Journal of Alzheimer's Disease - Volume 35, issue 3

Authors: Glodzik, Lidia | Randall, Catherine | Rusinek, Henry | de Leon, Mony J.

Article Type: Review Article

Abstract: There is growing evidence that cerebrovascular reactivity to carbon dioxide (CVRCO2 ) is impaired in Alzheimer's disease (AD). Preclinical and animal studies suggest chronic hypercontractility in brain vessels in AD. We review (a) preclinical studies of mechanisms for impaired CVRCO2 in AD; (b) clinical studies of cerebrovascular function in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition. Although results of clinical studies are inconclusive, an increasing number of reports reveal an impairment of vascular reactivity to carbon dioxide in subjects with AD, and possibly also in MCI. Thus, CVRCO2 may be an …attractive means to detect an early vascular dysfunction in subjects at risk. Show more

Keywords: Alzheimer's disease, carbon dioxide, cognitive impairment, vascular, vasoreactivity

DOI: 10.3233/JAD-122011

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 427-440, 2013

Authors: Javitt, Norman B.

Article Type: Review Article

Abstract: Evidence is emerging that during the development of Alzheimer's disease (AD), changes in the synthesis and metabolism of cholesterol and progesterone are occurring that may or may not affect the progression of the disease. The concept arose from the recognition that dehydrocholesterol 24-reductase (DHCR24/Seladin-1), one of the nine enzymes in the endoplasmic reticulum that determines the transformation of lanosterol to cholesterol, is selectively reduced in late AD. As a consequence, the tissue level of desmosterol increases, affecting the expression of ABC transporters and the structure of lipid rafts, both determinants of amyloid-β processing. However, the former effect is considered beneficial …and the latter detrimental to processing. Other determinants of desmosterol tissue levels are 24,25 epoxycholesterol and the ABCG1 and ABCG4 transporters. Progesterone and its metabolites are determinants of tissue levels of desmosterol and several other sterol intermediates in cholesterol synthesis. Animal models indicate marked elevations in the tissue levels of these sterols at early time frames in the progression of neurodegenerative diseases. The low level of neuroprogesterone and metabolites in AD are consonant with the low level of desmosterol and may have a role in amyloid-β processing. The sparse data that has accumulated appears to be a sufficient basis for proposing a systematic evaluation of the biologic roles of sterol intermediates in the slowly progressive neurodegeneration characteristic of AD. Show more

Keywords: ABC transporters, Alzheimer's disease, desmosterol, lanosterol, lipid rafts, neurodegeneration, progesterone, sterol intermediates

DOI: 10.3233/JAD-130044

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 441-450, 2013

Authors: Schmidt, Christian | Karch, André | Artjomova, Svetlana | Hoeschel, Martin | Zerr, Inga

Article Type: Short Communication

Abstract: Background: Pre-progression rates (PPR) in Alzheimer’s disease (AD) have been reported to be associated with cognitive and functional decline. Objective: The objective was to reevaluate PPRs in a prospective cohort of AD patients. Methods: A prospective AD cohort was analyzed. Multiple regression was used to examine associations of PPRs with short term decline on different cognitive and functional scales (MMSE, instrumental and basic ADL, GDS, UPDRS III). Results: PPRs were only associated with first year instrumental ADL declines. Conclusion: The predictive abilities of PPRs could partially be confirmed. These findings can help …to adapt patient care shortly after diagnosis. Show more

Keywords: Alzheimer's disease, cognitive decline, pre-progression rate, progression

DOI: 10.3233/JAD-130074

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 451-454, 2013

Authors: Cerami, Chiara | Marcone, Alessandra | Galimberti, Daniela | Zamboni, Michele | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Cappa, Stefano F.

Article Type: Research Article

Abstract: C9ORF72 repeat expansion is currently considered as a major genetic cause of amyotrophic lateral sclerosis (ALS) and, in particular, of combined frontotemporal dementia-motor neuron disorder (FTD-MND) pedigrees. Studies of large series of patients have indicated that various phenotypic presentations may be observed even in the same family. Here, we describe four patients carrying a C9ORF72 mutation with heterogeneous clinical presentation sharing a rapid disease course. Cases #1 and #2 presented with predominant semantic deficits, accompanied in one patient by clinical signs of ALS. Case #3 showed a phenotype compatible with a diagnosis of behavioral variant of FTD. Case #4 presented …with memory impairments, apathy, and social withdrawal, and had negative cerebrospinal fluid markers for Alzheimer's disease. Two patients showed a positive familiar history of MND and dementia (at least one first-degree family member affected). The two other patients were apparently sporadic cases. Our data provide further evidence for the heterogeneity of phenotypes associated with the C9ORF72 mutation and indicate its association with a fluent progressive aphasia phenotype. The present findings confirm the importance of screening for the hexanucleotide repeat expansion in chromosome 9 in the case not only of familial, but also of sporadic FTD, and in the presence of atypical cognitive disorders. Show more

Keywords: C9ORF72 mutation, frontotemporal dementia, frontotemporal lobar degeneration, mild cognitive impairment, motor neuron disorders, semantic dementia

DOI: 10.3233/JAD-122302

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 455-462, 2013

Authors: Zurita, Maria Paz | Muñoz, Gonzalo | Sepúlveda, Fernando J. | Gómez, Paulina | Castillo, Carolina | Burgos, Carlos F. | Fuentealba, Jorge | Opazo, Carlos | Aguayo, Luis G.

Article Type: Research Article

Abstract: Epidemiological studies have reported a decrease in the prevalence of Alzheimer's disease in individuals who chronically use non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trials, on the other hand, have been less positive. Nevertheless, it has been proposed that NSAIDs exert part of their effects by reducing long-term cerebral neuroinflammation, although this mechanism has not been proven. In this study, we report that ibuprofen, one of the more widely used non-steroidal anti-inflammatory drugs, was able to alter the ultrastructure of amyloid-β peptide (Aβ) and significantly decrease its association to neuronal membranes, and consequently, its synaptotoxic effect in rat primary hippocampal and cortical …cultures at 24 h incubation. In agreement with these results, we found that the decrease in the frequency of calcium transients with Aβ was partly recovered by addition of ibuprofen (8.0 × 10−2 Hz in control; 3.4 × 10−2 Hz in 5 μM Aβ, and 5.9 × 10−2 Hz in the presence of Aβ and 200 μM ibuprofen). Additionally, this effect correlated well with the increment and recovery of miniature spontaneous currents (47 ± 5% of control in 1 μM Aβ alone and 104 ± 14% in the presence of Aβ and ibuprofen). Our results suggest that ibuprofen could be exerting its neuroprotective effect by directly interacting with Aβ and altering its toxic aggregated forms. We postulate that other ibuprofen analogs with better pharmacological properties might have a higher efficacy in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, ibuprofen, neurotransmission, non-steroidal anti-inflammatory drugs

DOI: 10.3233/JAD-122314

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 463-473, 2013

Authors: Bhatia, Surabhi | Jenner, Andrew M. | Li, Hongyun | Ruberu, Kalani | Spiro, Adena S. | Shepherd, Claire E. | Kril, Jillian J. | Kain, Nupur | Don, Anthony | Garner, Brett

Article Type: Research Article

Abstract: Previous studies indicate that apolipoprotein D (apoD) may have a lipid antioxidant function in the brain. We have shown that apoD can reduce free radical-generating lipid hydroperoxides to inert lipid hydroxides in a reaction that involves conversion of surface exposed apoD methione-93 (Met93) residue to Met93-sulfoxide (Met93-SO). One consequence of this reaction is the formation of a stable dimerized form of apoD. As cerebral lipid peroxidation is associated with Alzheimer's disease (AD), in the present study we aimed to assess the possible presence of apoD dimers in postmortem hippocampal and cerebellar tissues derived from a cohort of pathologically defined cases …ranging from control to late stage AD. Both soluble and insoluble (requiring guanidine HCl extraction) fractions of tissue homogenates were analyzed for apoD and its dimerized form. We also assessed amyloid-β levels by ELISA and levels of lipid peroxidation by lipid conjugated diene and F2-isoprostane analysis. Our studies reveal a significant association between soluble apoD levels and AD Braak stage whereas apoD dimer formation appears to increase predominantly in the advanced stages of disease. The formation of apoD dimers is closely correlated to lipid conjugated diene levels and occurs in the hippocampus but not in the cerebellum. These results are consistent with the hypothesis that apoD acts as a lipid antioxidant in the brain. Show more

Keywords: Apolipoprotein D, lipid peroxidation, oxidative stress, protein dimerization

DOI: 10.3233/JAD-122278

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 475-486, 2013

Authors: Villa, Chiara | Ridolfi, Elisa | Fenoglio, Chiara | Ghezzi, Laura | Vimercati, Roberto | Clerici, Francesca | Marcone, Alessandra | Gallone, Salvatore | Serpente, Maria | Cantoni, Claudia | Bonsi, Rossana | Cioffi, Sara | Cappa, Stefano | Franceschi, Massimo | Rainero, Innocenzo | Mariani, Claudio | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: Altered gene expression occurs in central nervous system disorders, including Alzheimer's disease (AD). Transcription factor Sp1 (specificity protein 1) can regulate the expression of several AD-related proteins, including amyloid-β protein precursor and tau. Sp1 is regulated by oxidative stress, and Sp1 mRNA was found to be upregulated in AD cortex and hippocampus. The distribution of three single nucleotide polymorphisms (SNPs), including rs7300593, rs17695156, and rs12821290, covering 100% Sp1 genetic variability, has been determined in a population of 393 AD patients as compared with 412 controls. In addition, expression analysis of Sp1 and its regulatory microRNAs (hsa-miR-29b and hsa-miR-375) has been …performed in peripheral blood mononuclear cells (PBMCs), together with Sp1 protein analysis. No differences in all three SNP distributions were observed in AD patients as compared with controls. Stratifying according to gender, a significantly decreased frequency of Sp1 rs17695156 T allele was observed in male patients versus male controls. Significantly increased Sp1 relative expression levels were observed in PBMCs from AD patients as compared with controls. Western blot analysis paralleled mRNA increase in AD patients versus controls and correlated positively with Sp1 mRNA levels. Significantly decreased relative expression levels of hsa-miR-29b, but not of hsa-miR-375, were observed in AD patients versus controls and correlated negatively with Sp1 mRNA levels. According to these results, Sp1 and its regulatory hsa-miR-29b are deregulated in AD patients, possibly leading to aberrant production of downstream target genes involved in the pathogenesis. Moreover, Sp1 rs176951056 T allele is likely a protective factor in the male population. Show more

Keywords: Alzheimer's disease, expression, gene regulation, microRNAs, peripheral blood mononuclear cells, risk factor, Sp1

DOI: 10.3233/JAD-122263

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 487-494, 2013

Authors: Fernández, Alberto | Turrero, Agustín | Zuluaga, Pilar | Gil-Gregorio, Pedro | del Pozo, Francisco | Maestu, Fernando | Moratti, Stephan

Article Type: Research Article

Abstract: New diagnostic criteria for Alzheimer's disease (AD) stress the role of in vivo biomarkers. Neurophysiological markers are usually not considered as such criteria, although theoretical and practical reasons would justify them. In order to assess the value of neurophysiology as an AD biomarker, whole-head magnetoencephalographic (MEG) resting state recordings were obtained from 35 AD patients, 23 mild cognitive impairment (MCI) patients, and 24 healthy controls. The AD group was further split into two groups differing in severity according to the GDS/FAST criteria. A Minimum Norm Estimation procedure was utilized to estimate the cortical origin of slow brain oscillatory activity in …the delta band (2–4 Hz). Eight regions of interest (ROIs) discriminated between AD patients and controls. Delta current density (DCD) in all ROIs showed a significant negative correlation with cognitive status (p < 0.001). DCD values in posterior parietal, occipital, prerolandic, and precuneus cortices distinguished reliably between MCI patients, AD patients with different severity scores, and controls. Importantly, an increase of DCD in right parietal cortex and precuneus indexed the transition from MCI to mild dementia and from mild to more severe dementia. MEG delta mapping might be a serious candidate for a “neural degeneration” marker of AD reflecting dysfunctional synaptic transmission. More importantly, the localization of DCD values is in line with functional imaging markers of AD. However, MEG delta mapping is a totally non-invasive technique that directly measures neural activity. We propose that individuals with enhanced DCD in posterior parietal and precuneus cortices are at risk of progression to full dementia. Show more

Keywords: Alzheimer's disease, delta mapping, magnetoencephalography, mild cognitive impairment

DOI: 10.3233/JAD-121912

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 495-507, 2013

Authors: Mosconi, Lisa | Andrews, Randolph D. | Matthews, Dawn C. | For the Alzheimer's Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: This study compares the degree of brain amyloid-β (Aβ) deposition, glucose metabolism, and grey matter volume (GMV) reductions in mild cognitive impairment (MCI) patients overall and as a function of their parental history of dementia. Ten MCI with maternal history (MH), 8 with paternal history (PH), and 24 with negative family history (NH) received 11 C-PiB and 18 F-FDG PET and T1-MRI as part of the Alzheimer's Disease Neuroimaging Initiative. Statistical parametric mapping, voxel based morphometry, and Z-score mapping were used to compare biomarkers across MCI groups, and relative to 12 normal controls. MCI had higher PiB retention, hypometabolism, and …GMV reductions in Alzheimer-vulnerable regions compared to controls. Biomarker abnormalities were more pronounced in MCI with MH than those with PH and NH. After partial volume correction of PET, Aβ load exceeded hypometabolism and atrophy with regard to the number of regions affected and magnitude of impairment in those regions. Hypometabolism exceeded atrophy in all MCI groups and exceeded Aβ load in medial temporal and posterior cingulate regions of MCI MH. While all three biomarkers were abnormal in MCI compared to controls, Aβ deposition was the most prominent abnormality, with MCI MH having the greatest degree of co-occurring hypometabolism. Show more

Keywords: Alzheimer's disease, amyloid, family history, 18F-fluorodeoxyglucose (FDG), glucose metabolism, magnetic resonance imaging, mild cognitive impairment, positron emission tomography (PET) imaging, Pittsburgh Compound B

DOI: 10.3233/JAD-121867

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 509-524, 2013

Authors: Casarejos, Maria J. | Perucho, Juan | Gomez, Ana | Muñoz, Maria P. | Fernandez-Estevez, Marian | Sagredo, Onintza | Fernandez Ruiz, Javier | Guzman, Manuel | de Yebenes, Justo Garcia | Mena, Maria A.

Article Type: Research Article

Abstract: Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex® , a mixture of Δ9 -tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK-/- /TauVLW ) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex® , 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex® …on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK-/- /TauVLW mice developed the neurological deficits, but those treated with Sativex® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex® reduced the deposition of both in the hippocampus and cerebral cortex of PK-/- /TauVLW mice and increased autophagy. Sativex® , even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK-/- /TauVLW mice, a model of complex neurodegenerative disorders. Show more

Keywords: Amyloid, autophagy, cannabinoids, dopamine, frontotemporal dementia, lower motor neuron disease, parkin, parkinsonism, reactive oxygen species, Sativex®, tau

DOI: 10.3233/JAD-130050

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 525-539, 2013