Journal of Alzheimer's disease: JAD

Published by IOS Press
Online ISSN: 1875-8908
Print ISSN: 1387-2877
Publications
Inclusion and Exclusion Criteria for Study Sample NACC = National Alzheimer's Coordinating Center; CDR = Clinical Dementia Rating; MCI = Mild Cognitive Impairment; CDR= Clinical Dementia Rating 
The biological meaning of uncertain dementia ratings (CDR 0.5) and its treatment implications are unclear. Our study examines the frequency of anti-dementia medication use in individuals with CDR 0.5 and the cognitive, behavioral, and demographic factors associated with memantine and acetylcholinesterase inhibitor (AChEI) use. Subjects were drawn from the National Alzheimer Coordinating Center database, which collects data from 30 Alzheimer Disease Centers. There were 2,512 subjects with the following diagnoses: Normal, 11.8%; Mild cognitive impairment, 44.6%; Alzheimer's disease, 34.9%; and other dementias, 8.7%. Overall, 35% used AChEIs and 13% used memantine. AChEI and memantine use was greater in subjects who were referred by clinics and diagnosed with Alzheimer's disease. AChEI use was associated with being married, younger, male, and more educated while memantine use was associated with less severe apathy and other dementia diagnosis. Non-Hispanic whites were more likely to use AChEI and memantine than non-Hispanic blacks (OR = 2.2, 2.5). Hispanics were more likely to use AChEI than non-Hispanic blacks. It appears anti-dementia medication use in CDR 0.5 is frequent and represents evidence for extensive off label usage. Diagnosis, severity of impairment, and race, among other variables, affect the likelihood of AChEI and memantine use in this population.
 
MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.
 
Monitoring the genomic expression of patients in clinical trials for Alzheimer's disease (AD) can assist trial design and treatment response analysis. Here, we report on the identification in AD patients of blood-based transcriptomic signatures associated with treatment response of EHT 0202, a new compound with potential disease-modifying and symptomatic properties, in a 3-month, placebo-controlled, Phase IIA study aimed at determining the clinical safety, tolerability, and exploratory efficacy of EHT 0202 (40 and 80 mg bid) as adjunctive therapy to one cholinesterase inhibitor in mild to moderate AD patients. Genome-wide transcriptomic profiling was performed on blood samples taken prior to treatment and at study completion in a subpopulation of 60 AD patients selected as either the 10 worst disease decliners or the 10 best improvers of each treatment group, using ADAS-Cog scores as measure of disease severity. In the patients responding to EHT 0202, a pre-treatment (baseline) transcriptomic signature showed activation of pathways related to AD, CNS disorders, diabetes, inflammation, and autoimmunity, while a post-treatment signature indicated reduced activation of these pathways with induced metabolic and transcription stimulation. This pilot study demonstrates the utility of blood transcriptomic signatures used as biomarkers for predicting patient response or monitoring efficacy, for an administered therapeutic drug in a complex disease such as AD. For EHT 0202 or other AD drugs, such biomarkers may help to improve strategies to better identify appropriate patient populations for treatment, understand the drug mechanism of efficacy, and/or clarify the inherent subjectivity in most clinical endpoints used in this disease.
 
Dose groups and sacrifice schedule 
Mean ± SD ponezumab exposure at days 1, 171, and 261. 
Ponezumab human exposure ratios 
Ponezumab (PF-04360365) is a novel humanized IgG2Δa monoclonal antibody that binds to amyloid-β (Aβ). It is designed to have reduced immune effector function compared to other passive immunotherapies for Alzheimer's disease (AD). Toxicity was evaluated in cynomolgus monkeys treated intravenously with vehicle or 10, 30, or 100 mg/kg of ponezumab every 10th day for up to 39 weeks, and after a 12-week recovery phase. The Aβ peptide sequence of monkeys is identical to that of humans. No substantial difference in test article exposure between sexes was observed, and mean plasma Cmax and AUC0-n were approximately dose-proportional. Ponezumab was detectable approximately 9 weeks after cessation of dosing. All animals, except two males given 10 mg/kg, maintained exposure to test article. One of these males tested positive for anti-ponezumab antibodies. Ponezumab was detected in the cerebrospinal fluid (CSF) of animals given active treatment. The estimated CSF/plasma ponezumab concentration ratio was <0.008 after multiple doses. At the end of the dosing and recovery phases, plasma Aβ1-40 and Aβ1-x were increased in treated animals versus controls. No test article-related effects were seen after ophthalmogical, cardiovascular, physical examinations, and clinical and anatomic pathology evaluations. Plasma concentrations of ponezumab on day 261 at the no observed adverse effect level of 100 mg/kg were 22.4 and 5.3 times greater on a Cmax and AUC basis, respectively, than human exposures at the highest dose (10 mg/kg) in a single-dose Phase I trial. These data suggest an acceptable safety profile for ponezumab as an immunotherapy for AD.
 
Reduction of tau phosphorylation and aggregation by manipulation of heat shock protein (HSP) molecular chaperones has received much attention in attempts to further understand and treat tauopathies such as Alzheimer's disease. We examined whether endogenous HSPs are induced in Drosophila larvae expressing human tau (3R-tau) in motor neurons, and screened several chemical compounds that target the HSP system using medium-throughput behavioral analysis to assay their effects on tau-induced neuronal dysfunction in vivo. Tau-expressing larvae did not show a significant endogenous HSP induction response, whereas robust induction of hsp70 was detectable in a similar larval model of polyglutamine disease. Although pan-neuronal tau expression augmented the induction of hsp70 following heat shock, several candidate HSP inducing compounds induced hsp70 protein in mammalian cells in vitro but did not detectably induce hsp70 mRNA or protein in tau expressing larvae. The hsp90 inhibitors 17-AAG and radicicol nevertheless caused a dose-dependent reduction in total human tau levels in transgenic larvae without specifically altering tau hyperphosphorylated at S396/S404. These and several other HSP modulating compounds also failed to rescue the tau-induced larval locomotion deficit in this model. Tau pathology in tau-expressing larvae, therefore, induces weak de novo HSP expression relative to other neurodegenerative disease models, and unlike these disease models, pharmacological manipulation of the hsp90 pathway does not lead to further induction of the heat shock response. Forthcoming studies investigating the effects of HSP induction on tau-mediated dysfunction/toxicity in such models will require more robust, non-pharmacological (perhaps genetic) means of manipulating the hsp90 pathway.
 
A recent genome-wide study on late-onset Alzheimer's disease identified a SNP (rs5984894) on Xq21.3 in the PCDH11X gene strongly associated with LOAD individuals of European descent from the United States. We genotyped the same polymorphism in 1222 cases and 938 controls from central-northern Italy and could not confirm the association on the Italian population: multivariate logistic regression adjusted for gender and APOE epsilon4 allele resulted in a global p value of 0.56.
 
Seasonal or chronic vitamin D deficiency and/or insufficiency is highly prevalent in the human population. Receptors for 1,25-dihydroxyvitamin D3, the hormonal metabolite of vitamin D, are found throughout the brain. To provide further information on the role of this hormone on brain function, we analyzed the transcriptomic profiles of mixed neuron-glial cell cultures in response to 1,25-dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 treatment increases the mRNA levels of 27 genes by at least 1.9 fold. Among them, 17 genes were related to neurodegenerative and psychiatric diseases, or brain morphogenesis. Notably, 10 of these genes encode proteins potentially limiting the progression of Alzheimer's disease. These data provide support for a role of 1,25-dihydroxyvitamin D3 in brain disease prevention. The possible consequences of circannual or chronic vitamin D insufficiencies on a tissue with a low regenerative potential such as the brain should be considered.
 
Cumulative evidence indicates that amyloid-beta peptides exert some of their neurodegenerative effects through modulation of L-type voltage gated calcium channels, which play key roles in a diverse range of CNS functions. In this study we examined the expression of CaV1.2 L-type voltage gated calcium channels in transgenic mice overexpressing human AbetaPP751 with the London (V717I) and Swedish (K670M/N671L) mutations by immunohistochemistry in light and electron microscopy. In hippocampal layers of wild type and transgenic mice, CaV1.2 channels were predominantly localized to somato-dendritic domains of neurons, and to astrocytic profiles with an age-dependent increase in labeling density. In transgenic animals, CaV1.2-like immunoreactive clusters were found in neuronal profiles in association with amyloid-beta plaques. Both the number and density of these clusters depended upon age of animals and number of plaques. The most striking difference between wild type and transgenic mice was the age-dependent expression of CaV1.2 channels in reactive astrocytes. At the age of 6 month, CaV1.2 channels were rarely detected in reactive astrocytes of transgenic mice, but an incremental number of CaV1.2 expressing reactive astrocytes was found with increasing age of animals and number of amyloid-beta plaques. This study demonstrates that CaV1.2 channels are highly expressed in reactive astrocytes of 12-months of age transgenic mice, which might be a consequence of the increasing amyloid burden. Further studies should clarify which functional implications are associated with the higher availability of CaV1.2 channels in late stage Alzheimer's disease.
 
Glial fibrillary acidic protein (GFAP) and protein S-100B are established indicators of astrogliosis in neuropathology. As GFAP and S-100B are expressed in different cell populations, variable cerebrospinal fluid (CSF) concentrations of these proteins might reflect disease-specific pathological profiles. Therefore we investigated CSF of patients with Alzheimer's disease (AD), patients with Creutzfeldt-Jakob disease (CJD), and non-demented control patients (CON). Measurement of GFAP and S-100B in CSF was performed by commercially available ELISA. Our results show that, in AD, there are significantly higher levels of GFAP concentrations, compared to CON (p = 0.001) and CJD patients (p = 0.009), whereas S-100B is much higher in CJD, compared to AD (p = 0.001) and CON (p = 0.001). In conclusion, GFAP and S-100B represent astroglial markers and the different levels of these proteins in CSF of AD and CJD patients might point to a distinct pathophysiological involvement in these diseases. Apart from pathophysiological aspects, GFAP in particular might serve as an additional diagnostic tool for AD, due to the fact that this protein does not correlate to established markers like tau and amyloid-beta such that analysis of GFAP may be useful for further differential diagnostic approaches in neurodegenerative diseases.
 
Alzheimer's disease (AD) is a progressive disorder that is characterized by the accumulation of neuropathologic lesions and neurochemical alterations. Ultrastructural investigations in many association regions of the neocortex and the hippocampal dentate gyrus have demonstrated a disease-related decline in numerical synaptic density. This decline in brain connectivity occurs early in the disease process and strongly correlates with the cognitive decline observed in AD. The synapse loss does not appear to be an inevitable consequence of the aging process. This article reviews the ultrastructural studies assessing AD-related synaptic loss and the possible compensatory changes in the synaptic complex that occur as a result of the loss in brain connectivity.
 
Real-time primer amplification efficiency plots generated against (i) cDNA dilution series and (ii) recombinant plasmid standards for PSD-95, SAP-102, SYN, and RPL13 (A-D) respectively, using primer concentrations of 100–200 nM. Ct values were plotted against log 10 total RNA (ng) in each reaction for serial dilutions of cDNA (1:2, 1:5, 1:10 and 1:20) and 7.5 × 10 5 to 50 standard copies. Slopes (m) and correlation coefficients (r 2 ) were calculated. Amplification efficiencies (E) were determined by the equation 10 ( − 1 /slope ) . Reactions were carried out in 
continued. 
Case list details
Effects of age and postmortem delay. Regressions of transcript copy numbers (upper panels) and protein concentrations (lower panels) on the patient’s age at death (left-hand panels) and delay from death to autopsy (right-hand panels) are shown, together with the least-squares lines of best fit. Statistical parameters of the regressions are given in the text. 
APOE 4 genotype effects on PSD-95 and SAP-102 expression and AD severity. AD cases were separated by APOE genotype, ( ± ) ε 4. (A) Bar graph of mean mRNA transcript copy numbers adjusted for PMD, RIN, and housekeeper RPL13 expression per μ g of total RNA. mRNA levels did not differ significantly between groups of ( ± ) ε 4. (B) Mean total protein levels of PSD-95 and SAP-102 combined across all areas were graphed as a function of pmol of target protein per μ g of total membrane protein. SAP-102 protein expression showed a significant reduction in the group containing at least one copy of the ε 4 allele ( n = 21 and 24 for ( − ) ε 4 and ( + ) ε 4 respectively; ∗ p < 0.05, Newman-Keuls). (C) Cases were 
N-methyl-D-aspartate (NMDA) receptor-evoked excitotoxicity contributes to region-specific loss of glutamatergic synapses responsible for cognitive decline in Alzheimer's disease (AD). Here, the post-synaptic scaffold proteins PSD-95 and SAP-102, which regulate NMDA receptor synaptic activity and expression, were investigated in human AD autopsy brain tissue. Using absolute quantification real-time PCR, we detected reduced expression of synaptophysin in both the pathologically susceptible inferior temporal cortex and hippocampus, consistent with previous reports. PSD-95 and SAP-102 mRNA was reduced, albeit not significantly. Proteins were precisely quantified against recombinant truncated protein standards. No differences were observed for proteins in AD spared occipital cortex between AD cases and controls. PSD-95 and SAP-102 protein expression was markedly reduced in the AD inferior temporal cortex. Both mRNA and protein levels were reduced according to disease severity. SAP102 protein levels were significantly reduced in AD subjects carrying a copy of the APOEε4 allele. This is the first study to investigate SAP-102 in the aging human brain and suggest a possible mechanism for NMDA receptor expression aberrations in AD.
 
Although the etiology of psychotic symptoms (hallucinations and delusions) in Alzheimer's disease is still not known, alterations in serotonergic neurotransmission have been proposed. In a 3-year follow-up study, we evaluated the association of serotonin (5-HT) receptor 5-HT2a 102T/C polymorphism (allelic variants CC, CT and TT) with psychotic symptom severity and response to treatment with atypical antipsychotics (risperidone, olanzapine and quietapine) in 80 patients with a diagnosis of probable Alzheimer's disease. The Neuropsychiatric Inventory (NPI) was administered to determine the frequency and severity (FxS) of psychotic and other behavioral symptoms. There was a significant difference in the NPI FxS delusion score among the three variants of the 5-HT2a 102T/C polymorphism, with patients carrying the TT genotype the most delusional during the follow-up period. In particular, NPI FxS delusion score was higher in TT than in CC genotype at year 2. Moreover, patients with delusion symptoms carrying the CT and TT genotypes were resistant to the treatment with antipsychotic drugs. Thus our study, although at preliminary level, suggests that the presence of T allele of the 102T/C polymorphism in patients with Alzheimer's disease is associated with both increased presence of delusion symptoms and treatment-resistance to second generation antipsychotic drugs.
 
Prion diseases or transmissible spongiform encephalopathies, are neurodegenerative disorders that are genetic, sporadic, or infectious. The pathogenetic event common to all prion disorders is the conformational transformation of the cellular prion protein (PrP^C) to the scrapie form (PrP^Sc), that deposits in the brain parenchyma and induces neuronal death. Infectious prion disorders are caused by exogenously introduced PrP^Sc that acts as a template in the conversion of endogenous PrP^C to nascent PrP^Sc, and subsequently the process becomes autocatalytic. To understand the process of cellular uptake of PrP^Sc and its mechanism of cellular toxicity, previous studies have used a PrP fragment spanning residues 106-126 (PrP^Tx) that is toxic to primary neurons in culture, and mimics PrP^Sc in its biophysical properties [9,11,14]. Several possible mechanisms of cell death by PrP^Tx have been proposed [2,3,10,11,18], but the existing data are unclear. To identify the biochemical pathways of neurotoxicity by this fragment, we have isolated mutant neuroblastoma and NT-2 cells that are resistant to toxicity by PrP^Tx. We show that these cells bind and internalize PrP^Tx in a temperature dependent fashion, and the peptide accumulates in intracellular compartments, probably lysosomes, where it has an unusually long half-life. The PrP^Tx-resistant phenotype of the cells reported in this study could result from aberrant binding or internalization of the peptide, or due to an abnormality in the downstream pathway(s) of neuronal toxicity. The PrP^Tx-resistant cells are therefore a useful tool for evaluating the cellular and biochemical pathways that lead to cell death by this peptide, and will provide insight into the mechanism(s) of neurotoxicity by PrP^Sc.
 
MiR-107 is a microRNA (miRNA) that we reported previously to have decreased expression in the temporal cortical gray matter early in the progression of Alzheimer's disease (AD). Here we study a new group of well-characterized human temporal cortex samples (N=19). MiR-107 expression was assessed, normalized to miR-124 and let-7a. Correlation was observed between decreased miR-107 expression and increased neuritic plaque counts (P< 0.05) and neurofibrillary tangle counts (P< 0.02) in adjacent brain tissue. Adjusted miR-107 and BACE1 mRNA levels tended to correlate negatively (trend with regression P< 0.07). In sum, miR-107 expression tends to be lower relative to other miRNAs as AD progresses.
 
Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimer's disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB.
 
We investigated whether [11C]-PIB PET detects underlying amyloid deposition at clinically different stages of Alzheimer's disease (AD) and preclinical dementia. The Japanese cohort of 214 subjects underwent cognitive testing and 60-min dynamic [11C]-PIB PET. [11C]-PIB data were acquired from 35-60 min after injection. Regions of interest were defined on co-registered MRI. Distribution volume ratios (DVR) of PIB retention were determined using Logan graphical analysis. All 56 patients with AD showed a robust increase in PIB retention in cortical areas (typical PIB AD-pattern). A mean DVR value in 11 patients with moderate AD (CDR: 2.1 ± 0.4) showed significantly higher PIB retention (2.38 ± 0.42, p < 0.01) than amyloid-negative healthy control (HC) subjects. The DVR values in 23 patients with very mild AD (CDR: 0.5) and 22 patients with mild AD (CDR: 1.0) were 2.32 ± 0.45 and 2.34 ± 0.42, respectively, similar to moderate AD. In contrast, 28 (48%) of the 58 mild cognitive impairment (MCI) patients (MMSE: 27.3 ± 1.7) showed a typical AD-like pattern with a DVR value of 2.07 ± 0.34. Further, 17 (18%) of 91 HC subjects had a typical AD-like pattern with a DVR value of 2.06 ± 0.28. They did not significantly differ from very mild AD. The prevalence of AD among the 53 amyloid positive patients aged 75 years or older increased greatly to 74% whereas that of amyloid positive HC decreased by only 9% and amyloid positive MCI by 17%. Prodromal AD and AD dementia is identified, based on cognitive function and amyloid deposition by PIB PET imaging. Further, the cortical amyloid deposition could be detected at preclinical stage of AD.
 
To determine the existence of cortical thinning in subcortical vascular dementia (SVaD) with a negative 11C-Pittsburgh compound B (PiB) positron emission tomography scan and to compare the topography of cortical thinning between PiB-negative SVaD and Alzheimer's disease (AD), we enrolled 24 patients with PiB(-) SVaD, 81 clinically probable AD individuals, and 72 normal cognitive controls. Compared with controls, cortical thinning in PiB(-) SVaD was most profound in the perisylvian area, medial prefrontal area, and posterior cingulate gyri, while the precuneus and medial temporal lobes were relatively spared. When the cortical thickness of AD and PiB(-) SVaD were directly compared, PiB(-) SVaD demonstrated significant cortical thinning in the bilateral inferior frontal, superior temporal gyri, and right medial frontal and orbitofrontal lobes, while AD showed significant cortical thinning in the right medial temporal region. SVaD without amyloid burden may lead to substantial cortical atrophy. Moreover, characteristic topography of cortical thinning in PiB(-) SVaD suggests different mechanisms of cortical thinning in PiB(-) SVaD and AD.
 
Background: Two approaches are available for measuring Alzheimer's disease (AD) pathology in vivo. Biomarkers in cerebrospinal fluid (CSF) include amyloid-β1-42 (Aβ42) and tau. Furthermore, amyloid deposition can be visualized using positron emission tomography (PET) and [11C]Pittsburgh compound-B ([11C]PIB). Objective: We investigated concordance between CSF biomarkers and [11C]PIB PET as markers for AD pathology in a memory clinic cohort. Methods: We included 64 AD patients, 34 non-AD dementia patients, 22 patients with mild cognitive impairment (MCI), and 16 controls. [11C]PIB scans were visually rated as positive or negative. CSF biomarkers were considered abnormal based on Aβ42 alone (<550 ng/L), a more lenient Aβ42 cut-off (<640 ng/L) or a combination of both Aβ42 and tau ((373 + 0.82 tau)/Aβ42 > 1). Concordance between CSF biomarkers and [11C]PIB PET was determined. Results: Overall, concordance between [11C]PIB PET and CSF Aβ42 (<550 ng/L) was 84%. In discordant cases, [11C]PIB PET was more often AD-positive than Aβ42. When a more lenient Aβ42 cut-point (<640 ng/L) or a combination of Aβ42 and tau was used, concordance with [11C]PIB PET appeared to be even higher (90% and 89%). This difference is explained by a subgroup of mostly MCI and AD patients with Aβ42 levels just above cut-off. Now, in discordant cases, CSF was more often AD-positive than [11C]PIB PET. Conclusion: Concordance between CSF Aβ42 and [11C]PIB PET was good in all diagnostic groups. Discordance was mostly seen in MCI and AD patients close to the cut-point. These results provide convergent validity for the use of both types of biomarkers as measures of AD pathology.
 
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly and is also considered a progeroid genetic syndrome. The etiology of AD is complex and the mechanisms underlying its pathophysiology remain to be clarified. It has been suggested that a high serum cholesterol level is a risk factor for (AD), and that some polymorphisms of genes encoding proteins regulating cholesterol metabolism are associated with AD development. APOA5 is a recently discovered apolipoprotein involved primarily with triglyceride (TG) metabolism disorder. This study investigates the association of AD with the APOA5 gene -1131T>C polymorphisms in samples of 106 patients with Alzheimer's disease (AD), 76 elderly healthy controls and 93 young healthy controls. DNA samples were isolated from blood cells, amplified by PCR and digested with Tru1l. We observed that the genotype distributions of APOA5 variants were within Hardy-Weinberg equilibrium in all subject samples. Furthermore, chi-square test comparison for genotype distributions and allele frequencies did not reveal any significant difference among the three groups of subjects P>0.05). These results support the idea that these variants are not involved as a risk factor for developing AD.
 
Pedigree of the "SI" family. Three individuals (II:1, III:1, and III:2) were affected with progressive dementia, myoclonus, seizures and Parkinsonism. The proband is indicated by arrow, deceased individuals are indicated by slashes.
Amyloid β 40 and 42 (A β 40/42) deposits in the brain of PS1-Pro117Ser patient. Serial sections of CAI sector of the hippocampus (a,b), frontal neocortex (c,d), and cerebellum (e,f) were immunostained with commercial (BioSource) rabbit polyclonal antibodies specific for A β 40 (b,d,f) or A β 42 (a,c,e). In the CAI sector and the dentate gyrus (DG) of the hippocampus (a) and temporal cortex (c), there is a very heavy burden of A β 42- immunoreactive plaques. Only a very few of those plaques showed up on adjacent sections stained with anti-A β 40 antibody (b,d). In the cerebellum, anti-A β 42 antibody (e) detects plenty of diffuse plaques in the molecular layer and many fewer plaques in the granular layer. The staining of plaques in either layer with anti-A β 40 antibody (f) was entirely negative. Marked by arrows are vessels, which unlike most of the plaques, show the presence of both species of amyloid β . Amyloid deposition was particularly heavy in leptomeningeal vessels of the cerebellum. Original magnification for a,b,e,f: × 50; for c,d: × 100. 
Effect of Pro117 mutations on neurite outgrowth. Comparison of neurite load between N2a cell lines stably transfected with the wild-type (WT) or mutant (P1117L; P117S) PS1 gene. Upper panel: Microphotographs of representative test fields of each cell line taken for quantitation in computer-aided image analysis. Image magnification: × 400. Each bar on the graph below represents mean ± SD of 3 independent experiments. Results are expressed as percentage of a test field area occupied by neurites (neurite load). Significance (P < 0.05) was assessed by Mann-Whitney U test.
Effect of P117 mutations on Aβ 40/42 production. The ratio of Aβ 42/40 was measured in conditioned medium from human skin fibroblasts (clear bars) and PS1-transfected N2a (solid bars) cell cultures by a sandwich-ELISA as described under "Materials and Methods". Results represent mean values ± SD (n = 5, P < 0.05).
A novel presenilin-1 (PS1) mutation (P117S) in an American pedigree is described. We compare clinical, neuropathological and cell culture phenotypes produced by this mutation with another codon 117 mutation that was earlier discovered by our group in a Polish kindred. Both mutations are associated with an unusually severe Alzheimer disease (AD) phenotype, with the onset starting before the third decade of life, rapid disease progression and acute presentation of clinical symptoms. The severity of clinical phenotype was closely correlated with the abundance of pathology: massive deposition of Abeta42 in plaques, severe neurofibrillary degeneration and neuronal loss. When overexpressed in mouse neuroblastoma N2a cells, both mutations caused loss of an ability to promote neurite outgrowth and produced an increase in the ratio of secreted Abeta42/40 amyloid peptides. In stably transfected N2a cell lines only mutant proteins were endoproteolytically cleaved indicating some dependability of this process on the presence of mutation. Taken together, our results show that clinical and cell culture phenotypes produced by these 2 codon 117 mutations are closely related suggesting that the pathogenic action of PS1 may involve effect on neurite outgrowth and endoproteolytic cleavage of the full-length protein. Given the high potency in vivo and in vitro of both codon 117 mutations, this site of PS1 must be particularly important for its normal/pathogenic function.
 
Background/objective: Our aim was to elucidate factors that contribute to amyloid-β (Aβ) accumulation in the brains of the seemingly healthy elderly population, and whether there is interplay between those factors. Methods: We conducted a cross-sectional positron emission tomography (PET) study with the amyloid tracer 11C-PIB, in 64 cognitively healthy subjects (54-89 years). In addition to PET, magnetic resonance imaging, neuropsychological testing, and APOE genotyping was performed. The results were assessed with a statistical general linear model as well as with Statistical Parametric Mapping (SPM). Results: The effects of age (p < 0.001), APOE ε4 carrier status (p = 0.003), and gender (p = 0.001) on composite cortical 11C-PIB uptake were all significant. The effect of educational level was non-significant (p = 0.37). No significant interactions were found between any of the factors. Cortical 11C-PIB uptake increased, on the average, by 0.015 cortex/cerebellar cortical ratio unit, with every year of age. APOE ε4 positive subjects exhibited higher cortical 11C-PIB uptake than APOE ε4 negative subjects (unadjusted means 1.49 ± 0.34 versus 1.29 ± 0.26) and males had higher uptake than females (1.49 ± 0.39 versus 1.29 ± 0.22), irrespective of age. The results of the voxel-based (SPM) analysis were similar. In addition, SPM analysis showed that lower CERAD score was associated with higher 11C-PIB uptake in the frontal cortex. Conclusions: Age and APOE ε4 genotype were associated with higher 11C-PIB uptake. In this sample of cognitively healthy elderly individuals, men exhibited higher 11C-PIB uptake than women. Possible gender differences in Aβ accumulation have not been addressed in detail in previous studies, and deeper evaluation in the future is warranted.
 
Brain amyloid imaging is becoming an essential tool for the pre-mortem evaluation of Alzheimer's disease (AD). This study explores the pattern of 11C-PiB retention in a subject with Worster-Drought syndrome (WDS). A 55 year-old male carrier of the WDS gene mutation with mild signs of ataxia and subtle cognitive impairment underwent MRI and 11C-PiB-PET studies.Brain PiB regional distribution was compared to those from cohorts of healthy controls and AD patients. While no significant cortical 11C-PiB retention was present, a high degree of cerebellar 11C-PiB retention was observed in a genetically confirmed carrier of the WDS gene. We speculate that the sparsity of ABri plaques in the neocortex together with its high deposition in the cerebellum, might explain the observed pattern of 11C-PiB retention.
 
Although pyruvate dehydrogenase (PDH) is the major pathway of glucose metabolism and source for energy production, pyruvate carboxylase (PC) and pentose phosphate pathway (PPP) account for a significant fraction of glucose oxidation in the mature central nervous system. Flux through the PDH pathway has been reported to be reduced in Alzheimer's disease (AD) patients as well as in animal models of AD. However, fluxes through the PPP and PC pathways have not been explored under conditions of AD. The present study investigates the fluxes of PC and PPP in a 20-month-old AβPP-PS1 mouse model of AD using 13C NMR spectroscopy together with infusion of [2-13C]glucose. Mice were also administered [1,6-13C2]glucose or [1-13C]glucose for 10 or 90 min, respectively, to investigate PDH flux. AβPP-PS1 mice exhibit a significant reduction in the level of NAA and increase in level of myo-inositol. The flux through PDH was found to be significantly lower in the cerebral cortex (AβPP-PS1 0.39 ± 0.08; control 0.77 ± 0.08 μmol/g/min), hippocampus (AβPP-PS1 0.31 ± 0.04; control 0.64 ± 0.12 μmol/g/min), and striatum (AβPP-PS1 0.34 ± 0.06; control 0.56 ± 0.03 μmol/g/min) of AβPP-PS1 as compared with control mice. The fluxes through PC (AβPP-PS1 0.037 ± 0.006, control 0.079 ± 0.013 μmol/g/min) and PPP (AβPP-PS1 0.024 ± 0.005; control 0.062 ± 0.022 μmol/g/min) were found to be significantly reduced in AβPP-PS1 mice when compared with age-matched controls. The reduction in the fluxes of PC and PPP may lead to a weakened neural defense system of ammonia detoxification and antioxidant reserve in AβPP-PS1 mice, which may be responsible for the compromised neuronal viability and functions in AD.
 
MicroRNAs (miRNAs), a class of small, non-coding RNA molecules with gene regulatory functions, have emerged to play a critical role in the pathogenesis of a variety of diseases. Recently, circulating miRNAs have been reported as potential biomarkers for various pathologic conditions. The present study was performed to investigate the potential role of circulating miRNAs as diagnostic biomarkers for mild cognitive impairment (MCI). We collected 66 patients with MCI and 76 normal controls from our previous cross-sectional cohort study. Seven miRNAs (miR-206, miR-132, miR-193b, miR-130b, miR-20a, miR-296, and miR-329) related to Alzheimer's disease (AD) were detected in serum using a quantitative real-time PCR (qRT-PCR) method. Each miRNA's diagnostic performance was evaluated by receiver operating characteristic curves and the areas under curves (AUC) analysis. The levels of miR-206 and miR-132 in MCI patients' serum were significantly elevated compared to normal controls. Combining detection of miR-206 and miR-132 achieved the highest AUC of 0.981, followed by test of miR-206 (AUC = 0.880) and miR-132 (AUC = 0.912) separately. Importantly, miR-206 and miR-132 were respectively correlated with the Montreal Cognitive Assessment score in MCI patients. These results preliminarily indicated that circulating miR-206 and miR-132 as novel miRNAs upregulated in MCI patient were potential biomarkers for diagnosis of MCI.
 
Amyloid-beta peptide (Abeta) toxicity is thought to be responsible for the neurodegeneration associated with Alzheimer's disease. While the mechanism(s) that modulate this toxicity are still widely debated, it has previously been demonstrated that modifications to the three histidine residues (6, 13, and 14) of Abeta are able to modulate the toxicity. Therefore to further elucidate the potential role of the histidine (H) residues in Abeta toxicity, we synthesized Abeta peptides with single alanine substitutions for each of the three histidine residues and ascertained how these substitutions affect peptide aggregation, metal binding, redox chemistry, and cell membrane interactions, factors which have previously been shown to modulate Abeta toxicity. Abeta{42} H13A and Abeta{42} H6A modified peptides were able to induce significant cell toxicity in primary cortical cell cultures at levels similar to the wild-type peptide. However, Abeta{42} H14A did not induce any measurable toxicity in the same cultures. This lack of toxicity correlated with the inability of the Abeta{42} H14A to bind to cell membranes. The interaction of Abeta with cell membranes has previously been shown to be dependent on electrostatic interactions between Abeta and the negatively charged head group of phosphatidylserine. Our data suggests that it is the imidazole sidechain of histidine 14 that modulates this interaction and strategies inhibiting this interaction may have therapeutic potential for Alzheimer's disease.
 
Aggregation of tau proteins followed by formation of paired helical filaments and neurofibrillary tangles is considered as a hallmark of certain neurodegenerative disorders such as different tauopathies and Alzheimer's disease (AD). Tau aggregation is dependent on the presence of polyanions, cellular redox state, limited proteolysis, and different posttranslational modifications among which tau phosphorylation plays a particularly important role. Although it is still debatable whether tau aggregation is harmful or protective for the cell, detailed analysis of molecular mechanisms underlying this process seems to be of great importance for understanding AD pathogenesis. This review is focused on universal adapter proteins 14-3-3 that seem to be significant partners to tau protein in neurons. 14-3-3 interacts with nonphosphorylated tau and promotes its interaction with and phosphorylation by a number of protein kinases. 14-3-3 induces aggregation of nonphosphorylated tau and does not affect aggregation of tau phosphorylated at specific sites. Due to its high concentration in neurons, 14-3-3 can compete with tubulin for interaction with tau. Binding to phosphorylated tau, 14-3-3 might inhibit its dephosphorylation by protein phosphatases and by this means indirectly affect interaction of tau with microtubules and tau aggregation. Finally, 14-3-3 might promote sequestration of dangerous small tau oligomers and stabilize tau aggregates. We propose that 14-3-3 should be considered an important participant of the complex process of tau aggregation and as a potential therapeutic target in treating AD.
 
Background: Memory disorders and Alzheimer's disease (AD) share the same risk factors with cardiovascular diseases. Objective: We tested whether elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels would predict any incident dementia or AD. Methods: The association between NT-proBNP and the risk of dementia was evaluated in a total of 7,158 subjects without previous memory disorders in a prospective study with a median follow-up of 13.8 years. Results: A total of 220 new dementia cases occurred, of which 149 were AD. Baseline logNT-proBNP levels were associated significantly with the risk of dementia in the entire study population (HR 1.32, 95%CI 1.17-1.56, p = 0.001) per 1SD difference, adjusted for multiple cardiovascular risk factors. Integrated discrimination improvement (IDI) and continuous net-reclassification improvement (continuous NRI) were improved in the study population over 40 years of age: continuous NRI was 17.5% (95%CI 4.4-30.6%, p = 0.009) and IDI was 0.005 (95%CI 0.001-0.010, p = 0.021). Regarding AD, the HR for 1SD logNT-proBNP change was 1.23 (95%CI 1.01-1.49, p = 0.040) in the entire study population, but no IDI or continuous NRI improvement was seen. Conclusion: NT-proBNP is also an independent risk marker for dementia, and patient discrimination regarding dementia risk could be improved by using it.
 
CNI-1493 reduces A-induced toxicity in BV-2 cells and primary microglial cells. BV-2 cells (A) and primary microglial cells (B) were incubated with increasing concentrations of A 1-40 monomers and oligomers (black bars) or solvent (white bars). After 24 h, cell survival was measured using the MTT assay. To analyze the influence of CNI-1493 on cell survival, BV-2 cells (C) and primary microglial cells (D) were incubated with A 1-40 oligomers at concentrations ranging between 2.5 and 10 M, which had been pretreated with increasing concentrations of CNI-1493 (black bars) or DMSO only (white bars). Staurosporine induced toxicity was not affected following incubation with CNI-1493 (1E). Analysis of CNI-1493 on A oligomers and de novo oligomerization was performed using Dot blot (F) and Western blot (G). Oligomers were prepared as described. 50 M A and increasing concentrations of CNI-1493 were added prior to the oligomerization process (G). To show the possible interference of A with CNI-1493, 56 M of oligomer-enriched A was incubated in the presence of 56 M CNI-1493 for 30 min. 'Control' denotes the addition of A and the solvent solution of CNI-1493 without CNI-1493. All experiments were performed at least three times independently. Error bars describe standard deviation. Statistical significance to the level of p < 0.05 is highlighted by an asterisk. 
CNI-1493 prevents apoptosis in microglia. Cells were incubated with 4 M A 1-40 (lane 2), 4 M A 1-40 and 10 M CNI-1493 (lane 3) or solvent only (control, lane 1). Brefeldin A was used as a positive control as it induces caspase 12-dependent apoptosis (42 kDa, lane 4). Staurosporine was used to activate PARP (89 kDa) and p53 (53 kDa) in the positive control group (lane 4). Changes in the concentrations of activated proteins involved in apoptosis were demonstrated by immunoblots using specific antibodies (A). The actin loading control is shown in 3A as well and is representative for all experiments performed. Lane 1 represents treatment with solvent only. Here, some background activation can be observed. Densitometry was performed to show differences in band intensity and the results are shown as ratios below each band. Cells were also examined for p38 MAPK activation status in the context of A and CNI-1493. Four M A 1-40 were used to induce p38 phosphorylation (40 kDa) during an incubation time of 18 h. Co-incubation with 10 M CNI-1493 led to a decreased p38 phosphorylation status. Whole p38 (38 kDa) and GAPH (43 kDa) levels were uninfluenced by this treatment (3B). 
Influence of CNI-1493 on APP processing. A+B) BV-2 and primary microglial cells were treated with CNI-1493 at increasing concentrations for 24 h. Western blot analysis of cell lysates was performed to detect C83 APP fragments in these cells (A). In the same experiment full APP concentrations were determined to rule out the effect of CNI-1493, on APP. GAPDH was used as the loading control. Densitometric analysis is provided below each band. C) BV-2 cells were treated with CNI-1493 (10 M) for 24 h (C, i-iii). Using the respective kit for-,-, and-secretase activity measurement, we assessed the total activity of the-,-, and-secretase complex upon treatment of BV-2 cells with CNI-1493. Values are presented as the mean ± SD of three assays. The media of BV-2 cells treated with CNI-1493 (10 M) for 24 h and the secreted A 1-40 load was evaluated by ELISA. The mean values and the standard deviation of three independent experiments are shown (iv). D) RT-PCR of ADAM 9 (i) and ADAM 10 (ii) mRNA was run to investigate the influence of CNI-1493 on major-secretase enzymes. All experiments were normalized to the housekeeping gene-actin and repeated three times. 
Amyloid-β (Aβ) oligomer toxicity is a crucial factor in the development of Alzheimer's disease. Therefore, the aim of therapeutic research is to target the modification of secretase activity, increase Aβ degradation, reduce Aβ formation, and modulate Aβ-induced neuroinflammation. Recently, the p38 MAP kinase inhibitor CNI-1493 has been shown to reduce plaque load and has led to an improvement in memory performance in a transgenic mouse model. We examined the role of CNI-1493 in the microglial inflammatory response to Aβ using both a microglia cell line as well as primary microglia isolated from mesocortices. MTT assays were performed to quantify cell viability. FACS analysis was used to measure phagocytosis. We used ELISA to analyse cytokine concentrations in response to CNI-1493 treatment. Western-blot/Dot-blot techniques were used to show the interaction of CNI-1493 with Aβ-oligomers as well as to measure apoptosis in microglia cells. RT-PCR was used to analyze secretase expression, and secretase function was determined using fluorimetric assays. CNI-1493 is able to prevent oligomer formation as well as apoptosis in microglia. A significant reduction was found in the Aβ-induced release of IL-6 and TNF-α in the presence of CNI-1493. Phagocytosis is an essential Aβ removal mechanism and was enhanced by CNI-1493 in primary microglia. CNI-1493 also influenced the α-secretase product C83 with an increase in the treated cells, while a simultaneous reduction in Aβ secretion was also observed. We hypothesize that CNI-1493 not only reduces neuroinflammation and consequent neurodegeneration, but also leads to a shift in AβPP-processing towards the non-amyloidogenic pathway. Therefore, CNI-1493 is a promising candidate for the treatment of AD.
 
Age and gender adjusted survival function from Cox hazard regression. Y-axis: estimated survival percentages. X-axis: number of days. When not adjusting for age, patients with vascular dementia (VaD) has the highest mortality risk. A) Age-and-gender adjusted mortality risk was highest for Parkinson's disease with dementia (PDD). B) In the final model, after adjusting for age, gender, Mini- Mental State Exam, coresident, residential setting and number of medication at the beginning of diagnostic workup, frontotemporal dementia (FTD) presented the highest risk. AD, Alzheimer's disease; Mixed, mixed Alzheimer's disease and vascular dementia ; LBD, Lewy body dementia; Unspecified, unspecified dementia; Other, other dementia diagnoses.  
Characteristics of study subjects
Distribution of dementia types, age, and number of medication at diagnosis
Standardized mortality ratios in SveDem relative to the general Swedish population
Background: Knowledge on survival in dementia is crucial for patients and public health planning. Most studies comparing mortality risk included few different dementia diagnoses. Objectives: To compare mortality risk in the most frequent dementia disorders in a large cohort of patients with an incident diagnosis, adjusting for potential confounding factors. Methods: 15,209 patients with dementia from the national quality database, Swedish Dementia Registry (SveDem), diagnosed in memory clinics from 2008 to 2011, were included in this study. The impact of age, gender, dementia diagnosis, baseline Mini-Mental State Examination (MMSE), institutionalization, coresidency, and medication on survival after diagnosis were examined using adjusted hazard ratios (HR) with 95% confidence intervals (CI). Results: During a mean follow-up of 2.5 years, 4,287 deaths occurred, with 114 (95% CI 111-117) deaths/1,000 person-years. Adjusted HR of death for men was 1.56 (95% CI 1.46-1.66) compared to women. Low MMSE, institutionalization, and higher number of medications were associated with higher HR of death. All dementia diagnoses demonstrated higher HR compared to Alzheimer's disease, with vascular dementia presenting the highest crude HR. After adjusting, frontotemporal dementia had the highest risk with a HR of 1.91 (95% CI 1.52-2.39), followed by Lewy body dementia (HR 1.64; 95% CI 1.39-1.95), vascular dementia (HR 1.55; 95% CI 1.42-1.69), Parkinson's disease dementia (HR 1.47; 95% CI 1.17-1.84), and mixed Alzheimer's disease and vascular dementia (HR 1.32; 95% CI 1.22-1.44). Conclusion: Worse cognition, male gender, higher number of medications, institutionalization, and age were associated with increased death risk after dementia diagnosis. Adjusted risk was lowest in Alzheimer's disease patients and highest in frontotemporal dementia subjects.
 
The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer's Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p < 0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p < 0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.
 
Amyloid-β (Aβ40/42) aggregates containing the cross-β-sheet structure are associated with the pathogenesis of Alzheimer's disease (AD). It is generally accepted that the N-terminal peptide of Aβ40/42, Aβ1-16, does not aggregate, and is not cytotoxic. However, we here show that Aβ1-16 can aggregate, and form cytotoxic aggregates containing β-turns and regular non-amyloid β-sheet structures. Factors such as pH, ionic strength, and agitation were found to influence Aβ1-16 aggregation, and the amino acid residues Asp1, His6, Ser8, and Val12 in Aβ1-16 may play a role in this aggregation. Our MTT results showed that Aβ1-16 monomers or oligomers were toxic to SH-SY5Y cells, but Aβ1-16 fibrils exhibited less cytotoxicity. Our studies also indicate that Aβ1-16 aggregates can increase the formation of reactive oxygen species and nitric oxide, induce the loss of calcium homeostasis, and incur the microglial production of TNF-α and IL-4. Thus, our findings suggest that Aβ1-16 may contribute to AD pathogenesis.
 
Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ(1-15/16), Aβ(x-38), Aβ(x-40), Aβ(x-42), sAβPPα, and sAβPPβ. The CSF concentration of Aβ(1-15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ(x-38), Aβ(x-40), and Aβ(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.
 
Tauopathies, such as Alzheimer's disease (AD) and Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are characterized by tau accumulation. This accumulation could result from alterations in tau degradation by either the ubiquitin-proteasome system or the autophagy-lysosomal pathway. To analyze a possible alteration of the autophagy-lysosomal pathway in transgenic mice expressing human tau with three FTDP-17 missense mutations (TauVLW mice), we studied the lysosomal enzyme Cathepsin D. The hippocampi of TauVLW mice, where the human mutant tau accumulates, showed both increased Cathepsin D and partial colocalization of Cathepsin D with human mutant tau. At the ultrastructural level, some multivesicular bodies showed human mutant tau-immunopositive vesicles. This finding could provide insights into the molecular mechanisms of tau degradation in human tauopathies.
 
Human neurodegenerative diseases characterized by abnormal intraneuronal inclusions of the tau protein, or "tauopathies", include Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy, corticobasal degeneration as well as fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Several abnormalities of tau may contribute to the pathological processes, yet the mechanisms involved in tau cellular toxicity remain unclear. Previously, we demonstrated an interaction between various isoforms of tau and the immunophilin FKBP52 (FK506-Binding Protein), suggesting a direct involvement of FKBP52 in tau function. Here we analyze the expression of FKBP52 in human brains of patients with different tauopathies, including AD. Immunohistofluorescence studies carried out on cerebral cortex in different tauopathies reveal that FKBP52 is not sequestered by filamentous tau inclusions while FKBP52 is colocalized with tau in the control case brains. We found that FKBP52 expression level is abnormally low in frontal cortex of AD and FTDP-17 brains, as compared to controls, despite no alteration in the FKBP52 mRNA expression level. The possible involvement of FKBP52 in pathological tau expression/function is discussed.
 
Alzheimer's disease is growing in prevalence worldwide. Though many Western countries have developed programs of surveillance and care around Alzheimer's disease and dementia, certain regions of the world are beginning to recognize the magnitude of the disease burden in the general population. In the Middle East, there is growing awareness of the burden of Alzheimer's disease and how it impacts health economics, care delivery, and research. Here we summarize the proceedings of the 5th International Conference on Alzheimer's Disease in the Middle East. We had speakers from 20 countries updating the audience on progress toward improving healthcare and research related to AD in this region of the world.
 
17β-hydroxysteroid dehydrogenase 10 (HSD10) deficiency is a rare X-linked inborn error of isoleucine catabolism. Although this protein has been genetically implicated in Alzheimer's disease pathogenesis, studies of amyloid-β peptide (Aβ) in patients with HSD10 deficiency have not been previously reported. We found, in a severely affected child with HSD10 deficiency, undetectable levels of Aβ in the cerebrospinal fluid, together with low expression of brain-derived neurotrophic factor, α-synuclein, and serotonin metabolites. Confirmation of these findings in other patients would help elucidating mechanisms of synaptic dysfunction in this disease, and highlight the role of Aβ in both early and late periods of life.
 
Neuronal microtubules are morphologically abnormal in diseased regions of brain from patients with late-onset Alzheimer's disease (LOAD). Here we tested the hypothesis that tubulin derived from gray matter of patients with multiple forms of dementia was functionally impaired. Following taxol/GTP stimulation of tubulin polymerization of gray matter extracts we observed reduced capacity of tubulin to polymerize in LOAD, but not individuals with mild cognitive impairment (MCI), compared to controls. Moreover, we observed similarly reduced taxol/GTP-stimulated tubulin polymerization from gray matter obtained from patients with AD caused by PSEN2 N141I mutation or frontotemporal dementia with parkinsonism linked to chromosome-17 caused (FTDP-17) by TAU V337M or P301L mutation. Our results show that modification of tubulin function may contribute to intermediate or late stages in the pathogenesis of sporadic and inherited AD as well as FTDP-17.
 
Quantitative microanalysis of brains from patients with Alzheimer's disease (AD) find neuronal loss and neuroinflammation in structures that control cognitive function. Though historically difficult to recapitulate in experimental models, several groups have recently reported that by middle-age, transgenic mice that co-express high levels of two AD-associated mutations, amyloid-β protein precursor (AβPP(swe)) and presenilin 1 (PS1(ΔE9)), undergo significant AD-type neuron loss in sub-cortical nuclei with heavy catecholaminergic projections to the hippocampal formation. Here we report that by 13 months of age these dtg AβPP(swe)/PS1(ΔE9) mice also show significant loss of pyramidal neuron in a critical region for learning and memory, the CA1 subregion of hippocampus, as a direct function of amyloid-β (Aβ) aggregation. We used these mice to test whether 17α-estradiol (17αE2), a less feminizing and non-carcinogenic enantiomer of 17β-estradiol, protects against this CA1 neuron loss. Female dtg AβPP(swe)/PS1(ΔE9) mice were ovariectomized at 8-9 months of age and treated for 60 days with either 17αE2 or placebo via subcutaneous pellets. Computerized stereology revealed that 17αE2 ameliorated the loss of neurons in CA1 and reduced microglial activation in the hippocampus. These findings support the view that 17αE2, which may act through non-genomic mechanisms independent of traditional estrogen receptors, could prevent or delay the progression of AD in older men and women.
 
Oxidative stress is thought to be a pivotal factor in Alzheimer's disease (AD). Amyloid-beta (Abeta) induces oxidative damage, which is likely to be compounded by deficiencies in endogenous antioxidant capacity. Indeed, folate deprivation, which has been associated with AD, potentiates generation of reactive oxygen species (ROS) by Abeta. We examined whether the antioxidant 17-beta-estradiol could attenuate ROS generation following Abeta treatment in the presence and absence of folate using differentiated SH-SY-5Y human neuroblastoma cells. Folate-deprivation and Abeta treatment each induced an increase in ROS, and treatment of folate-deprived cultures with Abeta induced a synergistic increase in ROS. 17-beta-estradiol reduced ROS levels in beta-treated, folate-deprived cultures to ROS levels observed in cultures treated with Abeta in the presence of folate, suggesting that this antioxidant was able to prevent the synergistic impact of Abeta and folate deprivation on ROS generation. 17-beta-estradiol also completely prevented neuronal death induced by both Abeta and folate deprivation individually, and reduced neuronal death following Abeta treatment along with folate deprivation. These findings suggest that therapeutic approaches utilizing antioxidants may be particularly important in conditions such as AD, where multiple factors, including compromises in endogenous antioxidants, promote oxidative stress.
 
Work in 1980s and early 1990s established that the microtubule-associated protein tau is the major component of the paired helical filament of Alzheimer's disease. Similar filamentous deposits are also present in a number of other diseases, including progressive supranuclear palsy, corticobasal degeneration and Pick's disease. In 1998, the relevance of tau dysfunction for the neurodegenerative process became clear, when mutations in the tau gene were found to cause the inherited "frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)". The paper highlighted here [Spillantini M.G., Murrell J.R., Goedert M., Farlow M., Klug A. and Ghetti B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737-7741] reported a mutation at position + 3 in the intron following alternatively spliced exon 10 of the tau gene in a family.
 
Many studies have documented the role of risk and protective factors for late life dementing illnesses, particularly Alzheimer's disease. A "Systematic Review" from the US Agency for Healthcare Research and Quality and the National Institute on Aging concluded that because the overall quality of evidence was low, recommendations for public health could not be made. In order to gain evidence for the efficacy of lifestyle interventions, we propose a "Modest Proposal" to study 10,000 subjects over 40 years randomly assigned to groups of low or high saturated fat in the diet, head injury, and high or low levels of mental activity, physical activity, or inactivity as well as smoking or non-smoking. This proposed study cannot be accomplished. The "Modest Proposal" illustrates that the absence of definitive evidence should not restrict physicians from making reasonable recommendations based on the evidence that is available.
 
We studied the ability of four non-conjugated alpha7-subunit fragments of the nicotinic acetylcholine receptor to induce an immune response and to protect memory in olfactory bulbectomized mice which demonstrate abnormalities similar to Alzheimer's disease (AD). Vaccination only with the alpha7-subunit fragment 173-193 was shown to rescue spatial memory, to restore the level of alpha7 acetylcholine receptors in the cortex, and to prevent an increase in the amyloid-beta (Abeta) level in brain tissue in these animals. Antibodies against the peptide 173-193 were revealed in blood serum and cerebrospinal liquid in the bulbectomized mice. Passive immunization with mouse blood sera containing antibodies to the peptide 173-193 also restored memory in bulbectomized animals. The observed positive effect of both active and passive immunization with the fragment of alpha7-subunit on memory of bulbectomized mice provides a new insight into an anti-AD drug design.
 
Standardized mean difference (SMD) computed from the studies on Cu serum levels (mol/L). SMDs between patients and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random effects model, with the centre representing the point estimate and the width the associated 95% CI. Heterogeneity Chi-squared = 64.03 (d.f. = 16), p < 0.0001. I-squared (variation in SMD attributable to heterogeneity) = 75.0%. Estimate of between-study variance Tau-squared = 0. 1596; Test of SMD = 0: z = 3.99, p = 0.000.
Standardized mean difference (SMD) computed from the studies on Cu plasma levels (mol/L). SMDs between patients and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random effects model, with the centre representing the point estimate and the width the associated 95% CI. Heterogeneity Chi-squared = 53.98 (d.f. = 3), p = 0.000. I-squared (variation in SMD attributable to heterogeneity) = 94.4%. Estimate of between-study variance Tau-squared = 0.9357. Test of SMD = 0: z = 0.35, p = 0.726.  
Standardized mean difference (SMD) computed from the joint pool of studies on Cu serum and plasma levels (mol/L). SMDs between patients and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random effects model, with the centre representing the point estimate and the width the associated 95% CI. Heterogeneity Chi-squared = 118.53 (d.f. = 20), p < 0.001. I-squared (variation in SMD attributable to heterogeneity) = 83.1%. Estimate of between-study variance Tau-squared = 0.2577. Test of SMD = 0: z = 3.28, p = 0.001.  
Standardized mean difference (SMD) computed from the studies on Cu CSF levels (mol/L). SMDs between patients and controls are represented by squares, whose sizes are proportional to the sample size of the relative study. The whiskers represent the 95% confidence interval (CI). The diamond represents the pooled estimate based on the random effects model, with the centre representing the point estimate and the width the associated 95% CI. Heterogeneity Chi-squared = 44.32 (d.f. = 4), p < 0.0001. I-squared (variation in SMD attributable to heterogeneity) = 91.0%. Estimate of between-study variance Tau-squared = 1.04334. Test of SMD = 0: z = 0.81, p = 0.420.  
This contribution reviews and corrects data from our previous meta-analysis, which appeared in the Journal of Alzheimer's Disease in 2011 concerning the role of copper in Alzheimer's disease. We repeated the meta-analysis after excluding four of the five studies from our laboratory to avoid possible bias in the result. In addition, we included two studies on serum copper levels in Alzheimer's disease not previously considered. The results indicate higher levels of copper in Alzheimer's disease patients than in controls, confirming our previous conclusion.
 
Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17alpha-estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics.
 
Background: 18F-FDG-PET is defined as a biomarker of neuronal injury according to the revised National Institute on Aging–Alzheimer’s Association criteria. Objective: The objective of this multicenter prospective cohort study was to examine the value of 18F-FDG-PET in predicting the development of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). Methods: In total, 114 patients with MCI at 9 participating institutions underwent clinical and neuropsychological examinations, MRI, and 18F-FDG-PET at baseline. The cases were visually classified into predefined dementia patterns by three experts. Anautomated analysis for 18F-FDG-PET was also performed to calculate the PET score. Subjects were followed periodically for 3 years, and progression to dementia was evaluated. Results: In 47% of the patients with MCI, progression of symptoms justified the clinical diagnosis of “probable AD”. The PET visual interpretation predicted conversion to AD during 3-year follow-up with an overall diagnostic accuracy of 68%. Overall diagnostic accuracy of the PET score was better than that of PET visual interpretation at all follow-up intervals, and the optimized PET score threshold revealed the best performance at the 2-year follow-up interval with an overall diagnostic accuracy of 83%,a sensitivity of 70%, and a specificity of 90%. Multivariate logistic regression analysis identified the PET score as the most significant predictive factor distinguishing AD converters from non-converters. Conclusion: The PET score is the most statistically significant predictive factor for conversion from MCI to AD, and the diagnostic performance of the PET score is more promising for rapid converters over 2 years.
 
Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have developed a novel PHF-tau targeting positron emission tomography imaging agent, [F-18]-T807, which may be useful for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F-18]-T807.
 
Top-cited authors
Hilkka Soininen
  • University of Eastern Finland, Kuopio Finland
Ph Scheltens
  • Amsterdam University Medical Center
Carlo Caltagirone
  • University of Rome Tor Vergata and IRCCS Fondazione Santa Lucia , Roma
Harald J Hampel
Bruno Dubois
  • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix