Journal of Alzheimer's Disease - Volume 31, issue 2

Authors: Borroni, Barbara | Bianchi, Marta | Premi, Enrico | Alberici, Antonella | Archetti, Silvana | Paghera, Barbara | Cerini, Carlo | Papetti, Alice | Padovani, Alessandro

Article Type: Research Article

Abstract: Brain-derived neurotrophic factor (BDNF) promotes several functions in neurons and modulates neurotransmissions, especially in hippocampal regions. Frontotemporal lobar degeneration (FTLD) has a strong genetic background, but genetic risk factors associated with sporadic disease are unknown. Hippocampal involvement is frequently observed in FTLD. The aims of this study were: i) to evaluate if BDNF genetic variations are associated with an increased risk of developing FTLD; and ii) to assess the neuroimaging profiles associated with BDNF polymorphisms. Ninety-one FTLD patients who underwent SPECT imaging and blood sampling entered the study, and clinical, cognitive, and behavioral examinations were performed. A larger group of …FTLD patients (n = 194) and controls (n = 396; 162 healthy subjects and 234 Alzheimer's disease (AD) patients) underwent genetic analyses, considering BDNF polymorphisms (Val66Met, rs2049045 C/G, G11757C). A significant different distribution of G11757C genotype in FTLD (GG 53.1%, GC 42.8%, CC 4.1%) compared to controls (G/G 55.6%, G/C 34.6%, C/C 9.8%, p = 0.020) was found. No other significant differences in genotype and allele distributions were detected. The effect of BDNF polymorphisms on brain perfusion was analyzed. BDNF Val66Met A* carriers (A/A or G/A) showed a significant greater hypoperfusion parahippocampal regions as compared to G/G carriers (p < 0.005). No effect of G11757C polymorphism on brain perfusion was found. rs2049045 C/G was not considered as in linkage disequilibrium with Val66Met polymorphism. BDNF Val66Met polymorphism may play a role as a modulator of the FTLD expression and may drive a selective damage in specific brain region affected by the disease. Show more

Keywords: Brain-derived neurotrophic factor, frontotemporal dementia, hippocampus, SPECT ECD, statistical parametric mapping

DOI: 10.3233/JAD-2012-120226

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 243-251, 2012

Authors: Li, Feng-Jiao | Shen, Liang | Ji, Hong-Fang

Article Type: Research Article

Abstract: In view of the vital role of oxidative stress in the pathogenesis of Alzheimer's disease (AD), the potential of antioxidant supplements to prevent AD have gained much interest, while there are conflicting results on this topic in recent years. The purpose of the present study is to comprehensively evaluate the association between dietary intakes, instead of supplements, of the most common three antioxidants (vitamin E, vitamin C, and β-carotene) and the risk of AD on the basis of the meta-analysis studies published up to October 2011 in Medline and Scopus databases. In total, seven articles were included in the meta-analysis. …According to the pooled relative risk [(95% CI) 0.76 (0.67–0.84) for vitamin E, 0.83 (0.72–0.94) for vitamin C, and 0.88 (0.73–1.03) for β-carotene], dietary intakes of the three antioxidants can lower the risk of AD, with vitamin E exhibiting the most pronounced protective effects. The findings will be of significance to the prevention and interventional treatment of AD. Show more

Keywords: Alzheimer's disease, antioxidant, β-carotene, dietary intake, vitamin C, vitamin E

DOI: 10.3233/JAD-2012-120349

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 253-258, 2012

Authors: Brundel, Manon | Heringa, Sophie M. | de Bresser, Jeroen | Koek, Huiberdina L. | Zwanenburg, Jaco J.M. | Kappelle, L. Jaap | Luijten, Peter R. | Biessels, Geert Jan

Article Type: Research Article

Abstract: The prevalence of microbleeds on magnetic resonance imaging (MRI) in patients with Alzheimer's disease (AD) is lower than that of its presumed pathological correlate, cerebral amyloid angiopathy. We examined 18 patients with early AD or mild cognitive impairment (MCI) and 18 non-demented controls with ultra-high field strength 7Tesla MRI, to assess if the actual prevalence of microbleeds could be higher than is currently reported. One or more microbleeds were visualized in 78% of the MCI/AD patients and in 44% of the controls (p = 0.04). 7Tesla MRI shows that presence of microbleeds may be the rule, rather than exception in …patients with MCI/AD. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2012-120364

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 259-263, 2012

Authors: Steenland, Kyle | Karnes, Conny | Seals, Ryan | Carnevale, Claudine | Hermida, Adriana | Levey, Allan

Article Type: Research Article

Abstract: Identification of potentially modifiable risk factors for cognitive deterioration is important. We conducted a prospective study of 5,607 subjects with normal cognition and 2,500 subjects with mild cognitive impairment (MCI) at 30 Alzheimer's Disease Centers in the Unites States between 2005 and 2011. Cox regression was used to determine whether depression predicted transition from normal to MCI, or MCI to Alzheimer's disease (AD). Over an average of 3.3 visits, 15% of normal subjects transitioned to MCI (62/1000 per year), while 38% of MCI subjects transitioned to AD (146/1000 per year). At baseline, 22% of participants had recent (within the last …two years) depression defined by clinician judgment; 9% and 17% were depressed using the Geriatric Depression Scale (GDS score ≥5) and the Neuropsychiatric Inventory Questionnaire (NPI-Q), respectively. At baseline, depressed subjects performed significantly worse on cognitive tests. Those always depressed throughout follow-up had an increased risk for progression from normal to MCI (RR = 2.35; 95% CI 1.93–3.08) versus never depressed. Normal subjects, identified as depressed at first visit but subsequently improved, were found to have lower risk of progression (RR 1.40 (1.01–1.95)). The ‘always depressed’ had only a modest increased risk of progression from MCI to AD (RR = 1.21 (1.00–1.46). Results were similar using time-dependent variables for depression or when defining depression via the GDS or NPI-Q. We found no effect of earlier depression (>2 years past). The effect of recent depression did not differ by antidepressant treatment, APOE4 allele status, or type of MCI. In conclusion, late-life depression is a strong risk factor for normal subjects progressing to MCI. Show more

Keywords: Alzheimer's disease, dementia, depression, mild cognitive impairment

DOI: 10.3233/JAD-2012-111922

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 265-275, 2012

Authors: Zis, Panagiotis | Dickinson, Mark | Shende, Sima | Walker, Zuzana | Strydom, Andre

Article Type: Research Article

Abstract: By the age of 40, virtually all patients with Down syndrome (DS) have neuropathological changes characteristic of Alzheimer's disease (AD). The aim of our study was to investigate whether the levels of superoxide dismutase enzymes (SOD), glutathione peroxidase (GPx), or their ratio could predict cognitive decline in people with DS over a 4-year period. Thirty-two adults with DS participated in a longitudinal study with SOD and GPx assays at baseline. Informants rated their functional ability and memory function at baseline and at 4 years follow-up. The more able adults with DS also completed assessments of language skills and memory, at …two different time points 4 years apart. Twenty-six individuals with DS completed assessments of memory (Modified Memory Object Task, MOMT), adaptive behavior (ABAS), and receptive vocabulary (British Picture vocabulary, BPVS) at both time-points. SOD positively correlated with change on the MOMT score (r = 0.578, p = 0.015). There were no significant correlations between GPx level or SOD/GPx ratio and temporal changes in ABAS, BPVS, or MOMT scores. Our results suggest that SOD predicts memory decline over time and that these antioxidant enzymes could be a potential target for prevention of memory deterioration in adults with DS. Further research is required to test whether supplements which improve SOD function can also prevent cognitive decline. These findings may also have implications for prevention of cognitive decline in other groups which are at high risk of developing dementia, such as adults with familial AD or mild cognitive impairment. Show more

Keywords: Aging, Alzheimer's disease, Down syndrome, memory, oxidative stress, superoxide dismutase

DOI: 10.3233/JAD-2012-120073

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 277-283, 2012

Authors: Lomoio, Selene | López-González, Irene | Aso, Ester | Carmona, Margarita | Torrejón-Escribano, Benjamín | Scherini, Elda | Ferrer, Isidro

Article Type: Research Article

Abstract: Cerebellar amyloid-β (Aβ) deposition in the form of neuritic plaques and Purkinje cell loss are common in certain pedigrees of familial Alzheimer's disease (FAD) mainly linked to PS1 mutations. AβPP/PS1 transgenic mice, here used as a model of FAD, show a few Aβ plaques in the molecular layer of the cerebellum at 6 months, and which increase in number with age. Motor impairment is apparent in transgenic mice aged 12 months. Combined methods have shown degenerated parallel fibers as the main component of dystrophic neurites of Aβ plaques, loss of synaptic contacts between parallel fibers and dendritic spines of Purkinje …cells, and degeneration of granule cells starting at 12 months and increasing in mice 18/20 months old. In addition, abnormal mitochondria and focal loss of Purkinje and basket cells, together with occasional axonal torpedoes and increased collaterals of Purkinje cells in mice aged 18/20 months, is suggested to be a concomitant defect presumably related to soluble extracellular or intracellular Aβ. These observations demonstrate serious deterioration of the neuronal circuitry in the cerebellum of AβPP/PS1 transgenic mice, and they provide support for the interpretation of similar alterations occurring in certain pedigrees with FAD. Show more

Keywords: AβPP/PS1 transgenic mice, cerebellum, familiar Alzheimer disease, parallel fibers, Purkinje cell

DOI: 10.3233/JAD-2012-112198

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 285-300, 2012

Authors: Ho, Lap | Zhao, Wei | Dams-O'Connor, Kristen | Tang, Cheuk Y. | Gordon, Wayne | Peskind, Elaine R. | Yemul, Shrishailam | Haroutunian, Vahram | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible “window” into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts. We found three protein biomarker species, monocyte chemotactic protein-1 (MCP-1), insulin-like …growth factor-binding protein-3, and epidermal growth factor receptor, that are differentially regulated in plasma specimens of the TBI cases. A three-biomarker panel using all three proteins provides the best potential criterion for separating TBI and control cases. Plasma MCP-1 contents are correlated with the severity of TBI and the index of compromised axonal fiber integrity in the frontal cortex. Based on these findings, we evaluated postmortem brain specimens from 7 mild cognitive impairment (MCI) and 7 neurologically normal cases. We found elevated MCP-1 expression in the frontal cortex of MCI cases that are at high risk for developing Alzheimer's disease. Our findings suggest that additional application of the three-biomarker panel to current diagnostic criteria may lead to improved TBI detection and more sensitive outcome measures for clinical trials. Induction of MCP-1 in response to TBI might be a potential predisposing factor that may increase the risk for development of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, biomarker, long-term clinical TBI phenotypes, mild cognitive impairment, monocyte chemotactic protein-1, plasma, traumatic brain injury

DOI: 10.3233/JAD-2012-120598

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 301-313, 2012

Authors: Kim, Chi Hun | Seo, Sang Won | Kim, Geon Ha | Shin, Ji Soo | Cho, Hanna | Noh, Young | Kim, Suk-Hui | Kim, Min Ji | Jeon, Seun | Yoon, Uicheul | Lee, Jong-Min | Oh, Seung Jun | Kim, Jae Seung | Kim, Sung Tae | Lee, Jae-Hong | Na, Duk L.

Article Type: Research Article

Abstract: To determine the existence of cortical thinning in subcortical vascular dementia (SVaD) with a negative 11 C-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. Show more

Keywords: Alzheimer's disease, cortical thickness, Pittsburgh compound B, subcortical vascular dementia

DOI: 10.3233/JAD-2012-111832

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 315-323, 2012

Authors: Benoit, Michel | Berrut, Gilles | Doussaint, Johanna | Bakchine, Serge | Bonin-Guillaume, Sylvie | Frémont, Patrick | Gallarda, Thierry | Krolak-Salmon, Pierre | Marquet, Thierry | Mékiès, Claude | Sellal, François | Schuck, Stéphane | David, Renaud | Robert, Philippe

Article Type: Research Article

Abstract: Apathy and depression are the most frequent neuropsychiatric symptoms in Alzheimer's disease (AD). In a cross-sectional observational study of 734 subjects with probable mild AD, we evaluated the prevalence of apathy and depression. After the use of specific diagnostic criteria, we tested the interaction between the two syndromes and their relation with specific comorbidities, and different functional outcomes. Depression was diagnosed using the diagnostic criteria for depression in AD, and apathy with the diagnostic criteria for apathy in neuropsychiatric disorders. According to the specific diagnostic criteria, depression had a 47.9% prevalence, while apathy prevalence was 41.6%. Apathy and depression were …associated in 32.4% of patients (n = 225). 9.4% (n = 65) had only apathy, 15.4% (n = 107) had only depression, and 42.9% had no apathy and no depression (n = 298). The three most frequent depressive symptoms were fatigue or loss of energy (59.4%), decreased positive affect or pleasure in response to social contacts and activities (46.2%), and psychomotor agitation or retardation (36.9%). Concerning apathy, loss of goal-directed cognition was the most frequently altered (63.6%), followed by loss of goal-directed action (60.6%) and loss of goal-directed emotion (43.8%). Patients with both apathy and depression more frequently required a resource allowance for dependency. Neurological comorbidities were more frequent in the “apathy and depression” and “depression alone” groups (p < 0.001). Apathy and depression overlap considerably, and this might be explained by the presence of some non-specific symptoms in both diagnostic criteria. The need for social support is higher when a patient fulfills the two diagnostic criteria. Show more

Keywords: Alzheimer's disease, apathy, depressive symptoms, dementia

DOI: 10.3233/JAD-2012-112003

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 325-334, 2012

Authors: Portelius, Erik | Zetterberg, Henrik | Dean, Robert A. | Marcil, Alexandre | Bourgeois, Philippe | Nutu, Magdalena | Andreasson, Ulf | Siemers, Eric | Mawuenyega, Kwasi G. | Sigurdson, Wendy C. | May, Patrick C. | Paul, Steven M. | Holtzman, David M. | Blennow, Kaj | Bateman, Randall J.

Article Type: Research Article

Abstract: 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 Aβ1-15 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 Aβ1-15/16 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 Aβ1-15/16 , Aβx-38 , Aβx-40 , Aβx-42 , sAβPPα, and sAβPPβ. The CSF concentration of Aβ1-15/16 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 Aβx-38 , Aβx-40 , and Aβx-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 Aβ1-15/16 increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing. Show more

Keywords: Alzheimer's disease, amyloid-β, γ-secretase

DOI: 10.3233/JAD-2012-120508

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 335-341, 2012