Prolonged cholinergic enrichment influences regional cortical activation in early Alzheimer's disease

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) indicate that the short and long term actions of ChEIs are dissimilar. fMRI studies of the ChEI rivastigmine have focused on its short term action. In this exploratory study the effect of prolonged (20 weeks) rivastigmine treatment on regional brain activity was measured with fMRI in patients with mild AD. Eleven patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. There was an increase in task-related brain activity after treatment with activations more like those of normal healthy elderly. Behaviorally, however, there were no significant differences between baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Variable patient response and drug dynamic/kinetic factors in small patient groups will inevitably bias (either way) the effect size of any relevant drug related changes in activation. Future studies should take drug response into account to provide more insight into the benefits of ChEI drugs at the individual level.     

A review of SPECT studies in psychiatry in China

Background

Studies of mental disorders using single photon emission computed tomography (SPECT) have been done for many years in China. Many results have been obtained. We review these findings and introduce them to the outside world.

Methods

SPECT papers available on the Chinese Biomedical Bibliographic Database, focusing on depression, schizophrenia, Alzheimer’s disease (AD), vascular dementia (VD), anxiety disorder, and obsessive compulsive disorder (OCD) in China, were reviewed and the results were compared with those obtained outside China.

Results

We found that regional cerebral blood flow (rCBF) was abnormal in mental disorders, but the specificity of the abnormality is not yet consistent. Lower perfusion of rCBF could be seen in frontal, temporal, and parietal lobes of patients with depression, AD, schizophrenia, and VD. It seems that abnormality of the frontal lobe is more common in depression and schizophrenia, but temporal lobe abnormalities are more common in AD and VD. The perfusion of rCBF in the parietal lobe seems to be related to aging. Abnormalities in the occipital lobe and basal ganglia seem to be more associated with vascular problems. Thalamic dysfunction was mainly correlated with VD, and that of the cingulate largely with depression and schizophrenia. Hippocampal abnormalities were associated with AD. There were few reports on changes in anxiety disorders and other mental problems.

Conclusion

There is no specific biological marker of SPECT for individual mental disorders. Further study is needed to provide more specific information on the pathophysiology of mental disorders. It seems that brain abnormalities are similar in Chinese and non Chinese psychiatric patients.     

Diffusion tensor imaging investigations in Alzheimer’s disease: the resurgence of white matter compromise in the cortical dysfunction of the aging brain

Diffusion tensor imaging (DTI) is a sophisticated MRI-based neuroimaging technique that enables in vivo quantification of differences in molecular diffusion at the cellular level. Owing to the highly directional architecture of white matter (WM), DTI is providing important clues of the structure and geometric organization of this neural compartment. Since DTI can detect changes even in the case of radiologically “normal” appearing WM, researchers are using the technique for the study of WM integrity at the initial stages of the most common neurodegenerative disorders. Along with a well characterized cortical pathology (neuritic plaques and intracellular neurofibrillary tangles), WM changes have been also demonstrated in Alzheimer’s disease (AD). However, these changes had been for years found nonliable in the onset and progress of AD, basically due to lack of incriminatory evidence. The use of novel tools such as DTI has enabled the anatomical distribution of WM microstructural damage in the prodromal stages of AD to be gauged and determined, granting a long-delayed protagonic role to WM in the natural history of this highly prevalent neurodegenerative condition.     

一氧化氮在神经退行性疾病中的作用:非类固醇性抗炎药的治疗前景(英文)

一氧化氮(nitric oxide, NO)是一类胞内信使。研究表明,神经退行性病人脑组织中催化合成NO的酶的表达水平显著提高,提示NO与神经退行性疾病密切相关。此外,在这些组织中还检测到硝化的蛋白,提示NO在这些组织中具有生物活性。在神经免疫应答中,神经元和胶质细胞(包括小胶质细胞和星形胶质细胞)内都发生了NO水平的改变。很多神经退行性疾病都伴随有神经炎症,抑制神经炎症的信号通路能延迟这些疾病的发展。因此,NO及其释放通路已逐渐成为神经退行性疾病研究领域的热点,对它们的理解能帮助我们找到合适的方案来预防、减缓或者治愈这些疾病。     

Metabolomics: a novel approach to identify potential diagnostic biomarkers and pathogenesis in Alzheimer’s disease

Although the pathogenesis of Alzheimer’s disease (AD) is still not fully understood, it is acknowledged that intervention should be made at the early stage. Therefore, identifying biomarkers for the clinical diagnosis is critical. Metabolomics, a novel "omics", uses methods based on low-molecular-weight molecules, with high-throughput evaluation of a large number of metabolites that may lead to the identification of new disease-specific biomarkers and the elucidation of pathophysiological mechanisms. This review discusses metabolomics investigations of AD and potential future developments in this field.     

Clustering and switching during a semantic verbal fluency test contribute to differential diagnosis of cognitive impairment

The verbal fluency test (VFT) can be dissociated into "clustering" (generating words within subcategories) and "switching" (shifting between clusters), which may be valuable in differential diagnosis. In the current study, we investigated the validity of VFT in the differential diagnosis of Alzheimer’s disease (AD, n = 65), vascular dementia (VaD, n = 65), mild cognitive impairment (MCI, n = 92), and vascular cognitive impairment without dementia (VCIND, n = 76) relative to cognitively normal senior controls (NC, n = 374). We found that in the NC group, the total correct score was significantly correlated with age and education; males generated more subcategories; cluster size increased with education, and subcategory and switching decreased with age. A significantly progressive advantage was observed in VFT scores in the sequence NC > MCI/VCIND > AD/VaD, and this significantly discriminated dementia patients from the other groups. AD patients performed better in all four VFT scores than VaD patients. Subcategory and switching scores significantly distinguished AD from VaD patients (AD > VaD; mean difference, 0.50 for subcategory, P <0.05; 0.71 for switching, P <0.05). MCI patients scored higher than VCIND patients, but the difference did not reach statistical significance. These results suggest that semantic VFT is useful for the detection of MCI and VCIND, and in the differential diagnosis of cognitive impairment.     

Rhodanine and thiohydantoin derivatives for detecting tau pathology in Alzheimer's brains

A novel series of rhodanin (RH) and thiohydantoin (TH) derivatives were designed and synthesized for detecting tau pathology in the brains of patients with Alzheimer's disease (AD). In experiments in vitro using tau and β-amyloid (Aβ) aggregates, the TH derivative, TH2, showed high specific binding to tau aggregates. In hippocampal sections obtained from AD patients, TH2 intensely stained neurofibrillary tangles. In experiments using normal mice, [(125)I]TH2 showed good uptake (1.54%ID/g, 2 min postinjection) into and a rapid washout (0.25%ID/g, 60 min postinjection) from the brain. [(123)I]TH2 should be further investigated as a potential imaging agent for detecting tau pathology.     

Conceptualization of depression in Parkinson's disease

AIMS: To discuss the current methodological and conceptual difficulties inherent in characterizing the emotional manifestations of neurodegenerative disease through critically reviewing depression as a manifestation of idiopathic Parkinson's disease (PD). METHODS: Selective literature review of the neurobiological, psychological, and physical basis of depressive symptoms in PD from 1993-2003, with reference to key earlier articles. CONCLUSIONS: There are difficulties in defining the syndromes of PD itself as well as depression in PD. The use of more conceptually reductionistic definitions of emotion and behavior in comprehensive longitudinal studies of the natural history of PD is recommended.     

Association between NMDA receptor subunit 2b gene polymorphism and Alzheimer’s disease in Chinese Han population in Shanghai

Objective

N-methyl-D-aspartate (NMDA) receptor has been indicated to be involved in the pathogenesis of Alzheimer’s disease (AD). The NMDA receptor subunit 2b (NR2B) has attracted more attention due to its characteristic distribution and selective reduction in AD brain. The present study aimed to explore the association between NMDA gene polymorphism and AD.

Methods

A total of 63 AD patients and 68 normal controls in Shanghai city were employed in this study. Genotype of C2664T variant (rs1806201) in the exon13 of GRIN2B gene was determined by gene sequencing.

Results

Among AD patients, 15 (23.6%) subjects were identified as C/C genotype, and 35 (55.6%) were identified as C/T genotype. The left 13 (20.6%) subjects were identified as T/T genotype. In normal controls, 15 (22.1%) subjects were identified as C/C genotype, 39 (57.4%) as C/T genotype and 14 (20.6%) as T/T genotype. The distribution frequency of neither GRIN2B C2664T genotype (P=0.895) nor allele (P=0.790) was significantly different between AD patients and normal controls, even when the subjects were stratified by gender and age of disease onset in AD patients.

Conclusion

The results suggest that there is no relation between GRIN2B C2664T polymorphism and AD in Chinese Han population of Shanghai City.

     

Amyloid-β peptide is a substrate of the human 20S proteasome

Intraneuronal accumulation of ubiquitin conjugates is a pathological feature of neurodegenerative disorders such as Alzheimer's disease (AD). Previous reports propose that accumulation of ubiquitinated species in AD is a result of inhibition of proteasomal activity by amyloid-β (Aβ) peptides, which leads to blocking of ubiquitin-dependent protein degradation by the proteasome. Here, we provide additional insight into proteasomal dysfunction by Aβ peptides by revealing that aggregated forms of Aβ(1-42) peptides (especially small oligomers) are, in fact, competitive substrates for the chymotrypsin-like activity of the human 20S (h20S) proteasome. In addition to examining the kinetics of the h20S proteasome activity in the presence or absence of Aβ peptides, we use gel electrophoresis, LC-MS, and TOF-MS/MS analyses to examine the degradation of Aβ(1-42) by the h20S proteasome. The observed peptide fragments resulting from proteolytic cleavage of Aβ were consistent with predicted cleavage sites from proteasome degradation. These results support that the interaction of Aβ peptides with the proteasome may play a mechanistic role in proteasomal dysfunction in AD pathology. These results may also reveal a previously unknown natural pathway for clearance of Aβ in normal or diseased cells.     

Present and prospective clinical therapeutic regimens for Alzheimer’s disease

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder that produces cognitive impairments that increase in severity as the disease progresses. The clinical symptoms are related to the presence of neuritic plaques and neurofibrillary tangles in the cerebral cortex which represent the pathophysiological hallmarks of AD. The debilitating nature of the disease can result in clinical burden for the patient, emotional strain for those that care for patients with Alzheimer’s, and significant financial burden to society. The goals of current treatments, such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist, are to reduce the severity or slow the progression of cognitive symptoms. Although these treatments have demonstrated modest clinical benefit, they are unable to prevent, prohibit, or reverse the underlying pathophysiology of AD. Considerable progress has been made toward the development of disease-modifying treatments. Treatments currently under development mainly target the production, aggregation, and removal of existing amyloid β-peptide aggregates which are believed to instigate the overall development of the neuropathology. Additional strategies that target tau pathology are being studied to promote neural protection against AD pathology. The current research has continued to expand our knowledge toward the development of disease modifying Alzheimer’s therapies; however, no specific treatment strategy capable of demonstrating empirical efficacy and safety has yet to emerge.     

Regenerative glutamate release by presynaptic NMDA receptors contributes to spreading depression

Spreading depression (SD) is a slowly propagating neuronal depolarization that underlies certain neurologic conditions. The wave-like pattern of its propagation suggests that SD arises from an unusual form of neuronal communication. We used enzyme-based glutamate electrodes to show that during SD induced by transiently raising extracellular K⁺ concentrations ([K⁺]_o) in rat brain slices, there was a rapid increase in the extracellular glutamate concentration that required vesicular exocytosis but unlike fast synaptic transmission, still occurred when voltage-gated sodium and calcium channels (VGSC and VGCC) were blocked. Instead, presynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs) were activated during SD and could generate substantial glutamate release to support regenerative glutamate release and propagating waves when VGSCs and VGCCs were blocked. In calcium-free solutions, high [K⁺]_o still triggered SD-like waves and glutamate efflux. Under such a condition, glutamate release was blocked by mitochondrial Na⁺/Ca²⁺ exchanger inhibitors that likely blocked calcium release from mitochondria secondary to NMDA-induced Na⁺ influx. Therefore presynaptic NMDA receptor activation is sufficient for triggering vesicular glutamate release during SD via both calcium entry and release from mitochondria by mitochondrial Na⁺/Ca²⁺ exchanger. Our observations suggest that presynaptic NMDARs contribute to a cycle of glutamate-induced glutamate release that mediate high [K⁺]_o-triggered SD.     

Clusterin in Alzheimer’s disease: a player in the biological behavior of amyloid-beta

Alzheimer’s disease (AD) remains a major killer, and although its pathogenesis varies, one dominant feature is an increase in the expression, formation, and sedimentation of senile plaques of amyloid-beta (Aβ) peptides in the brain. The chaperone protein clusterin has, since its first discovery at the end of the 20^th century, been labeled as a cytoprotector. However, epigenetic studies showing that clusterin is associated with the severity and risk of AD, especially in the hippocampus, triggered studies to clarify its role in the pathogenesis of AD. It is true that clusterin can inhibit the aggregation of Aβ and therefore prevent further formation of senile plaques in the AD brain, yet it induces the formation of soluble forms of Aβ which are toxic to neurons. Another problematic finding is that clusterin is involved in a pathway through which Aβ has neurodegenerative effects intracellularly. Although the role of clusterin in the pathogenesis of AD is still not clear, this review specifically discusses the interactions between clusterin and Aβ, to open up the possibility of a potential therapeutic approach for treating AD.     

Strategies for molecular imaging dementia and neurodegenerative diseases

Dementia represents a heterogeneous term that has evolved to describe the behavioral syndromes associated with a variety of clinical and neuropathological changes during continuing degenerative disease of the brain. As such, there lacks a clear consensus regarding the neuropsychological and other constituent characteristics associated with various cerebrovascular changes in this disease process. But increasing this knowledge has given more insights into memory deterioration in patients suffering from Alzheimer's disease and other subtypes of dementia. The author reviews current knowledge of the physiological coupling between cerebral blood flow and metabolism in the light of state-of-the-art-imaging methods and its changes in dementia with special reference to Alzheimer's disease. Different imaging techniques are discussed with respect to their visualizing effect of biochemical, cellular, and/or structural changes in dementia. The pathophysiology of dementia in advanced age is becoming increasingly understood by revealing the underlying basis of neuropsychological changes with current imaging techniques, genetic and pathological features, which suggests that alterations of (neuro) vascular regulatory mechanisms may lead to brain dysfunction and disease. The current view is that cerebrovascular deregulation is seen as a contributor to cerebrovascular pathologies, such as stroke, but also to neurodegenerative conditions, such as Alzheimer's disease. The better understanding of these (patho) physiological mechanisms may open an approach to new interventional strategies in dementia to enhance neurovascular repair and to protect neurovascular coupling.     

ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue

A new family of fluorescent markers containing an Amino Naphthalenyl-2-Cyano-Acrylate (ANCA) motif has been synthesized and evaluated for its capability to associate with aggregated β-amyloid (Aβ) peptides. These fluorescent probes contain a nitrogen donor group that is connected via a naphthalene unit to an electron acceptor motif containing Water Solubilizing Groups (WSG). Chemical modifications were introduced to explore their effect on the capability of the ANCA-based probes to fluorescently label aggregated Aβ peptides. All synthesized probes bind to aggregated Aβ fibrils with low micromolar affinity and fluorescently stain amyloid deposits in human brain tissue from patients with Alzheimer's disease. We found that structural modifications of the WSG site do not affect considerably the binding affinity. However, changes of the nitrogen donor group alter significantly the binding affinity of these probes. Also, increasing the hydrophilicity of the donor group leads to improved contrast between the Aβ deposits and the surrounding tissue in histological staining experiments.     

NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans.

Previous brain imaging studies with [(11)C]raclopride have suggested that the psychotogenic effects of the noncompetitive N-methyl-D-aspartate antagonist ketamine in humans might be mediated by increased dopamine (DA) release and increased stimulation of DA D(2) receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D(2) receptor availability in subregions of the striatum (dorsal caudate, DCA; dorsal putamen, DPU; ventral striatum, VST) in humans. Ten healthy subjects were studied twice. In a first group of five subjects, PET scanning was obtained twice for 90 min during bolus plus constant infusion of [(11)C]raclopride. No significant differences were observed in [(11)C]raclopride specific-to-nonspecific activity ratios (V(")(3)) measured during an early interval (30-50 min) and late interval (70-90 min), confirming that a state of sustained equilibrium had been established from 30-90 min (end of infusion). In a second group of five subjects, a similar experiment was performed twice, except that ketamine was administered beginning at 50 min (0.12 mg/kg i.v. bolus followed by 0.65 mg/kg/h i.v. infusion for 70 min). Raclopride V(")(3) measured before ketamine (30-50-min interval) was compared to [(11)C]raclopride V(")(3) measured during ketamine infusion (70-90-min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D(2) receptor availability measured before and during the ketamine infusion (n = 10) in any of the regions examined (DCA, DPU, and VST). These data fail to demonstrate an effect of ketamine on [(11)C]raclopride BP and are consistent with microdialysis studies in rodents and nonhuman primates which reported only small effects of acute NMDA receptor blockade on extracellular striatal DA concentration.     

A Key Role for Lysine Residues in Amyloid β-Protein Folding, Assembly, and Toxicity

A combination of hydrophobic and electrostatic interactions is important in initiating the aberrant self-assembly process that leads to formation of toxic oligomers and aggregates by multiple disease-related proteins, including amyloid β-protein (Aβ), whose self-assembly is believed to initiate brain pathogenesis in Alzheimer's disease. Lys residues play key roles in this process and participate in both types of interaction. They also are the target of our recently reported molecular tweezer inhibitors. To obtain further insight into the role of the two Lys residues in Aβ assembly and toxicity, here we substituted each by Ala in both Aβ40 and Aβ42 and studied the impact of the substitution on Aβ oligomerization, aggregation, and toxicity. Our data show that each substitution has a major impact on Aβ assembly and toxicity, with significant differences depending on peptide length (40 versus 42 amino acids) and the position of the substitution. In particular, Lys16→Ala substitution dramatically reduces Aβ toxicity. The data support the use of compounds targeting Lys residues specifically as inhibitors of Aβ toxicity and suggest that exploring the role of Lys residues in other disease-related amyloidogenic proteins may help understanding the mechanisms of aggregation and toxicity of these proteins.     

Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer’s disease

Since abnormal post-translational modifications or gene mutations of tau have been detected in over twenty neurodegenerative disorders, tau has attracted widespread interest as a target protein. Among its various post-translational modifications, phosphorylation is the most extensively studied. It is recognized that tau hyperphosphorylation is the root cause of neurodegeneration in Alzheimer’s disease (AD); however, it is not clear how it causes neurodegeneration. Based on the findings that tau hyperphosphorylation leads to the escape of neurons from acute apoptosis and simultaneously impairs the function of neurons, we have proposed that the nature of AD neurodegeneration is the consequence of aborted apoptosis induced by tau phosphorylation. Therefore, proper manipulation of tau hyperphosphorylation could be promising for arresting AD neurodegeneration. In this review, the neuroprotective and neurodegenerative effects of tau hyperphosphorylation and our thoughts regarding their relationship are presented.     

单核细胞和阿尔茨海默病

阿尔茨海默病(Alzheimer's disease,AD)是神经退行性疾病中最常见的类型.胞外β淀粉样蛋白(amyloid beta,AB)的沉积和胞内神经原纤维的缠结是典型的AD神经病理学特征.单核细胞是天然免疫细胞,可以有效清除坏死细胞及碎片.在AD模型鼠上的许多实验研究表明,Aβ可以使单核细胞向大脑募集,从而限...     

CSF tau protein and FDG PET in patients with aging-associated cognitive decline and Alzheimer’s disease

Introduction

In Alzheimer’s disease (AD), accelerated neurofibrillary tangle formation occurs which is associated with increased tau protein release into the cerebrospinal fluid (CSF). Recent studies found significantly increased CSF tau already in patients at risk of developing AD, indicating its potential as a biochemical marker of AD. Cerebral glucose metabolism is reduced in frontotemporoparietal and cingulate cortices in patients with mild AD. However, few studies have investigated CSF tau protein and cerebral glucose metabolism changes in patients at risk to develop AD.

Methods

48 patients with AD, 88 patients with aging-associated cognitive decline (AACD), and 39 healthy controls were included. In all participants, CSF levels of tau were determined by ELISA at baseline and compared between the diagnostic groups. 14 AACD patients and 14 controls underwent ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET).

Results

AD patients showed the highest CSF tau levels compared with AACD patients and controls. AACD patients had significantly higher tau levels than the controls but lower than the AD patients. AACD patients were characterized by reduced glucose metabolism in bilateral middle temporal cortex, left posterior cingulate cortex, right angular gyrus, and right precuneus compared with controls.

Conclusion

In conclusion, our findings reflect and confirm the clinical judgment of an incipient neurodegenerative disorder in a considerable portion of AACD patients. In patients with AACD, CSF tau levels and cerebral glucose metabolism show an altered pattern comparable with that found in AD and thus may facilitate early diagnosis.