Journal of Alzheimer's Disease - Volume 28, issue 4

Authors: Beach, Thomas G. | Sue, Lucia I. | Walker, Douglas G. | Sabbagh, Marwan N. | Serrano, Geidy | Dugger, Brittany N. | Mariner, Monica | Yantos, Kim | Henry-Watson, Jonette | Chiarolanza, Glenn | Hidalgo, Jose A. | Souders, Leslie

Article Type: Research Article

Abstract: Amyloid imaging may revolutionize Alzheimer's disease (AD) research and clinical practice but is critically limited by an inadequate correlation between cerebral cortex amyloid plaques and dementia. Also, amyloid imaging does not indicate the extent of neurofibrillary tangle (NFT) spread throughout the brain. Currently, the presence of dementia as well as a minimal brain load of both plaques and NFTs is required for the diagnosis of AD. Autopsy studies suggest that striatal amyloid plaques may be mainly restricted to subjects in higher Braak NFT stages that meet clinicopathological diagnostic criteria for AD. Striatal plaques, which are readily identified by amyloid imaging, …might therefore be used to predict the presence of a higher Braak NFT stage and clinicopathological AD in living subjects. This study determined the sensitivity and specificity of striatal plaques for predicting a higher Braak NFT stage and clinicopathological AD in a postmortem series of 211 elderly subjects. Subjects included 87 clinicopathologically classified as non-demented elderly controls and 124 with AD. A higher striatal plaque density score (moderate or frequent) had 95.8% sensitivity, 75.7% specificity for Braak NFT stage V or VI and 85.6% sensitivity, 86.2% specificity for the presence of dementia and clinicopathological AD (National Institute on Aging – Reagan Institute “intermediate” or “high”). Amyloid imaging of the striatum may be useful as a predictor, in living subjects, of Braak NFT stage and the presence or absence of dementia and clinicopathological AD. Validation of this hypothesis will require autopsy studies of subjects that had amyloid imaging during life. Show more

Keywords: Alzheimer's disease, amyloid imaging, amyloid plaques, asymptomatic, autopsy, diagnosis, preclinical, striatum, therapy

DOI: 10.3233/JAD-2011-111340

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 869-876, 2012

Authors: Saint-Aubert, Laure | Planton, Mélanie | Hannequin, Didier | Albucher, Jean-François | Delisle, Marie-Bernadette | Payoux, Pierre | Hitzel, Anne | Viallard, Gérard | Péran, Patrice | Campion, Dominique | Laquerrière, Annie | Barbeau, Emmanuel J. | Puel, Michéle | Raposo, Nicolas | Chollet, François | Pariente, Jérémie

Article Type: Research Article

Abstract: We report the case of a 62-year-old asymptomatic carrier of AβPP gene duplication. He was investigated by MRI and the amyloid ligand 18 F-AV45, and compared to Alzheimer's disease patients (n = 11) and healthy controls (n = 11). The neuropsychological examination was normal. Cortical thickness and AV45 retention were comparable to Alzheimer's disease patients. AβPP duplication was diagnosed because cerebral amyloid angiopathy and Alzheimer's disease pathology were found on the neuropathological examination of his youngest brother, who died at 42 from intracerebral hemorrhage. This is the first description of a pre-symptomatic AβPP duplication carrier over 60, despite widespread cerebral …amyloid angiopathy, “Alzheimer's like” atrophy, and amyloid deposition. Show more

Keywords: AβPP duplication, Alzheimer's disease, amyloid, AV45 PET, cerebral amyloid angiopathy, genetics, MRI

DOI: 10.3233/JAD-2011-111598

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 877-883, 2012

Authors: Lemos, Raquel | Figueiredo, Patrícia | Santana, Isabel | Simões, Mário R. | Castelo-Branco, Miguel

Article Type: Research Article

Abstract: The nature of visual impairments in Alzheimer's disease (AD) and their relation with other cognitive deficits remains highly debated. We asked whether independent visual deficits are present in AD and amnestic forms of mild cognitive impairment (MCI) in the absence of other comorbidities by performing a hierarchical analysis of low-level and high-level visual function in MCI and AD. Since parietal structures are a frequent pathophysiological target in AD and subserve 3D vision driven by motion cues, we hypothesized that the parietal visual dorsal stream function is predominantly affected in these conditions. We used a novel 3D task combining three critical …variables to challenge parietal function: 3D motion coherence of objects of unknown orientation, with constrained temporal integration of these cues. Groups of amnestic MCI (n = 20), AD (n = 19), and matched controls (n = 20) were studied. Low-level visual function was assessed using psychophysical contrast sensitivity tests probing the magnocellular, parvocellular, and koniocellular pathways. We probed visual ventral stream function using the Benton Face Recognition task. We have found hierarchical visual impairment in AD, independently of neuropsychological deficits, in particular in the novel parietal 3D task, which was selectively affected in MCI. Integration of local motion cues into 3D objects was specifically and most strongly impaired in AD and MCI, especially when 3D motion was unpredictable, with variable orientation and short-lived in space and time. In sum, specific early dorsal stream visual impairment occurs independently of ventral stream, low-level visual and neuropsychological deficits, in amnestic types of MCI and AD. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, parietal lobe, vision

DOI: 10.3233/JAD-2011-110719

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 885-896, 2012

Authors: Wirths, Oliver | Dins, Annika | Bayer, Thomas A.

Article Type: Research Article

Abstract: The triple-transgenic Alzheimer's disease (AD) mouse model, 3xTg-AD, played an important role in supporting the intraneuronal amyloid-β (Aβ) hypothesis in AD. However, recent evidence claims that the 3xTg-AD mice accumulate amyloid-β protein precursor (AβPP) instead of Aβ within neurons. In the present report, we re-investigated the 3xTg-AD mouse model and confirmed recent findings of age-dependent AβPP accumulations. In addition, intraneuronal Aβ was detected mainly in the neocortex using conformation-specific as well as antibodies directed against Aβ neo-epitopes. In contrast to previous work, however, only minor levels of intraneuronal Aβ were detected in the CA1 region of the hippocampus in aged …3xTg-AD mice. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β protein precursor, immunohistochemistry, intraneuronal amyloid-β, pyroglutamate amyloid-β, transgenic mice

DOI: 10.3233/JAD-2011-111529

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 897-904, 2012

Authors: Dobos, Nikoletta | de Vries, Erik F.J. | Kema, Ido P. | Patas, Konstantinos | Prins, Marloes | Nijholt, Ingrid M. | Dierckx, Rudi A. | Korf, Jakob | den Boer, Johan A. | Luiten, Paul G.M. | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [11 C]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, …we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior. Show more

Keywords: Depression, indoleamine 2, 3-dioxygenase, lipopolysaccharide, neuroinflammation, positron emission tomography

DOI: 10.3233/JAD-2011-111097

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 905-915, 2012

Authors: Elfrink, Hyung Lim | Zwart, Rob | Cavanillas, María L. | Schindler, Adam Jay | Baas, Frank | Scheper, Wiep

Article Type: Research Article

Abstract: The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER), the first compartment of the secretory pathway. The UPR is activated in non-tangle bearing neurons in Alzheimer's disease (AD) brain, indicating it is an early phenomenon. We found that the level of Rab6, implicated in anterograde and retrograde trafficking in the secretory pathway, is increased in brains of AD patients. Rab6 expression, closely correlated with the extent of UPR activation, is not controlled by the UPR. This suggests that Rab6 and UPR activation are both increased in response to early pathogenic changes in AD. Here we …demonstrate that Rab6 modulates the UPR, increased levels inhibit whereas decreased levels augment UPR induction. Rab6 is not involved in the initial phase of the UPR; it only affects the UPR after prolonged ER stress. We propose that Rab6 is involved in the recovery from an ER stress insult. The increased Rab6 levels in AD brain in combination with UPR activation suggest that a failure to recover from ER stress may contribute to neurodegeneration in AD. The Rab6 mediated recovery pathway may provide a target to selectively inhibit the destructive pathways of the UPR. Show more

Keywords: Alzheimer's disease, endoplasmic reticulum stress, Rab6, unfolded protein response

DOI: 10.3233/JAD-2011-110971

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 917-929, 2012

Authors: Creavin, Samuel T. | Gallacher, John | Bayer, Antony | Fish, Mark | Ebrahim, Shah | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: We have examined whether metabolic syndrome is associated with intermediate risk of impaired cognition between people with and without diabetes. Men aged 45 to 59 years were identified from Caerphilly in South Wales, United Kingdom. Participation rate was 89% (41% of the original cohort) and 2,512 men were examined in phase one from July 1979 until September 1983. Follow-up examinations occurred at four intervals until 2004 when 1,225 men participated. Participants were categorized on the basis of their exposure to metabolic syndrome not diabetes (MSND) and diabetes (with or without metabolic syndrome) at each of the first three phases. Neuropsychological …outcomes and clinical diagnosis of cognitive impairment not dementia (CIND) and dementia were assessed at phase five. The prevalence of MSND increased from 1% to 5% and for diabetes from 3% to 9% between phase one and phase three. 15% of participants had CIND and 8% dementia. People with diabetes, but not those with MSND, at phases one, two, or three had poorer cognition at phase five (adjusted β coefficient AH4 −4.3 95% CI −7.9, −0.7; phase two: −2.5 95% CI −4.7, −0.3; phase three: −2.3 95% CI −4.2, −0.5). The adjusted odds ratio (phase one) for diabetes and CIND was 4.0 (95% CI 1.4, 11.5) and dementia 0.61 (95% CI 0.07, 5.37). After adjustment, higher systolic blood pressure was the only component of the metabolic syndrome associated with worse cognitive outcomes. Diabetes in mid-life, but not MSND, is associated with impaired cognition and increased odds of CIND in later life. Show more

Keywords: Cognition disorders/epidemiology, cohort studies, diabetes mellitus Type 2/complications, metabolic syndrome X/epidemiology, risk factors

DOI: 10.3233/JAD-2011-111550

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 931-939, 2012

Authors: Premi, Enrico | Pilotto, Andrea | Alberici, Antonella | Papetti, Alice | Archetti, Silvana | Seripa, Davide | Daniele, Antonio | Masullo, Carlo | Garibotto, Valentina | Paghera, Barbara | Caobelli, Federico | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Primary progressive aphasia (PPA) is a heterogeneous disorder characterized by progressive language impairment. Polymorphisms within forkhead box P2 gene (FOXP2) gene have been associated with speech and language impairment. Apolipoprotein E (APOE) genotype and PRNP 129 codon status have been demonstrated to increase the risk of PPA, but with contrasting results. In the present study, we have evaluated the impact of FOXP2, APOE and PRNP genetic variations as risk factors and/or disease-modulators in PPA. 94 PPA patients and 200 age-matched healthy controls were considered and FOXP2 polymorphisms (rs1456031, rs17137124), APOE genotype, and PRNP codon 129 polymorphism analyzed. In 34 PPA …patients, SPECT imaging data were analyzed by Statistical Parametric Mapping (SPM8). Genetic distributions and allele frequencies of FOXP2 and PRNP polymorphisms did not differ between groups while APOE ε4 was more represented in PPA as compared to controls. PPA patients carrying at-risk FOXP2 polymorphisms (rs1456031 and/or rs17137124) showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus and the right cingulated gyrus compared to non-carriers (p < 0.005). PPA patients carrying at least one ε4 allele had greater hypoperfusion in orbitofrontal regions (superior frontal gyrus and orbital gyrus) as compared to non-carriers ε4 (p < 0.005). PRNP codon 129 homozigosity correlated with left frontotemporal hypoperfusion (p < 0.005). Genetic variations within FOXP2, APOE, and PRNP modulate PPA disease, leading to a specific regional hypoperfusion according to different molecular pathways. APOE ε4 is overrepresented in PPA, thus likely acting as genetic risk factor on disease development. Show more

Keywords: Apolipoprotein E ε4, FOXP2, primary progressive aphasia, progressive non-fluent aphasia, PRNP, semantic dementia, SPECT, statistical parametric mapping

DOI: 10.3233/JAD-2011-111541

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 941-950, 2012

Authors: Erickson, Michelle A. | Niehoff, Michael L. | Farr, Susan A. | Morley, John E. | Dillman, Lucy A. | Lynch, Kristin M. | Banks, William A.

Article Type: Research Article

Abstract: The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer's disease has a natural mutation leading to age-related increases in the amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in the brain, memory impairment, and deficits in Aβ removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AβPP can decrease AβPP expression and Aβ production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 μg of AβPP or control antisense 3 times over 2 week intervals to …12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AβPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aβ40 . Our results show that AβPP antisense completely reverses a 30% age-associated increase in AβPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aβ40 increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AβPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AβPP antisense and show a unique association between AβPP and LRP-1 expression in the SAMP8 mouse. Show more

Keywords: Abcb1, amyloid-β peptides, amyloid-β protein precursor, antisense, blood-brain barrier, LRP1, oligonucleotides, Pgp, RAGE, SAMP8

DOI: 10.3233/JAD-2011-111517

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 951-960, 2012

Authors: Boddapati, Shanta | Levites, Yona | Suryadi, Vick | Kasturirangan, Srinath | Sierks, Michael R.

Article Type: Research Article

Abstract: Misfolding and aggregation of amyloid-β (Aβ) is an important early event in the pathogenesis of Alzheimer's disease. Aβ is produced by sequential proteolysis of the amyloid-β protein precursor (AβPP) by β- and γ-secretases. A third protease, α-secretase, cleaves AβPP in the middle of the Aβ sequence precluding formation of Aβ. The levels of Aβ generated from AβPP can therefore be controlled by tailoring activity of these proteases toward AβPP. We previously showed that β-secretase proteolysis of AβPP could be selectively inhibited using the single chain antibody fragment (scFv) iBSEC1, which blocks the cleavage site on AβPP, and α-secretase proteolysis of …AβPP could be selectively enhanced using a proteolytic scFv (Asec1A) engineered to have α-secretase-like activity. Here we show that DIA10D, a novel tandem bispecific scFv combining iBSEC1 with the ASec1A can control amyloidogenic processing of AβPP by simultaneously inhibiting β-secretase and increasing α-secretase processing of AβPP. When expressed in H4 (neuroglioma) cells overexpressing AβPP, DIA10D potently reduces levels of extracellular Aβ by around 50% while also increasing levels of neuroprotective sAβPPα. DIA10D activity has been designed to selectively target AβPP, so this modulation of AβPP processing should not affect endogenous activity of α-and β-secretases towards other substrates. Show more

Keywords: AβPP processing, bispecific tandem scFv, α-secretase, β-secretase

DOI: 10.3233/JAD-2011-111196

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 961-969, 2012