Journal of Alzheimer's Disease - Volume 31, issue 3

Authors: Antonell, Anna | Gil, Silvia | Sánchez-Valle, Raquel | Balasa, Mircea | Bosch, Beatriz | Prat, Ma Carmen | Chiollaz, Anne-Cécile | Fernández, Manel | Yagüe, Jordi | Molinuevo, José Luis | Lladó, Albert

Article Type: Research Article

Abstract: Progranulin gene (GRN) mutations cause frontotemporal lobar degeneration (FTLD) with TDP43-positive inclusions, although its clinical phenotype is heterogeneous and includes patients classified as behavioral variant-FTLD (bvFTLD), progressive non-fluent aphasia (PNFA), corticobasal syndrome, Alzheimer's disease (AD), or Parkinson's disease (PD). Our main objective was to study if low serum progranulin protein (PGRN) levels may detect GRN mutations in a Spanish cohort of patients with FTLD or AD. Serum PGRN levels were measured in 112 subjects: 17 bvFTLD, 20 PNFA, 4 semantic dementia, 34 sporadic AD, 9 AD-PSEN1 mutation carriers, 10 presymptomatic-PSEN1 mutation carriers, and 18 control individuals. We detected 5 patients …with PGRN levels below 94 ng/mL: two of them had a clinical diagnosis of bvFTLD, two of PNFA, and one of AD. The screening for GRN mutations detected two probable pathogenic mutations (p.C366fsX1 and a new mutation: p.V279GfsX5) in three patients and one mutation of unclear pathogenic nature (p.C139R) in one patient. The other patient showed a normal GRN sequence but carried a PRNP gene mutation. We observed no differences in serum PGRN levels between controls (mean = 145.5 ng/mL, SD = 28.5) and the other neurodegenerative diseases, except for the carriers of pathological GRN gene mutations (mean = 50.5 ng/mL, SD = 21.2). Null GRN mutation carriers also showed lower serum PGRN levels than the patient who was a carrier of p.C139R (92.3 ng/mL) and the one who was a carrier of the PRNP mutation (76.9 ng/mL). In conclusion, we detected GRN null mutations in patients with severely reduced serum PGRN levels, but not in patients with slightly reduced PGRN levels. Show more

Keywords: Alzheimer's disease, biomarker, exon skipping, frameshift, frontotemporal lobar degeneration, mutation, progranulin, serum, splicing

DOI: 10.3233/JAD-2012-112120

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 581-591, 2012

Authors: Koch, Giacomo | Di Lorenzo, Francesco | Bonnì, Sonia | Ponzo, Viviana | Caltagirone, Carlo | Martorana, Alessandro

Article Type: Research Article

Abstract: In animal models of Alzheimer's disease (AD), amyloid-β fragments interfere with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). In the current study, we applied repetitive transcranial magnetic stimulation over the primary motor cortex (M1) in AD patients and in age-matched healthy controls, using protocols of theta burst stimulation (TBS) that are known to induce plastic changes resembling the LTP and LTD mechanisms described in animal models. AD patients showed consistent LTD-like effects that were comparable to those obtained in healthy controls when submitted to 40 seconds of continuous TBS. Conversely, AD patients did not …show any LTP-like after effect when submitted to two different TBS protocols that induced an LTP-like effect in healthy controls such as intermittent TBS and 20 seconds of continuous TBS followed by one minute of muscular contraction. These results demonstrate the impairment of LTP-like together with normal LTD-like cortical plasticity in AD patients. Show more

Keywords: Alzheimer's disease, cortical plasticity, long-term potentiation, transcranial magnetic stimulation

DOI: 10.3233/JAD-2012-120532

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 593-599, 2012

Authors: Zhang, Wei | Arteaga, Janna | Cashion, Daniel K. | Chen, Gang | Gangadharmath, Umesh | Gomez, Luis F. | Kasi, Dhanalakshmi | Lam, Chung | Liang, Qianwa | Liu, Changhui | Mocharla, Vani P. | Mu, Fanrong | Sinha, Anjana | Szardenings, A. Katrin | Wang, Eric | Walsh, Joseph C. | Xia, Chunfang | Yu, Chul | Zhao, Tieming | Kolb, Hartmuth C.

Article Type: Research Article

Abstract: Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer's disease and are considered to be targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. While there are a number of amyloid-β positron emission tomography (PET) tracers currently in different stages of clinical development and commercialization, there have been very few reports on imaging agents selectively targeting tau aggregates. In search of [18F]-PET tracers that possess great binding affinity and selectivity toward tau tangles, we tested more than 900 compounds utilizing a unique screening process. A competitive autoradiography assay was set up to test …compounds for binding to native tau tangles and amyloid-β plaques on human brain tissue sections. In our in vitro assays, the 18F labeled compound [18F]-T808 displayed a high level of binding affinity and good selectivity for tau aggregates over amyloid-β plaques. [18F]-T808 showed rapid uptake and washout in rodent brains. Our in vitro and preclinical in vivo studies suggest that [18F]-T808 possesses suitable properties and characteristics to be a specific and selective PET probe for imaging of paired helical filament tau in human brains. Show more

Keywords: Alzheimer's disease, amyloid-β, neurofibrillary tangles, neuroimaging, paired helical filaments, PET imaging, radiotracers, tau, tau aggregates

DOI: 10.3233/JAD-2012-120712

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 601-612, 2012

Authors: Velarde, Carla | Perelstein, Elizabeth | Ressmann, Wendy | Duffy, Charles J.

Article Type: Research Article

Abstract: We tested whether visual processing impairments in aging and Alzheimer's disease (AD) reflect uniform posterior cortical decline, or independent disorders of visual processing for reading and navigation. Young and older normal controls were compared to early AD patients using psychophysical measures of visual word and motion processing. We find elevated perceptual thresholds for letters and word discrimination from young normal controls, to older normal controls, to early AD patients. Across subject groups, visual motion processing showed a similar pattern of increasing thresholds, with the greatest impact on radial pattern motion perception. Combined analyses show that letter, word, and motion processing …impairments are independent of each other. Aging and AD may be accompanied by independent impairments of visual processing for reading and navigation. This suggests separate underlying disorders and highlights the need for comprehensive evaluations to detect early deficits. Show more

Keywords: Aging, Alzheimer's disease, language, motion, vision

DOI: 10.3233/JAD-2012-112201

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 613-621, 2012

Authors: Cavedo, Enrica | Galluzzi, Samantha | Pievani, Michela | Boccardi, Marina | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Brain reserve allows some people to be more resilient to neurodegeneration processes and brain diseases. Structural markers of brain reserve are hippocampus, lateral ventricles, and white matter lesions volume (HV, LVV, WMLV). Subjects in the low end of the distribution of these markers are at higher risk to develop brain diseases such as Alzheimer's disease. We described the distribution of the above markers in a large group of cognitively-intact persons. A sample of 158 people aged between 40 to 90 years (mean ± SD: 60 ± 12 years, education 9 ± 4 years, MMSE score 28 ± 2) belonging to …the Italian Brain Normative Archive was selected. HV, LVV, and WMLV were measured with validated procedures. The HV and LVV were measured by manual segmentation and the Freesurfer software, respectively, and normalized by head size; WMLV was measured with semi-automated thresholding. Test-retest reliability was >0.83 for all measures. No relationship was found between HV and age, whereas a significant relationship was found for LVV and WMLV (ventricle left: B 0.02, 95% CI 0.22 to 0.34; ventricle right: B 0.02 95% CI 0.23 to 0.34 p < 0.001; WML: B 0.04; 95% CI 0.03 to 0.06 p < 0.005). The 5th percentile threshold indicating lower brain reserve were: (i) HV below 2,260 mm3 at 40 and 2,000 mm3 at 90; (ii) LVV above 17,000 mm3 at 40 and 60,000 mm3 at 90; and (iii) WMLV above 1,200 mm3 at 40 and 8,700 mm3 at 90. Normative data of brain reserve markers can be used to estimate the brain resilience to neurodegeneration. Show more

Keywords: Brain reserve, cognitively-intact adults, hippocampal volume, normative distribution, ventricular volume, white matter lesion volume

DOI: 10.3233/JAD-2012-111817

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 623-633, 2012

Authors: Sun, Xiaqin | Meng, Xiaolu | Zhang, Jie | Li, Yonghui | Wang, Liping | Qin, Xiaoyan | Sui, Nan | Zhang, Yan

Article Type: Research Article

Abstract: GABA (gamma-aminobutyric acid) receptor modulators have been investigated as a potential treatment strategy in Alzheimer's disease (AD). In the present study, we found that GABA levels were different in wild type (WT) and AβPP/PS1 mouse brains. GABA downregulated amyloid-β (Aβ) uptake in neurons through the receptor for advanced glycation end-products. Therefore, relative high levels of GABA decreased cytotoxicity induced by Aβ in WT mice. GABA treatment decreased basal levels of cell death and the cell death induced by hydrogen peroxide in WT and AβPP/PS1 neurons. Application of GABA during early life before 2 months of age can improve cognitive function …significantly in AβPP/PS1 mice. However, GABA treatment at 6 and 8 months of age cannot improve water maze performance. Activating or suppressing GABAA receptors by optogenetic methods also confirmed that GABA activation before 2 months of age increased water maze performance in AβPP/PS1 mice. Our data suggest that GABA administration during early life can be a potential treatment for AD. Show more

Keywords: Amyloid-β, cell death, cognitive impairment, endocytosis, GABA

DOI: 10.3233/JAD-2012-120535

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 635-649, 2012

Authors: Schütze, Sandra | Loleit, Tobias | Zeretzke, Moritz | Bunkowski, Stephanie | Brück, Wolfgang | Ribes, Sandra | Nau, Roland

Article Type: Research Article

Abstract: Activated microglia is considered to be involved in the progression of Alzheimer's disease (AD). We investigated the effect of amyloid-β1-40 (Aβ40 ) and exogenous agonists of Toll-like receptor (TLR) 1/2 (Pam3 CSK4 ) and TLR4 (LPS) on neurons in primary murine neuron-microglia co-cultures. Neuronal viability, assessed by quantifying the number of intact neuronal extensions and their crossings using a newly developed Definiens Cognition Network Technology-based method, was significantly decreased after treatment with Pam3 CSK4 , LPS, and Aβ40 . Combined treatment with Aβ40 and Pam3 CSK4 or LPS had an additive effect. Hence, in patients with AD, …synergistic microglial activation by Aβ and bacterial products during infections might contribute to disease progression. Show more

Keywords: Amyloid-β, co-cultures, computer-assisted analysis, Definiens Cognition Network Technology, LPS, microglia, neuronal injury, neuronal viability, Toll-like receptor, Pam3CSK4

DOI: 10.3233/JAD-2012-120856

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 651-657, 2012

Authors: Honea, Robyn A. | Vidoni, Eric D. | Swerdlow, Russell H. | Burns, Jeffrey M. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: A family history of Alzheimer's disease (AD) increases one's risk of developing late-onset AD (LOAD), and a maternal family history of LOAD influences risk more than a paternal family history. Accumulating evidence suggests that a family history of dementia associates with AD-typical biomarker changes. We analyzed cross-sectional data from non-demented, mild cognitive impairment (MCI), and LOAD participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 99) and cerebrospinal fluid (CSF) analysis (n = 403) for amyloid-β peptide (Aβ) and total tau. We assessed the relationship of CSF and PiB biomarkers and …family history of dementia, as well as parent gender effects. In the larger analysis of CSF biomarkers, we assessed diagnosis groups individually. In the overall sample, CSF Aβ, tau/Aβ ratio, and global PiB uptake were significantly different between family history positive and negative groups, with markers of increased AD burden associated with a positive maternal family history of dementia. Moreover, a maternal family history of dementia was associated with significantly greater PiB Aβ load in the brain in the parietal cortex, precuneus, and sensorimotor cortex. Individuals with MCI positive for a maternal family history of dementia had significantly more markers of AD pathophysiology than individuals with no family history of dementia. A family history of dementia is associated with AD-typical biomarker changes. These biomarker associations are most robust in individuals with a maternal family history, suggesting that a maternally inherited factor influences AD risk. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, genetics, PET

DOI: 10.3233/JAD-2012-120676

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 659-668, 2012

Authors: Wallin, Karin | Solomon, Alina | Kåreholt, Ingemar | Tuomilehto, Jaakko | Soininen, Hilkka | Kivipelto, Miia

Article Type: Research Article

Abstract: Inflammation has been associated with Alzheimer's disease (AD) and dementia. The association between rheumatoid arthritis (RA) or arthritis and dementia/AD has been investigated in several case-control or hospital- and register-based studies with mixed results. This long-term population-based study investigates the association between presence of joint disorders (RA and other joint disorders) in midlife and cognitive status later in life. 1,449 participants were first evaluated in 1972, 1977, 1982, and 1987 and follow-up was performed after 21 years. A self-administered questionnaire including questions on joint disorders was used at both evaluations. Cognitive status (control, mild cognitive impairment, dementia/AD) was assessed at …follow-up. The presence of any joint disorder in midlife was significantly associated with a worse cognitive status later in life: OR (95% CI) in an ordinal logistic regression analysis adjusted for age, gender, follow-up time, education, APOEε4, body mass index, smoking, drug treatment, and diabetes was 1.96 (1.17–3.28). For RA only, OR (95% CI) was 2.77 (1.26–6.10). The correlation remained significant for RA when AD was considered instead of dementia OR (95% CI) 2.49 (1.09–5.67). The presence of joint disorders, especially RA, at midlife seems to be associated with a worse cognitive status later in life. Given the chronic inflammatory component of RA, this study suggests that inflammatory mechanisms may have an important role in increasing the risk of cognitive impairment and dementia/AD. Show more

Keywords: Alzheimer's disease, cognitive impairment, dementia, epidemiology, inflammation, joint disorders, longitudinal, rheumatoid arthritis

DOI: 10.3233/JAD-2012-111736

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 669-676, 2012

Authors: Adamson, Maheen M.

Article Type: Article Commentary

DOI: 10.3233/JAD-2012-111767

Citation: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 677-678, 2012