1.
Altered CSF Orexin and α-Synuclein Levels in Dementia Patients.
Source
Molecular Memory Research Unit, The Wallenberg Lab, Lund University, Department of Clinical Sciences Malmö, Sweden.
Abstract
Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation, and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.
Determinants of Acute Kidney Injury Duration After Cardiac Surgery: An Externally Validated Tool.
Source
The Dartmouth Institute for Health Policy and Clinical Practice, Section of Cardiology Dartmouth-Hitchcock Medical Center, and Dartmouth Medical School, Lebanon, New Hampshire.
Abstract
BACKGROUND:
Acute kidney injury (AKI) duration after cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what perioperative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify perioperative risk factors that predict duration of AKI, a complication that effects short and long-term survival.
METHODS:
We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. Acute kidney injury was defined as a 0.3 or greater (mg/dL) or 50% or greater increase in serum creatinine from baseline. Duration of AKI was defined by the number of days AKI was present. Stepwise multivariable negative binomial regression analysis was conducted using perioperative risk factors for AKI duration. The c-index was estimated by Kendall's tau.
RESULTS:
Acute kidney injury developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had a duration of 0 days. Independent predictors of AKI duration included baseline patient and disease characteristics, and operative and postoperative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (Translational Research Investigating Biomarker Endpoints-AKI). The c-index was 0.65 (p < 0.001) for the derivation cohort and 0.62 (p < 0.001) for the validation cohort.
CONCLUSIONS:
We identified and externally validated perioperative predictors of AKI duration. These risk factors will be useful to evaluate a patient's risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long-term survival. The levels of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI.
Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice.
Source
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; New York University School of Medicine, New York, NY, USA.
Abstract
We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) β-amyloidosis, the APP23 mouse, reduces β-amyloid (Aβ) pathology and Aβ levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Aβ plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Aβ plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with Aβ pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Aβ pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Aβ pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Aβ pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors.
Copyright © 2011 Elsevier Inc. All rights reserved.
Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and non-inflamed patients.
Abstract
ABSTRACT:
INTRODUCTION:
Delirium occurs frequently in critically ill patients and is associated with disease severity and infection. Although several pathways for delirium have been described, biomarkers associated with delirium in ICU patients is not well studied. We examined plasma biomarkers in delirious and non-delirious patients and the role of these biomarkers on long-term cognitive function.
METHODS:
In an exploratory observational study we included 100 ICU patients with or without delirium and with ("inflamed") and without ("non-inflamed") infection/SIRS. Delirium was diagnosed using the confusion assessment method-ICU (CAM-ICU). Within 24 hours following the onset of delirium, blood was obtained for biomarker analysis. There were no differences in patient characteristics between delirious and non-delirious patients. To determine associations between biomarkers and delirium univariate and multivariate logistic regression analyses was performed. Eighteen months after ICU discharge, a cognitive failure questionnaire was distributed to the ICU survivors.
RESULTS:
In total 50 delirious and 50 non-delirious patients were included. We found that IL-8, MCP-1, PCT, cortisol and S100-beta were significantly associated with delirium in inflamed patients (N=46). In the non-inflamed group of patients (N=54) IL-8, IL-1ra, IL-10 ratio A-beta1-42/40 and ratio A-betaN-42/40 were significantly associated with delirium. In multivariate regression analysis IL-8 was independently associated (odds ratio 9.0; 95%CI 1.8-44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95%CI 1.1 - 5.9) and A-beta1-42/40 (OR 0.03; 95%CI 0.002 - 0.50) with delirium in non-inflamed patients. Furthermore, levels of several amyloid-beta forms, but not human Tau or S100-beta, were significantly correlated with self reported cognitive impairment 18 months after ICU discharge, while inflammatory markers were not correlated to impaired long-term cognitive function.
CONCLUSIONS:
In inflamed patients the proinflammatory cytokine IL-8 was associated with delirium. While in non-inflamed patients anti-inflammatory cytokine IL-10 and A-beta1-42/40 were associated with delirium. This suggests that the underlying mechanism governing the development of delirium in inflamed patients differs from that in non-inflamed patients. Finally, elevated levels of amyloid-beta correlate with long-term subjective cognitive impairment delirium may represent the first sign of a (subclinical) dementia process. Future studies need to confirm these results.
Phosphorus Dendrimers Affect Alzheimer's (Aβ1-28) Peptide and MAP-TauProtein Aggregation.
Abstract
Alzheimer's disease (AD) is characterized by pathological aggregation of β-amyloid peptides and MAP-Tau protein. β-amyloid (Aβ) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Aβ are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Aβ1-28) and MAP-Tau protein. We have demonstrated that CPDs are able to affect β-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Aβ1-28 aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer'sdisease.
Tau reduction does not prevent motor deficits in two mouse models of Parkinson's disease.
Source
Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
Abstract
Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer'sdisease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau(+/+), Tau(+/-) and Tau(-/-) backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and thattau reduction may not be of benefit in the latter condition.
Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions.
Source
Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden.
Abstract
Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.
Regulation of Physiologic Actions of LRRK2: Focus on Autophagy.
Source
Department of Pharmacology, Boston University School of Medicine, Boston, Mass., USA.
Abstract
Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.
Copyright © 2011 S. Karger AG, Basel.
Spines, plasticity, and cognition in Alzheimer's model mice.
Source
Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
Abstract
The pathological hallmarks of Alzheimer's disease (AD)-widespread synaptic and neuronal loss and the pathological accumulation of amyloid-beta peptide (Aβ) in senile plaques, as well as hyperphosphorylated tau in neurofibrillary tangles-have been known for many decades, but the links between AD pathology and dementia and effective therapeutic strategies remain elusive. Transgenic mice have been developed based on rare familial forms of AD and frontotemporal dementia, allowing investigators to test in detail the structural, functional, and behavioral consequences of AD-associated pathology. Here, we review work on transgenic AD models that investigate the degeneration of dendritic spine structure, synaptic function, and cognition. Together, these data support a model of AD pathogenesis in which soluble Aβ initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. These changes in synapse structure and function as well as frank synapse and neuronal loss contribute to the neural system dysfunction which causes cognitive deficits. Understanding the underpinnings of dementia in AD will be essential to develop and evaluate therapeutic approaches for this widespread and devastatingdisease.
The role of mTOR signaling in Alzheimer disease.
Source
Department of Physiology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio. 7703 Floyd Curl Drive, San Antonio, TX 78229.
Abstract
The buildup of Abeta and tau is believed to directly cause or contribute to the progressive cognitive deficits characteristic of Alzheimer disease. However, the molecular pathways linking Abeta and tau accumulation to learning and memory deficits remain elusive. There is growing evidence that soluble forms of Abeta and tau can obstruct learning and memory by interfering with several signaling cascades. In this review, I will present data showing that the mammalian target of rapamycin (mTOR) may play a role in Abeta and tau induced neurodegeneration.
- PMID:
- 22202101
- [PubMed - in process]
The contributions of unscheduled neuronal cell cycle events to the death of neurons in Alzheimer's disease.
Source
Dept. of Cell Biology and Neuroscience, Nelson Biological Laboratories, 604 Allison Road, Piscataway, NJ 0854.
Abstract
Alzheimer's disease is a neurodegenerative disorder that accounts for the majority of the dementia in individuals over the age of 65. While much has been learned about the biology and biochemistry of the tau tangles and beta-amyloid plaques, less is known about the cell biology of the neuronal cell death process. This review examines one feature of this process, the unexpected occurrence of unscheduled cell cycle events in mature and normally non-mitotic neurons in the at-risk neuronal populations. The correlation of neuronal cell cycling and cell death is not unique to Alzheimer's, but the evidence in both human Alzheimer's disease and its mouse models suggests that these events are earlydisease related processes, that they are driving forces of the disease rather than indirect symptoms. Defining the biochemistry behind cell cycle initiation holds promise as a fresh therapeutic approach in the battle against this devastating disease.
- PMID:
- 22202022
- [PubMed - in process]
Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease.
Source
Departments of Neurology, Neurosurgery, and Neuropathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI.
Abstract
Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.
- PMID:
- 22201977
- [PubMed - in process]
Metals in alzheimer's disease: a systemic perspective.
Source
Department of Neuroscience, AFaR, Fatebenefratelli Hospital, Rome, Italy, Department of Neurology, Campus Biomedico, University, Rome, Italy.
Abstract
Many results from in vitro and animal studies have highlighted the important role played by specific metals, such as copper, iron and zinc, in the diverse toxic pathways on which Alzheimer's disease (AD) develops. Metals seem to mediate the aggregation and neurotoxicity of amyloid-beta (ABeta), the main constituent of the amyloid plaques, commonly seen in AD (1). The link between metals and AD has been mostly investigated with a focus on their local accumulation in defined areas of the brain critical for AD. In the present review, I have instead approached the issue from the different perspective of a systemic, rather than local, alteration of copper and iron status. This view is supported by the results of a series of in vivo studies demonstrating that abnormalities of metals homeostasis correlate with the main deficits and specific markers of AD, such as ABeta and Tau proteins in the cerebrospinal fluid. These findings clearly suggest that local metals accumulation in brain areas critical for AD should be viewed within a wider framework of metals systemic alteration.
- PMID:
- 22201755
- [PubMed - in process]
Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitors.
Source
Department of Neurology, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA; Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract
Alzheimer's disease (AD) is the most common cause of memory impairment and dementia in the elderly. AD is pathologically characterized by extracellular deposits of beta-amyloid (Aβ) peptide, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, neuronal loss, and neurotransmitter dysfunction. Clinically, AD is characterized by progressive cognitive decline that usually starts with memory impairment and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms. These symptoms collectively lead to a progressive and relentless decline in the ability to perform functions of daily living, eventually leading to total incapacitation. The incidence and prevalence of AD are expected to exponentially increase with the aging of the population. Currently approved treatments, including the acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine and rivastigmine, and the N-methyl-D-aspartate (NMDA) antagonist memantine, do not halt the progression of the disease, and have provided marginal therapeutic benefits. Accordingly, there is an urgent need to develop novel and effective medications for AD that go beyond AChEIs and NMDA antagonists. Modern research has focused on discovering effective disease-modifying therapies, which specifically target the pathophysiologic cascade, hoping to delay the onset of the disease and slow its progression. In this review, different pharmacological drugs and therapeutic approaches will be discussed, with an emphasis on novel therapies that are currently being investigated in clinical trials.
Copyright © 2011. Published by Elsevier Inc.
Comparative evaluation of Logan and relative-equilibrium graphical methods for parametric imaging of dynamic [(18)F]FDDNP pet determinations.
Source
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Abstract
Logan graphical analysis with cerebellum as reference region has been widely used for the estimation of the distribution volume ratio (DVR) of [(18)F]FDDNP as a measure of amyloid burden and tau deposition in human brain because of its simplicity and computational ease. However, spurious parametric DVR images may be produced with shorter scanning times and when the noise level is high. In this work, we have characterized a relative-equilibrium-based (RE) graphical method against the Logan analysis for parametric imaging and region-of-interest (ROI) analysis.
METHODS:
Dynamic [(18)F]FDDNP PET scans were performed on 9 control subjects and 12 patients diagnosed with Alzheimer's disease. Using the cerebellum as reference input, regional DVR estimates were derived using both the Logan analysis and the RE plot approach. Effects on DVR estimates obtained at voxel and ROI levels by both graphical approaches using data in different time windows were investigated and compared with the standard values derived using the Logan analysis on a voxel-by-voxel basis for the time window of 35-125min used in previous studies.
RESULTS:
Larger bias and variability were observed for DVR estimates obtained by the Logan graphical analysis at the voxel level when short time windows (85-125 and 45-65min) were used, because of high noise levels in voxel-wise parametric imaging. However, when the Logan graphical analysis was applied at the ROI level over those short time windows, the DVR estimates did not differ significantly from the standard values derived using the Logan analysis on the voxel level for the time window of 35-125min, and their bias and variability were remarkably lower. Conversely, the RE plot approach was more robust in providing DVR estimates with less bias and variability even when short time windows were used. The DVR estimates obtained at voxel and ROI levels were consistent. No significant differences were observed in DVR estimates obtained by the RE plot approach for all paired comparisons with the standard values.
CONCLUSIONS:
The RE plot approach provides less noisy parametric images and consistent and reliable regional DVR estimates at both voxel and ROI levels, indicating that it is preferred over the Logan graphical analysis for analyzing [(18)F]FDDNP PET data.
Copyright © 2011. Published by Elsevier Inc.
Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I).
Source
Instituto Cajal, CSIC, Madrid, España.
Abstract
INTRODUCTION:
Many publications consider that the Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the disease in humans, both in the neuropathological changes and cognitive-behavioural symptoms.
DEVELOPMENT:
In this work, the results published (PubMed) on the senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. Even in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein, are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are present in some senile individuals with greater intensity when compared with both normal adult individuals and other senile individuals of the species. The importance of the determination of the longevity of the species in different habitats (natural habitats, new habitats, semi-liberty, captivity) is stressed in these studies.
CONCLUSIONS:
Morphological and histochemical and cognitive-behavioural features similar to those observed in normal aged man are present in senile non-human primates. Moreover, other characteristics of the non-human primates could be indicative of a pathological «Alzheimer type» ageing.
Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
Isoflurane-induced spatial memory impairment by a mechanism independent of amyloid-beta levels and tau protein phosphorylation changes in aged rats.
Source
Chaoyang Hospital, Capital Medical University, Beijing, China.
Abstract
OBJECTIVES:
The molecular mechanism of postoperative cognitive dysfunction is largely unknown. Isoflurane has been shown to promote Alzheimer's disease neuropathogenesis. We set out to determine whether the effect of isoflurane on spatial memory is associated with amyloid-beta (A-beta) levels and tau phosphorylation in aged rats.
METHODS:
Eighteen-month-old male Sprague-Dawley rats were randomly assigned as anesthesia group (n = 31, received 1·4% isoflurane for 2 hours and had behavioral testing), training group (n = 20, received no anesthesia but had behavioral testing), and control group (n = 10, received no anesthesia and had no behavioral testing). Spatial memory was measured before and 2 days after the anesthesia by the Morris water maze. We divided the anesthesia group into an isoflurane-induced severe memory impairment group (SIG, n = 6) and a no severe memory impairment group (NSIG, n = 25), according to whether the escape latency was more than 1·96 stand deviation of that from the training group. Levels of A-beta and tau in the hippocampus were determined by enzyme-linked immunosorbent assay and quantitative western blot at the end of behavioral testing.
RESULTS:
We found that isoflurane increased the escape latency in the SIG as compared to that in the training group and NSIG without affecting swimming speed. However, there were no differences in the levels of A-beta and tau among SIG, NSIG, training, and control groups.
CONCLUSIONS:
Isoflurane may induce spatial memory impairment through non-A-beta or tau neuropathogenesis mechanisms in aged rats.
- PMID:
- 22196855
- [PubMed - in process]
Diagnostic Utility of CSF Tau and Aβ(42) in Dementia: A Meta-Analysis.
Source
Department of Neurochemistry, Institute of Human Behaviour & Allied Sciences, Dilshad Garden, Delhi 110095, India.
Abstract
CSF tau and Aβ42 are considered as important markers to diagnose Alzheimer's disease in early stages. Hence, it is important to assess their status in different types of dementia. The main objective of this study was to assess whether these CSF biomarkers can be used to make the differential diagnosis of AD. In the present study, articles published from 1998 till 2009 were taken and meta-analysis was performed to clarify the consistency in trends of biomarkers- CSFtau and Aβ(42) in AD and other dementias and whether the same can be used as diagnostic biomarkers for its early diagnosis. 11 out of 60 for CSF tau and 07 out of 40 for CSF Aβ(42), dementia case-control studies were selected for final analysis. Descriptive statistics shows that median effect size (raw mean difference) of CSF tau was 429 pg/mL (range: 32 to 910 pg/mL) in AD whereas in Dementia due to other causes (DOC) studies it was 69 pg/mL (range: -53 to 518 pg/mL). Similarly the median effect size of CSF Aβ(42) levels was -442 pg/mL (range: -652 to -41.200 pg/mL) whereas in DOC studies it was -193 pg/mL (range: -356 to -33 pg/mL).
Clinical and Pathological Characteristics of LRRK2 G2019S Patients with PD.
Source
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Abstract
The objective of this study is to describe the neuropathologic findings in three LRRK2 G2019S carriers with Parkinson'sdisease (PD). We cross-referenced a list of 956 PD individuals that had been previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients. All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy body (LB) pathology, tau inclusions, and amyloid pathology consistent with advanced Alzheimer's disease; one had diffuse cortical LB; and one had only brainstem predominant LB pathology. Cognitive impairment may be a long-term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow-up of LRRK2 G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.
Olfaction in Parkinson's disease and related disorders.
Abstract
Olfactory dysfunction is an early 'pre-clinical' sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclean- and tau-related pathology, or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances.
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