-AD, n = 14), AD (n = 14) …and neurologically healthy controls (n = 14) recruited from the Göteborg MCI study. In MCI-AD patients prior to conversion to AD and AD patients, the respective increases in oxidized sLRP and free plasma Aβ40 and Aβ42 levels were 4.9 and 3.7-fold, 1.8, and 1.7-fold and 4.3 and 3.3-fold (p < 0.05, ANOVA with Tuckey post-hoc test). In MCI-AD and AD patients increases in oxidized sLRP and free plasma Aβ40 and Aβ42 correlated with increases in CSF tau/Aβ42 ratios and reductions in MMSE scores (p < 0.05, Pearson analysis). A heterogeneous group of 'stable' MCI patients that was followed over 2–4 years (n = 24) had normal CSF tau/Aβ42 ratios but increased oxidized sLRP levels (p < 0.05, Student's t test). Data suggests that a deficient sLRP-Aβ binding might precede and correlate later in disease with an increase in the tau/Aβ42 CSF ratio and global cognitive decline in MCI individuals converting into AD, and therefore is an early biomarker for AD-type dementia. Show more
Keywords: Aging, Alzheimer's disease, biomarker, mild cognitive impairment, soluble low density lipoprotein receptor-related protein (sLRP)
Predicting Disease Progression in Alzheimer's Disease: The Role of Neuropsychiatric Syndromes on Functional and Cognitive Decline
Authors: Palmer, Katie | Lupo, Federica | Perri, Roberta | Salamone, Giovanna | Fadda, Lucia | Caltagirone, Carlo | Musicco, Massimo | Cravello, Luca
Abstract: Patients with Alzheimer's disease (AD) have heterogeneous rates of disease progression. The aim of the current study is to investigate whether neuropsychiatric disturbances predict cognitive and functional disease progression in AD, according to failure theory. We longitudinally examined 177 memory-clinic AD outpatients (mean age = 73.1, SD = 8.1; 70.6% women). Neuropsychiatric disturbances at baseline were categorized into five syndromes. Patients were followed for up to two years to detect rapid disease progression defined as a loss of ≥ 1 abilities in Activities of Daily living (ADL) or a drop of ≥ 5 points on Mini-Mental State Examination (MMSE). Hazard …ratios (HR) were calculated with Gompertz regression, adjusting for sociodemographics, baseline cognitive and functional status, and somatic comorbidities. Most patients (74.6%) exhibited one or more neuropsychiatric syndromes at baseline. The most common neuropsychiatric syndrome was Apathy (63.8%), followed by Affective (37.3%), Psychomotor (8.5%), Manic (7.9%), and Psychotic (5.6%) syndromes. The variance between the observed (Kaplen Meier) and predicted (Gompertz) decline for disease progression in cognition (0.30, CI = 0.26–0.35), was higher than the variance seen for functional decline (0.22, CI = 0.18–0.26). After multiple adjustment, patients with the Affective syndrome had an increased risk of functional decline (HR = 2.0; CI = 1.1–3.6), whereas the risk of cognitive decline was associated with the Manic (HR = 3.2, CI = 1.3–7.5) syndrome. In conclusion, specific neuropsychiatric syndromes are associated with functional and cognitive decline during the progression of AD, which may help with the long-term planning of care and treatment. These results highlight the importance of incorporating a thorough psychiatric examination in the evaluation of AD patients. Show more
Keywords: Activities of daily living, anxiety, apathy, behavioral and psychological symptoms of dementia, failure theory, cognitive impairment, dementia, depression, disease progression, Gompertz
Increasing the Predictive Accuracy of Amyloid-β Blood-Borne Biomarkers in Alzheimer's Disease
Authors: Watt, Andrew D. | Perez, Keyla A. | Faux, Noel G. | Pike, Kerryn E. | Rowe, Christopher C. | Bourgeat, Pierrick | Salvado, Olivier | Masters, Colin L. | Villemagne, Victor L. | Barnham, Kevin J.
Abstract: Diagnostic measures for Alzheimer's disease (AD) commonly rely on evaluating the levels of amyloid-β (Aβ) peptides within the cerebrospinal fluid (CSF) of affected individuals. These levels are often combined with levels of an additional non-Aβ marker to increase predictive accuracy. Recent efforts to overcome the invasive nature of CSF collection led to the observation of Aβ species within the blood cellular fraction, however, little is known of what additional biomarkers may be found in this membranous fraction. The current study aimed to undertake a discovery-based proteomic investigation of the blood cellular fraction from AD patients (n = 18) and healthy …controls (HC; n = 15) using copper immobilized metal affinity capture and Surface Enhanced Laser Desorption/Ionisation Time-Of-Flight Mass Spectrometry. Three candidate biomarkers were observed which could differentiate AD patients from HC (ROC AUC > 0.8). Bivariate pairwise comparisons revealed significant correlations between these markers and measures of AD severity including; MMSE, composite memory, brain amyloid burden, and hippocampal volume. A partial least squares regression model was generated using the three candidate markers along with blood levels of Aβ. This model was able to distinguish AD from HC with high specificity (90%) and sensitivity (77%) and was able to separate individuals with mild cognitive impairment (MCI) who converted to AD from MCI non-converters. While requiring further characterization, these candidate biomarkers reaffirm the potential efficacy of blood-based investigations into neurodegenerative conditions. Furthermore, the findings indicate that the incorporation of non-amyloid markers into predictive models, function to increase the accuracy of the diagnostic potential of Aβ. Show more
Keywords: Amyloid-β, biomarkers, blood, copper, diagnostics, SELDI-TOF-MS
Folic Acid Plus α-Tocopherol Mitigates Amyloid-β-Induced Neurotoxicity through Modulation of Mitochondrial Complexes Activity
Authors: Figueiredo, Cláudia P. | Bicca, Maíra A. | Latini, Alexandra | Prediger, Rui Daniel S. | Medeiros, Rodrigo | Calixto, João B.
Abstract: Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and α-tocopherol protects mice against the Aβ-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus α-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aβ1–40 -induced cognitive decline, synaptic loss, and neuronal death. However, …chronic treatment comprising folic acid plus α-tocopherol was ineffective on Aβ-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our study suggest that mitochondrial energy metabolism is impaired by the Aβ peptide, and upregulation of mitochondrial genes may be a compensatory response, as demonstrated by the increase in mitochondrial complexes I, II, and IV activity, in the hippocampus of mice, after Aβ1–40 injection. Of note, the chronic treatment comprising folic acid plus α-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by Aβ1–40 . Together, these results show the antioxidant effect of the combination of folic acid and α-tocopherol, as observed by the decrease in NO generation from iNOS and nNOS, preventing an increase in the activity of mitochondrial complexes, mainly I and IV, and the neuronal death induced by the Aβ1–40 peptide. Show more
Keywords: Alpha-tocopherol, amyloid-β, cognition, folic acid, mitochondrial complexes
Increased Protein and Lipid Oxidative Damage in Mitochondria Isolated from Lymphocytes from Patients with Alzheimer's Disease: Insights into the Role of Oxidative Stress in Alzheimer's Disease and Ini…
Authors: Sultana, Rukhsana | Mecocci, Patrizia | Mangialasche, Francesca | Cecchetti, Roberta | Baglioni, Mauro | Butterfield, D. Allan
Abstract: Alzheimer's disease (AD) is histopathologically characterized by the presence of senile plaques, neurofibrillary tangles, and synapse loss. The main component of senile plaques is amyloid β-peptide (Aβ), which has been shown to induce oxidative stress in in vitro and in vivo studies. AD is associated with elevated levels of oxidative damage in brain and peripheral lymphocytes. Further Aβ has been found to be accumulated in mitochondria, which might contribute to the reported alterations in the mitochondrial morphology, and impaired mitochondrial energy metabolism in AD brain. Biomarkers are desperately needed for earlier diagnosis of AD and to monitor efficacy of new …therapies. Hence, in the present study we show that markers of oxidative damage are elevated in mitochondria isolated from AD lymphocytes suggesting that these oxidative stress indices potentially could serve as a viable biomarker for AD. Show more
Keywords: Alzheimer's disease, lymphocytes, mitochondria, 3-nitrotyrosine, oxidative stress, protein-bound 4 hydroxy-2 trans nonenal, protein carbonyls
The Flavonoid Apigenin Protects Brain Neurovascular Coupling against Amyloid-β 25-35-Induced Toxicity in Mice
Authors: Liu, Rui | Zhang, Tiantai | Yang, Haiguang | Lan, Xi | Ying, Jian | Du, Guanhua
Abstract: Apigenin, one of the most common flavonoids, has demonstrated anti-inflammatory, anticarcinogenic, and free radical-scavenging activities. Recent studies revealed its protective effects against amyloid-β (Aβ)-induced neurotoxicity, but the mechanism was unclear. In the present study, we aimed to explore the anti-amnesic and protective effects of apigenin against Aβ25-35 -induced toxicity and the underlying mechanisms in the cerebral cortex in mice. The learning and memory impairments, changes in morphology of major components of neurovascular unit, ultrastructural changes and oxidative stress of cerebral cortex, cerebrovascular dysfunction, and neuronal changes were detected after oral administration of apigenin continuously for 8 days. Our results demonstrate …that oral administration of apigenin for Aβ25-35 -induced amnesic mice conferred robust neurovascular coupling protection, involving improvement of the learning and memory capabilities, maintenance of neurovascular unit integrity, modulation of microvascular function, reduction of neurovascular oxidative damage, increase of regional cerebral blood flow, improvement of cholinergic system involving the inhibition of AChE activity and elevation of ACh level, and modification of BNDF, TrkB, and phospho-CREB levels. Show more
Keywords: Amyloid-β peptide, apigenin, blood-brain barrier, neurovascular unit
Citation: Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 85-100, 2011