Brain Regions Of Alzheimer's Disease Patients Research Articles

Predicting the efficacy of donepezil intervention in Alzheimer’s disease patients using regional homogeneity in the inferior orbitofrontal cortex

BackgroundAlthough donepezil is a commonly used drug for treating Alzheimer's disease (AD), the mechanisms by which it affects patients’ functional brain activity, and thus modulates clinical symptoms, remain unclear.MethodsIn the present study, we used resting-state functional magnetic resonance imaging (MRI) and regional homogeneity (ReHo) to investigate the effects of donepezil on local brain activity in AD patients. Resting-state functional MRI data were collected from 32 subjects: 16 healthy controls and 16 AD patients. All 16 AD patients underwent 6 months of donepezil treatment and received two MRI scans (pre- and post-intervention). Analysis of covariance and post hoc analyses were used to compare ReHo differences among the healthy controls, pre-intervention AD patients, and post-intervention AD patients. Pearson correlation analysis was used to examine relationships between ReHo values in differential brain regions and clinical symptoms.ResultsCompared with healthy controls, post-intervention AD patients had reduced ReHo in the orbital part of the inferior frontal gyrus, and pre-intervention AD patients had reduced ReHo in the orbital part of the right inferior frontal gyrus. Pattern recognition models revealed that pre-intervention ReHo values in abnormal brain regions of AD patients were 76% accurate for predicting the efficacy of donepezil on cognitive function and 65% accurate for predicting its efficacy on depressive symptoms.ConclusionsThese findings deepen our understanding of the brain mechanisms underlying the clinical efficacy of donepezil in AD patients, and provide a novel way to predict its clinical efficacy in such patients.

Associations of quantitative susceptibility mapping with cortical atrophy and brain connectome in Alzheimer's disease: A multi-parametric study

Aberrant susceptibility due to iron level abnormality and brain network disconnections are observed in Alzheimer's disease (AD), with disrupted iron homeostasis hypothesized to be linked to AD pathology and neuronal loss. However, whether associations exist between abnormal quantitative susceptibility mapping (QSM), brain atrophy, and altered brain connectome in AD remains unclear. Based on multi-parametric brain imaging data from 30 AD patients and 26 healthy controls enrolled at the China-Japan Friendship Hospital, we investigated the abnormality of the QSM signal and volumetric measure across 246 brain regions in AD patients. The structural and functional connectomes were constructed based on diffusion MRI tractography and functional connectivity, respectively. The network topology was quantified using graph theory analyses. We identified seven brain regions with both reduced cortical thickness and abnormal QSM (p < 0.05) in AD, including the right superior frontal gyrus, left superior temporal gyrus, right fusiform gyrus, left superior parietal lobule, right superior parietal lobule, left inferior parietal lobule, and left precuneus. Correlations between cortical thickness and network topology computed across patients in the AD group resulted in statistically significant correlations in five of these regions, with higher correlations in functional compared to structural topology. We computed the correlation between network topological metrics, QSM value and cortical thickness across regions at both individual and group-averaged levels, resulting in a measure we call spatial correlations. We found a decrease in the spatial correlation of QSM and the global efficiency of the structural network in AD patients at the individual level. These findings may provide insights into the complex relationships among QSM, brain atrophy, and brain connectome in AD.

In Silico Analysis Reveals the Modulation of Ion Transmembrane Transporters in the Cerebellum of Alzheimer's Disease Patients.

Alzheimer's disease (AD) is the most common neurodegenerative disorder. AD hallmarks are extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. It is interesting to notice that Aβ plaques appear in the cerebellum only in late stages of the disease, and then it was hypothesized that it can be resistant to specific neurodegenerative mechanisms. However, the role of cerebellum in AD pathogenesis is not clear yet. In this study, we performed an in silico analysis to evaluate the transcriptional profile of cerebellum in AD patients and non-AD subjects in order to deepen the knowledge on its role in AD. The analysis evidenced that only the molecular function (MF) "active ion transmembrane transporter activity" was overrepresented. Regarding the 21 differentially expressed genes included in this MF, some of them may be involved in the ion dyshomeostasis reported in AD, while others assumed, in the cerebellum, an opposite regulation compared to those reported in other brain regions in AD patients. They might be associated to a protective phenotype, that may explain the initial resistance of cerebellum to neurodegeneration in AD. Of note, this MF was not overrepresented in prefrontal cortex and visual cortex indicating that it is a peculiarity of the cerebellum.

Brain Region-Dependent Alternative Splicing of Alzheimer Disease (AD)-Risk Genes Is Associated With Neuropathological Features in AD.

Alzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is heterogeneity in features across brain regions between AD patients, leading to different severity and progression rates; however, brain region-specific AS mechanisms still remain unclear. Therefore, we aimed to systemically investigate AS in multiple brain regions of AD patients and how they affect clinical features. We analyzed RNA sequencing (RNA-Seq) data obtained from brain regions (frontal and temporal) of AD patients. Reads were mapped to the hg19 reference genome using the STAR aligner, and exon skipping (ES) rates were estimated as percent spliced in (PSI) by rMATs. We focused on AD-risk genes discovered by genome-wide association studies, and accordingly evaluated associations between PSI of skipped exons in AD-risk genes and Braak stage and plaque density mean (PM) for each brain region. We also integrated whole-genome sequencing data of the ascertained samples with RNA-Seq data to identify genetic regulators of feature-associated ES. We identified 26 and 41 ES associated with Braak stage in frontal and temporal regions, respectively, and 10 and 50 ES associated with PM. Among those, 10 were frontal-specific (CLU and NTRK2), 65 temporal-specific (HIF1A and TRPC4AP), and 26 shared ES (APP) that accompanied functional Gene Ontology terms, including axonogenesis in shared-ES genes. We further identified genetic regulators that account for 44 ES (44% of the total). Finally, we present as a case study the systematic regulation of an ES in APP, which is important in AD pathogenesis. This study provides new insights into brain region-dependent AS regulation of the architecture of AD-risk genes that contributes to AD pathologies, ultimately allowing identification of a treatment target and region-specific biomarkers for AD.

Synthesis, biological evaluation, and molecular modeling simulations of new heterocyclic hybrids as multi-targeted anti-Alzheimer's agents

The widespread and the recognition of the multifactorial nature of Alzheimer disease (AD) increased the demands for multi-targeted directed ligands (MTDLs) to overcome possible drug-drug interactions of the combination therapy, and to acquire superior therapeutic profile than single targeted molecules. Two main scaffolds namely: pyrazolopyridine and tetrahydroacridine (THA) were used to synthesize four different series of integrated multi-targeted synthons possessing ChE (hAChE or hBuChE), Aβ1-42 aggregation inhibition potency, in addition to optimum metal chelating capability. Structure modifications were performed to 9-amino function of THA core of tacrine and the pyrazolopyridine scaffolds linked to a variety of cyclic secondary amines directly or using amide spacers or ethylamine bridge or engaging THA with pyrazolopyridine to produce hybrid compounds. Different 9-amino substitutions improved the in vitro hAChE activity of 7- or 6,7-disubstituted THA derivatives. Compounds 16 and 28 proved to be multimodal anti-AD agents as they were potent hAChE inhibitors, in addition, they could bind with the amino acids of the peripheral anionic site (PAS) affecting Aβ aggregation and hence Aβ-dependent neurotoxicity especially compound 16 which was almost twofold more active than donepezil. Furthermore, both compounds directly inhibited Aβ1-42 self-aggregation and chelated bio-metals such as Fe2+, Zn2+ and Cu2+ preventing reactive oxygen species (ROS) generation by Aβ and its oxidative damage in the brain regions of AD patients. Compound 28 had superior privilege by its dual ChE activity resulting in better cognitive improvement. Compounds 16 and 28 showed acceptable relative safety upon hepG2 cell line and excellent BBB penetration with wide safety margin as their LD50 were higher than 120 mg/kg.

Insights from RNA-Seq analysis of Alzheimer's data suggest upregulation of GPCRs

Alzheimer's disease (AD) a complex neurodegenerative disorder and the most common cause of dementia in older people. Recently computational approaches have been integrated with genomics to discover novel genes involved in pathogenesis as well as to understand their mechanism. In this study we analyzed RNA-Seq data from different brain regions of AD patients and compared them with healthy individuals. Quantitative analysis of AD and control samples helped to find out differentially expressed genes (DEGs). Gene enrichment and pathway analysis were also performed to explore additional knowledge about DEGs. Study about protein-protein interaction/gene interaction, hub genes and modules helped in identifying crucial genes. It was revealed that ACKR3, CXCR4, DACH1, CDC6, GMNC, PELI2, DPP4, HSPA1L and PCGF genes were downregulated while CHRM5, CYSTLTR2, DRD5, HTR2C, PTGFR, TACR3, TRHR, MAS1, CARTPTs, DDX3Y, KDMD5, SST, GALR1, NOV, SERPINE1, HLA-B, TRIM26, and BAG-6 genes were found to be upregulated in case of AD. Network analysis of DEGs helped in understanding key pathways involved in AD disease. The analytics revealed a connection between upregulated GPCRs, presence of Aβ granules and formation of Neurofibrillary tangles. It also provides a basis of identification of novel markers and therapeutic targets for Alzheimer's disease.

Iron Pathophysiology in Alzheimer's Diseases.

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition associated with pathological accumulation of amyloid plaques and with the appearance of deposit of neurofibrillary tangles. Increasing evidence suggests that disorders of metal ion metabolism in the brain are one of the risk factors for the pathogenesis of AD. Iron, one of the endogenous metal ions, involves in many important physiological activities in the brain. Iron metabolism mainly depends on iron regulatory proteins including ferritin, transferrin and transferrin receptor, hepcidin, ferroportin, lactoferrin. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, leads to cell death, and ultimately influences the process of β-amyloid (Aβ) misfolding and plaque aggregation. Although the results are different, in general, iron has deposition in different brain regions of AD patients, which may impair normal cognitive function and behavior. Therefore, neuroimaging changes have so far been largely attributed to focal iron deposition accompanying the plaques at preclinical stages of AD, and iron-targeted therapeutic strategies have become a new direction. Iron chelators have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Future research will also focus on iron as an opportunity to study the mechanism of the occurrence and development of AD from the iron steady state to more fully clarify the etiology and prevention strategies.

Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer's Disease: A PET (THK5351, PiB) and Resting fMRI Study.

Background: Imaging studies in Alzheimer’s disease (AD) have yet to answer the underlying questions concerning the relationship among tau retention, neuroinflammation, network disruption and cognitive decline. We compared the spatial retention patterns of 18F-THK5351 and resting state network (RSN) disruption in patients with early AD and healthy controls.Methods: We enrolled 23 11C-Pittsburgh compound B (PiB)-positive patients with early AD and 24 11C-PiB-negative participants as healthy controls. All participants underwent resting state functional MRI and 18F-THK5351 PET scans. We used scaled subprofile modeling/principal component analysis (SSM/PCA) to reduce the complexity of multivariate data and to identify patterns that exhibited the largest statistical effects (variances) in THK5351 concentration in AD and healthy controls.Findings: SSM/PCA identified a significant spatial THK5351 pattern composed by mainly three clusters including precuneus/posterior cingulate cortex (PCC), right and left dorsolateral prefrontal cortex (DLPFC) which accounted for 23.6% of the total subject voxel variance of the data and had 82.6% sensitivity and 79.1% specificity in discriminating AD from healthy controls. There was a significant relationship between the intensity of the 18F-THK5351 covariation pattern and cognitive scores in AD. The spatial patterns of 18F-THK5351 uptake showed significant similarity with intrinsic functional connectivity, especially in the PCC network. Seed-based connectivity analysis from the PCC showed significant decrease in connectivity over widespread brain regions in AD patients. An evaluation of an autopsied AD patient with Braak V showed that 18F-THK5351 retention corresponded to tau deposition, monoamine oxidase-B (MAO-B) and astrogliosis in the precuneus/PCC.Interpretation: We identified an AD-specific spatial pattern of 18F-THK5351 retention in the precuneus/PCC, an important connectivity hub region in the brain. Disruption of the functional connections of this important network hub may play an important role in developing dementia in AD.

The Abnormal Functional Connectivity between the Hypothalamus and the Temporal Gyrus Underlying Depression in Alzheimer's Disease Patients.

Hypothalamic communication with the rest of the brain is critical for accomplishing a wide variety of physiological and psychological functions, including the maintenance of neuroendocrine circadian rhythms and the management of affective processes. Evidence has shown that major depressive disorder (MDD) patients exhibit increased functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Neurofibrillary tangles are also found in the hypothalamus of Alzheimer’s disease (AD) patients, and AD patients exhibit abnormal changes in the HPA. However, little is known of how the hypothalamus interacts with other brain regions in AD patients with depression (D-AD). Functional connectivity (FC) analysis explores the connectivity between brain regions that share functional properties. Here, we used resting-state (rs) magnetic resonance imaging (MRI) technology and the FC method to measure hypothalamic connectivity across the whole brain in 22 D-AD patients and 21 non-depressed AD patients (nD-AD). Our results showed that D-AD patients had reduced FC among the hypothalamus, the right middle temporal gyrus (MTG) and the right superior temporal gyrus (STG) compared with the FC of nD-AD patients, suggesting that the abnormal FC between the hypothalamus and the temporal lobe may play a key role in the pathophysiology of depression in AD patients.

IN VITRO BINDING STUDIES TO EVALUATE THE NFT-SPECIFICITY OF [3H]MK-6240 AND [3H]AV-1451 BINDING IN SUBCORTICAL REGIONS OF HUMAN AD BRAIN

[18F]MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in Alzheimer's Disease (AD) patients1, 2. In clinical studies, [18F]MK-6240 shows high levels of retention in brain regions expected to contain NFT pathology in AD patients, including the amygdala region, but not in healthy control. To increase confidence that the in vivo retention of [18F]MK-6240 in these brain regions of AD patients is due to NFT binding, in vitro studies were carried out using human brain tissues. Similar studies were done with [3H]AV-1451 (T-807) to compare two tracer binding patterns in the same brain sample. Frozen, age-matched AD and non-AD brains were used in the study. [3H]MK-6240 and [3H]AV-1451 were synthesized in house. Autoradiography (ARG) was performed using frozen brain slices. Brain homogenates were used for filtration binding assays. Immunohistochemistry (IHC) was performed with brain slices adjacent to those of ARG study using antibodies made against amyloid plaque (6E10) and NFTs (AT8). In AD amygdala slices, both [3H]MK-6240 and [3H]AV-1451 bind to brain regions with AD tauopathy as shown by co-localization of tau tracer binding with positive AT8 IHC stain (NFTs & neurites) from adjacent slices. However, in non-AD brain samples with negative AT8 IHC stain, [3H]MK-6240 shows minimal or no displaceable binding, while [3H]AV-1451 exhibits displaceable binding of moderate density in these brain samples, including the amygdala, pineal gland, raphe nucleus, substantia nigra, choroid plexus, cerebellum, and dura mater. [3H]MK-6240 does not block MAO-B tracer binding in non-AD brain homogenates, but [3H]AV-1451 does (Ki = 60 nM), in addition to its binding to MAO-A as previously reported. These results validate the expectation that MK-6240 binding in the amygdala is due to binding NFT pathology, and confirms the specificity of [3H]MK-6240 binding to NFTs in human AD brains. In contrast, [3H]-AV-1451 shows dis-placeable binding in regions that do not correlate with AT8 IHC staining, consistent with previous reports1,3–5.

Expression of microRNA-34a in Alzheimer's disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity

Polygenetic risk factors and reduced expression of many genes in late-onset Alzheimer's disease (AD) impedes identification of a target(s) for disease-modifying therapies. We identified a single microRNA, miR-34a that is over expressed in specific brain regions of AD patients as well as in the 3xTg-AD mouse model. Specifically, increased miR-34a expression in the temporal cortex region compared to age matched healthy control correlates with severity of AD pathology. miR-34a over expression in patient's tissue and forced expression in primary neuronal culture correlates with concurrent repression of its target genes involved in synaptic plasticity, oxidative phosphorylation and glycolysis. The repression of oxidative phosphorylation and glycolysis related proteins correlates with reduced ATP production and glycolytic capacity, respectively. We also found that miR-34a overexpressed neurons secrete miR-34a containing exosomes that are taken up by neighboring neurons. Furthermore, miR-34a targets dozens of genes whose expressions are known to be correlated with synchronous activity in resting state functional networks. Our analysis of human genomic sequences from the tentative promoter of miR-34a gene shows the presence of NFκB, STAT1, c-Fos, CREB and p53 response elements. Together, our results raise the possibilities that pathophysiology-induced activation of specific transcription factor may lead to increased expression of miR-34a gene and miR-34a mediated concurrent repression of its target genes in neural networks may result in dysfunction of synaptic plasticity, energy metabolism, and resting state network activity. Thus, our results provide insights into polygenetic AD mechanisms and disclose miR-34a as a potential therapeutic target for AD.

Small-worldness of functional networks in Alzheimer's disease

To construct the functional networks of human brains by resting-state functional magnetic resonance imaging (fMRI) and examine whether or not the small-world property of functional brain networks changes in patients with Alzheimer disease (AD). A total of 33 AD patients and 20 healthy old volunteers were recruited. Their cognitive functions were evaluated by the mini-mental state examination (MMSE) and Mattis dementia rating scale (DRS). The resting-state BOLD-fMRI data were acquired and preprocessed. Then the correlation coefficient of every pair of 90 regions was calculated and correlation matrix Z (N×N, N = 90) generated by Fisher Z transformation. The small-world property of functional brain networks was tested for AD patients and normal elders according to the definition of small-worldness. The changes of relevant parameters in AD patients were examined by two sample t-tests. Behavioral results: the MMSE scores of AD group and normal controls (NOR) were 20.60 ± 2.30 and 28.20 ± 1.80 respectively. The DRS scores of AD and NOR groups were 96.00 ± 10.82 and 123.22 ± 13.74 respectively. The MMSE and DRS scores were statistically different between two groups. Calculation of small-world parameters: Within the range of 0.1 ≤ Sparsity ≤ 0.4, both groups satisfied the small-world property. However, the clustering coefficient Cp and the average shortest path Lp of AD group were significantly higher than those of NOR group at each threshold (P < 0.05). The functional brain networks in AD patients still have the property of small-world. But the levels of Cp and Lp are higher in AD patients than those in normal controls. It suggests that the capacity of information transmission in functional brain networks and the ability of information integration in different brain regions in AD patients are impaired. This finding is of great importance in elucidating the pathological mechanisms of AD from the viewpoint of networks.

Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains

BackgroundAlzheimer's disease (AD) is a major neurodegenerative disorder leading to amnesia, cognitive impairment and dementia in the elderly. Usually this type of lesions results from dysfunctional protein cooperations in the biological pathways. In addition, AD progression is known to occur in different brain regions with particular features. Thus identification and analysis of crosstalk among dysregulated pathways as well as identification of their clusters in various diseased brain regions are expected to provide deep insights into the pathogenetic mechanism.ResultsHere we propose a network-based systems biology approach to detect the crosstalks among AD related pathways, as well as their dysfunctions in the six brain regions of AD patients. Through constructing a network of pathways, the relationships among AD pathway and its neighbor pathways are systematically investigated and visually presented by their intersections. We found that the significance degree of pathways related to the fatal disorders and the pathway overlapping strength can indicate the impacts of these neighbored pathways to AD development. Furthermore, the crosstalks among pathways reveal some evidence that the neighbor pathways of AD pathway closely cooperate and play important tasks in the AD progression.ConclusionsOur study identifies the common and distinct features of the dysfunctional crosstalk of pathways in various AD brain regions. The global pathway crosstalk network and the clusters of relevant pathways of AD provide evidence of cooperativity among pathways for potential pathogenesis of the neuron complex disease.

Phenylbutyric Acid Rescues Endoplasmic Reticulum Stress-Induced Suppression of APP Proteolysis and Prevents Apoptosis in Neuronal Cells

BackgroundThe familial and sporadic forms of Alzheimer's disease (AD) have an identical pathology with a severe disparity in the time of onset [1]. The pathological similarity suggests that epigenetic processes may phenocopy the Familial Alzheimer's disease (FAD) mutations within sporadic AD. Numerous groups have demonstrated that FAD mutations in presenilin result in ‘loss of function’ of γ-secretase mediated APP cleavage [2], [3], [4], [5]. Accordingly, ER stress is prominent within the pathologically impacted brain regions in AD patients [6] and is reported to inhibit APP trafficking through the secretory pathway [7], [8]. As the maturation of APP and the cleaving secretases requires trafficking through the secretory pathway [9], [10], [11], we hypothesized that ER stress may block trafficking requisite for normal levels of APP cleavage and that the small molecular chaperone 4-phenylbutyrate (PBA) may rescue the proteolytic deficit. Methodology/Principal FindingsThe APP-Gal4VP16/Gal4-reporter screen was stably incorporated into neuroblastoma cells in order to assay γ-secretase mediated APP proteolysis under normal and pharmacologically induced ER stress conditions. Three unrelated pharmacological agents (tunicamycin, thapsigargin and brefeldin A) all repressed APP proteolysis in parallel with activation of unfolded protein response (UPR) signaling—a biochemical marker of ER stress. Co-treatment of the γ-secretase reporter cells with PBA blocked the repressive effects of tunicamycin and thapsigargin upon APP proteolysis, UPR activation, and apoptosis. In unstressed cells, PBA stimulated γ-secretase mediated cleavage of APP by 8–10 fold, in the absence of any significant effects upon amyloid production, by promoting APP trafficking through the secretory pathway and the stimulation of the non-pathogenic α/γ-cleavage.Conclusions/SignificanceER stress represses γ-secretase mediated APP proteolysis, which replicates some of the proteolytic deficits associated with the FAD mutations. The small molecular chaperone PBA can reverse ER stress induced effects upon APP proteolysis, trafficking and cellular viability. Pharmaceutical agents, such as PBA, that stimulate α/γ-cleavage of APP by modifying intracellular trafficking should be explored as AD therapeutics.

Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction

Recent evidence has suggested a role for soluble oligomeric Aβ species in the pathology of Alzheimer's disease (AD). Fibrillar plaque deposits are present in non-demented individuals and levels of soluble Aβ correlate better with cognitive dysfunction in AD and transgenic mouse models. We have previously reported that there are at least two conformationally distinct types of Aβ oligomers: prefibrillar oligomers that are kinetic intermediates in fibril assembly reactions and are specifically recognized by A11 antibody and fibrillar oligomers that may represent fibril seeds or small pieces of fibrils and are recognized by a fibril specific antibody, OC. We have examined the levels of these two types of oligomers in the PBS soluble fraction of brain tissue from control cases, cases with senile degenerative changes (SDC) and AD patients. We found that the levels of soluble fibrillar oligomers detected by OC antibody are significantly elevated in multiple brain regions of AD patients. The elevated fibrillar oligomer levels were found not to be an artifact of tissue homogenization, nor a result of increased Aβ or APP levels. The concentration of fibrillar oligomers in adjacent brain regions of the same patient can vary widely and were not detected in post-mortem cerebrospinal fluid. In contrast, the level of prefibrillar oligomers are variable in both AD and age matched controls, indicating that they are not correlated with cognitive dysfunction and suggesting that they precede dementia in AD. Significant correlations were found between the levels of fibrillar oligomers and cognitive decline (MMSE scores) as well as the neuropathological hallmarks of AD. These results indicate that fibrillar oligomers may play a key role in the pathology of AD and may be a new target for diagnostic and therapeutic development.

Principal component analysis with pre-normalization improves the signal-to-noise ratio and image quality in positron emission tomography studies of amyloid deposits in Alzheimer's disease

This study introduces a new approach for the application of principal component analysis (PCA) with pre-normalization on dynamic positron emission tomography (PET) images. These images are generated using the amyloid imaging agent N-methyl [11C]2-(4′-methylaminophenyl)-6-hydroxy-benzothiazole ([11C]PIB) in patients with Alzheimer's disease (AD) and healthy volunteers (HVs). The aim was to introduce a method which, by using the whole dataset and without assuming a specific kinetic model, could generate images with improved signal-to-noise and detect, extract and illustrate changes in kinetic behavior between different regions in the brain. Eight AD patients and eight HVs from a previously published study with [11C]PIB were used. The approach includes enhancement of brain regions where the kinetics of the radiotracer are different from what is seen in the reference region, pre-normalization for differences in noise levels and removal of negative values. This is followed by slice-wise application of PCA (SW-PCA) on the dynamic PET images. Results obtained using the new approach were compared with results obtained using reference Patlak and summed images. The new approach generated images with good quality in which cortical brain regions in AD patients showed high uptake, compared to cerebellum and white matter. Cortical structures in HVs showed low uptake as expected and in good agreement with data generated using kinetic modeling. The introduced approach generated images with enhanced contrast and improved signal-to-noise ratio (SNR) and discrimination power (DP) compared to summed images and parametric images. This method is expected to be an important clinical tool in the diagnosis and differential diagnosis of dementia.

A distinct [18F]MPPF PET profile in amnestic mild cognitive impairment compared to mild Alzheimer's disease

To date, two positron emission tomography (PET) studies have explored 5-HT1A receptor density in the hippocampus of Alzheimer's disease (AD) patients. They showed early changes of 5-HT1A receptors in this brain region, known to have a dense serotonergic innervation. These studies only reported measurements in hippocampus. In the present PET study, we used an antagonist of 5-HT1A receptors, the [18F]MPPF (1) to explore 5-HT1A receptor density in the whole brain of AD patients at a mild stage of dementia and amnestic mild cognitive impairment (aMCI) patients compared to a control population; (2) to explore more precisely the 5-HT1A receptor density in the limbic brain regions of AD patients and aMCI patients compared to controls. Voxel-based analyses were performed to assess differences in the [18F]MPPF binding potential (BP) between AD patients and aMCI patients compared to controls. Analyses of whole-brain [18F]MPPF BP showed a global decrease in AD brains in contrast with a global increase in aMCI brains. In AD brains, a significant decrease of BP was detected in hippocampus and parahippocampal gyrus, whereas a significant increase of BP was observed in the inferior occipital gyrus in aMCI brains. These whole brain results are in accordance to hippocampal data reported in a previous study, showing an increase of [18F]MPPF binding in the aMCI group contrasting with a decrease in the AD group. Altogether, these results suggest the implication of a compensatory mechanism illustrated by an up regulation of serotonergic metabolism at the aMCI stage before a breakdown of this mechanism at the AD stage. This difference of serotonergic receptor labeling allows to distinguish the groups of aMCI patients from mild AD patients with specific [18F]MPPF PET profiles for each patient group.

A comparative assessment of γ-secretase activity in transgenic and non-transgenic rodent brain

Amyloid-beta (Aβ) deposits are one of the hallmarks of the neuropathological degeneration observed in Alzheimer's disease (AD) and Aβ concentrations have been reported to vary in different brain regions of AD patients. Aβ is produced by the sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase, respectively. Previous studies have shown that over-expression of the γ-secretase complex leads to increased γ-secretase proteolytic activity increasing Aβ production. However, it is not known whether brain regions with highest Aβ concentration also express relatively higher levels of γ-secretase activity. Accordingly, the relationship between Aβ levels and γ-secretase activity across brain regions was investigated and correlated in the brains of transgenic and non-transgenic rodents commonly used in AD research. The data demonstrated that Aβ levels do vary in different brain regions in both transgenic and non-transgenic mice but are not correlated with regional γ-secretase activity. Furthermore, this study demonstrated that while mutations in the APP and PS1 sequences affect the absolute Aβ levels this is not reflected in an increase in γ-secretase proteolytic activity. The data in the current paper indicate that this assay is able to measure the level of γ-secretase activity in rodent species. Using this methodology will aid our understanding of physiological γ-secretase function.

Brain Regional Quantification of F-Ring and D-/E-Ring Isoprostanes and Neuroprostanes in Alzheimer’s Disease

Isoprostanes (IsoP) are produced exclusively from free radical damage to arachidonic acid, a fatty acid that is evenly distributed throughout white matter and gray matter, whereas neuroprostanes (NPs) are generated analogously from docosahexaenoic acid (DHA), a fatty acid enriched in gray matter where it is concentrated in neurons. IsoP and NPs derive from endoperoxide intermediates that isomerize to D/E-ring forms or that are reduced to F-ring compounds. We quantified F-ring and D/E-ring IsoP and NPs in temporal and parietal cortex, hippocampus, and cerebellum of nine definite Alzheimer's disease (AD) patients and 11 age-matched controls. Total NP levels (F-ring plus D/E-ring), but not total IsoP, were significantly greater in AD than controls (P: < 0.0001); only cerebral regions in AD patients had NPs greater than controls (P: < 0.05). The F-ring to D/E-ring ratio for NPs, but not IsoP, was 40 to 70% lower in all brain regions of AD patients compared to controls (P: < 0.005). These data extend results from in situ techniques, that have localized reactive products of lipid peroxidation primarily to neurons, by quantifying significantly greater free radical damage to the DHA-containing compartments in cerebrum in AD patients than controls, and suggest that one mechanism of increased oxidative stress may be diminished reducing capacity in DHA-containing compartments.

4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease.

Increasing age and inheritance of the epsilon 4 allele of apolipoprotein E (APOE4) are significant risk factors for sporadic and late onset familial Alzheimer disease (AD); however, the mechanisms by which either leads to AD are unknown. Numerous studies have associated advancing age with increased indices of oxidative challenge to brain, and with still further increased oxidative damage to relevant brain regions in AD patients. A major consequence of oxidative damage to brain is lipid peroxidation with production of the neurotoxic metabolite 4-hydroxy-2-nonenal (HNE). HNE reacts with protein to yield several adducts, including a pyrrole adduct that forms irreversibly in biological systems. Previously, we have shown in a small number of AD and control patients that HNE pyrrole adduct antiserum is immunoreactive with neurofibrillary tangles (NFT), and that this reactivity was significantly associated with inheritance of APOE4. Others have confirmed this pattern of immunoreactivity in AD brain but did not observe an association with APOE4. Herein, we have expanded the study group to 19 AD patients homozygous for APOE4 or APOE3, as well as 30 patients with other neurodegenerative diseases, including diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy, Parkinson's disease, and human immunodeficiency virus-1 encephalitis. HNE pyrrole adduct immunoreactivity on NFT in AD patients was strongly associated with APOE4 homozygosity. With the exception of rare immunoreactive Pick bodies in one case of Pick's disease, no other structure was recognized by HNE pyrrole adduct antiserum in this series of patients. We propose that there is a significant difference between the interaction of apoE3 and apoE4 with lipid peroxidation in the brains of AD patients.