Journal of Alzheimer's Disease - Volume 29, issue 1

Authors: Wennström, Malin | Londos, Elisabet | Minthon, Lennart | Nielsen, Henrietta M

Article Type: Research Article

Abstract: Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences …in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-Tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation. Show more

Keywords: Alpha-synuclein, Alzheimer's disease, biomarker, dementia with Lewy bodies, orexin

DOI: 10.3233/JAD-2012-111655

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 125-132, 2012

Authors: Ford, Andrew H. | Almeida, Osvaldo P.

Article Type: Research Article

Abstract: Elevated total plasma homocysteine has been linked to the development of cognitive impairment and dementia in later life and this can be reliably lowered by the daily supplementation of vitamin B6, B12, and folic acid. We performed a systematic review and meta-analysis of 19 English language randomized, placebo-controlled trials of homocysteine lowering B-vitamin supplementation of individuals with and without cognitive impairment at the time of study entry. We standardized scores to facilitate comparison between studies and to enable us to complete a meta-analysis of randomized trials. In addition, we stratified our analyses according to the folate status of the country …of origin. B-vitamin supplementation did not show an improvement in cognitive function for individuals with (SMD = 0.10, 95%CI −0.08 to 0.28) or without (SMD = −0.03, 95%CI −0.1 to 0.04) significant cognitive impairment. This was irrespective of study duration (SMD = 0.05, 95%CI −0.10 to 0.20 and SMD = 0, 95%CI −0.08 to 0.08), study size (SMD = 0.05, 95%CI −0.09 to 0.19 and SMD = −0.02, 95%CI −0.10 to 0.05), and whether participants came from countries with low folate status (SMD = 0.14, 95%CI −0.12 to 0.40 and SMD = −0.10, 95%CI −0.23 to 0.04). Supplementation of vitamins B12, B6, and folic acid alone or in combination does not appear to improve cognitive function in individuals with or without existing cognitive impairment. It remains to be established if prolonged treatment with B-vitamins can reduce the risk of dementia in later life. Show more

Keywords: Cognition, dementia, homocysteine, meta-analysis, vitamin B

DOI: 10.3233/JAD-2012-111739

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 133-149, 2012

Authors: Warren, Matthew W. | Hynan, Linda S. | Weiner, Myron F. | The Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: To determine if measures of adipokines and other blood lipids differentiate between normal controls and persons with Alzheimer's disease (AD), we examined levels of leptin, adiponectin, total cholesterol, high density lipoproteins (HDL), calculated low density lipoproteins (LDL), triglycerides and apolipoprotein E allele status in 148 early AD subjects and 198 normal controls. We were unable to demonstrate a significant difference in leptin and adiponectin levels between normal controls and AD subjects. We were able to confirm observations of lower HDL and higher total and LDL cholesterol concentration in AD subjects than in controls. As expected, the presence of the apolipoprotein …E4 allele distinguished between the two groups. Show more

Keywords: Adiponectin, Alzheimer's disease, cholesterol, leptin

DOI: 10.3233/JAD-2012-111385

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 151-157, 2012

Authors: Costa, Montserrat | Ortiz, Ana M. | Jorquera, Juan I.

Article Type: Research Article

Abstract: Clearance of plasma amyloid-β (Aβ) through plasma exchange and replacement with therapeutic albumin to facilitate net Aβ efflux from the brain to plasma is a novel approach for the treatment of Alzheimer's disease. Therefore, thorough characterization of the capacity of therapeutic albumin to bind Aβ is warranted. In this study, Aβ40 and Aβ42 were quantified by commercial ELISA or Araclon ABtest® in samples of Grifols' therapeutic albumin (Albutein® ) 5%, 20%, and 25%. The capacity of Albutein® to bind Aβ was assessed by: a) ELISA in serially diluted therapeutic albumin (0–45 mg/ml protein concentration) to which …80 pg/ml of synthetic Aβ peptide (sAβ40 or sAβ42 ) were added; b) ELISA in samples of the therapeutic albumin containing serially diluted sAβ40 or sAβ42 (60–400 pg/ml); and c) surface plasmon resonance (SPR) for sAβ42 binding. The Aβ content in Albutein® was below the quantification threshold of the ELISA tests (<25 to <62.5 pg/ml) and ABtest® (<3.125 pg/ml). Quantification of exogenously added sAβ42 decreased in parallel with increasing protein concentration (59–78% at 45 mg/ml albumin). Recovery of sAβ serially diluted in Albutein® was ∼60% for sAβ40 and ∼70% for sAβ42, but was ∼100% in control samples without albumin. The KD by SPR analysis for sAβ42 interaction with Albutein® was 1.72 ± 0.24 × 10−6 M. In conclusion, Grifols' therapeutic albumin has undetectable content of Aβ40 and Aβ42 . Moreover, Grifols' therapeutic albumin consistently binds peptides containing the primary sequence of human Aβ. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, plasma albumin, plasma exchange, plasmapheresis

DOI: 10.3233/JAD-2012-111139

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 159-170, 2012

Authors: Santos, Alexander Navarrete | Ewers, Michael | Minthon, Lennart | Simm, Andreas | Silber, Rolf-Edgar | Blennow, Kaj | Prvulovic, David | Hansson, Oskar | Hampel, Harald

Article Type: Research Article

Abstract: Oligomers of the amyloid-β peptide (Aβ) are thought to be the most toxic form of Aβ and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Aβ-oligomers by flow cytometry. The …CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ)42 were determined using ELISA. CSF Aβ-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Aβ-oligomers/Aβ42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Aβ-oligomers and the Mini-Mental Status Exam score (r = −0.65; p = 0.013) in AD patients. The detection of Aβ-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, cognitive decline, flow cytometry, oligomers

DOI: 10.3233/JAD-2012-111361

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 171-176, 2012

Authors: Lott, Ira T. | Doran, Eric | Nguyen, Vinh Q. | Tournay, Anne | Movsesyan, Nina | Gillen, Daniel L.

Article Type: Research Article

Abstract: The objective of this study was to determine the association of seizures and cognitive decline in adults with Down syndrome (DS) and Alzheimer's-type dementia. A retrospective data analysis was carried out following a controlled study of antioxidant supplementation for dementia in DS. Observations were made at baseline and every 6 months for 2 years. Seizure history was obtained from study records. The primary outcome measures comprised the performance-based Severe Impairment Battery (SIB) and Brief Praxis Test (BPT). Secondary outcome measures comprised the informant-based Dementia Questionnaire for Mentally Retarded Persons and Vineland Adaptive Behavior Scales. Because a large proportion of patients …with seizures had such severe cognitive decline as to become untestable on the performance measures, time to “first inability to test” was measured. Adjustments were made for the potentially confounding co-variates of age, gender, APOE4 status, baseline cognitive impairment, years since dementia onset at baseline, and treatment assignment. The estimated odds ratio for the time to “first inability to test” on SIB comparing those with seizures to those without is 11.02 (95% CI: 1.59, 76.27), a ratio that is significantly different from 1 (p = 0.015). Similarly, we estimated an odds ratio of 9.02 (95% CI: 1.90, 42.85) on BPT, a ratio also significantly different than 1 (p = 0.006). Results from a secondary analysis of the informant measures showed significant decline related to seizures. We conclude that there is a strong association of seizures with cognitive decline in demented individuals with DS. Prospective studies exploring this relationship in DS are indicated. Show more

Keywords: Alzheimer's disease, dementia, Down syndrome, seizures

DOI: 10.3233/JAD-2012-111613

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 177-185, 2012

Authors: Antequera, Desiree | Portero, Aitziber | Bolos, Marta | Orive, Gorka | Hernández, Rosa Ma | Pedraz, José Luis | Carro, Eva

Article Type: Research Article

Abstract: Vascular endothelial growth factor (VEGF) promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the Alzheimer's disease (AD) brain is still unknown. We examined the proliferation of neuronal precursors with an ex vivo approach, using encapsulated VEGF secreting cells, in AβPP/PS1 mice, a mouse model of AD. Overexpression of VEGF and VEGF receptor flk-1 was observed in the cerebral cortex from VEGF microcapsules-treated AβPP/PS1 mice at 1, 3 and 6 months after VEGF-microcapsule implantation. Stereological counting of 5-bromodeoxyuridine positive cells revealed that encapsulated VEGF secreting cells significantly enhanced cellular proliferation in the hippocampal dentate …gyrus (DG). The number of neuronal precursors in VEGF microcapsules-treated AβPP/PS1 mice was also greater, and this effect remains after 6 months. We also confirmed that encapsulated VEGF secreting cells also stimulated angiogenesis in the cerebral cortex and hippocampal dentate gyrus. In addition, we found that VEGF-microcapsule treatment was associated with a depressed expression and activity of acetylcholinesterase in the hippocampus of AβPP/PS1 mice, a similar pattern as first-line medications for the treatment of AD. We conclude that stereologically-implanted VEGF-microcapsules exert an acute and long-standing neurotrophic effects, and could be utilized to improve potential therapies to control the progression of AD. Show more

Keywords: Acetylcholinesterase, Alzheimer's disease, angiogenesis, neurogenesis, transgenic mice, VEGF microcapsules

DOI: 10.3233/JAD-2011-111646

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 187-200, 2012

Authors: Ding, Qunxing | Zhu, Haiyan | Zhang, Bing | Soriano, Augusto | Burns, Roxanne | Markesbery, William R.

Article Type: Research Article

Abstract: It is widely accepted that oxidative stress is involved in neurodegenerative disorders such as Alzheimer's disease (AD). Ribosomal RNA (rRNA) is one of the most abundant molecules in most cells and is affected by oxidative stress in the human brain. Previous data have indicated that total rRNA levels were decreased in the brains of subjects with AD and mild cognitive impairment concomitant with an increase in rRNA oxidation. In addition, level of 5S rRNA, one of the essential components of the ribosome complex, was significantly lower in the inferior parietal lobule (IP) brain area of subjects with AD compared with …control subjects. To further evaluate the alteration of 5S rRNA in neurodegenerative human brains, multiple brain regions from both AD and age-matched control subjects were used in this study, including IP, superior and middle temporal gyro, temporal pole, and cerebellum. Different molecular pools including 5S rRNA integrated into ribosome complexes, free 5S rRNA, cytoplasmic 5S rRNA, and nuclear 5S rRNA were studied. Free 5S rRNA levels were significantly decreased in the temporal pole region of AD subjects and the oxidation of ribosome-integrated and free 5S rRNA was significantly increased in multiple brain regions in AD subjects compared with controls. Moreover, a greater amount of oxidized 5S rRNA was detected in the cytoplasm and nucleus of AD subjects compared with controls. These results suggest that the increased oxidation of 5S rRNA, especially the oxidation of free 5S rRNA, may be involved in the neurodegeneration observed in AD. Show more

Keywords: Alzheimer's disease, human, oxidative stress, ribosomal, RNA, 5S rRNA

DOI: 10.3233/JAD-2012-111058

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 201-209, 2012

Authors: Nizzari, Mario | Barbieri, Federica | Gentile, Maria Teresa | Passarella, Daniela | Caorsi, Calentina | Diaspro, Alberto | Taglialatela, Maurizio | Pagano, Aldo | Colucci-D'Amato, Luca | Florio, Tullio | Russo, Claudio

Article Type: Research Article

Abstract: Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-β protein precursor (AβPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-β peptides from AβPP is the primary event that subsequently induces abnormal …tau phosphorylation. In this work, we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects, there is a stable pool of phospho-tau which remains strictly confined to neuronal nuclei, while nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AβPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons. Show more

Keywords: Alzheimer disease, amyloid β-protein precursor, cell-cycle, tau protein

DOI: 10.3233/JAD-2011-101590

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 211-227, 2012

Authors: Parnetti, Lucilla | Chiasserini, Davide | Eusebi, Paolo | Giannandrea, David | Bellomo, Gianni | De Carlo, Claudia | Padiglioni, Chiara | Mastrocola, Sara | Lisetti, Viviana | Calabresi, Paolo

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40 , Aβ1-42 , t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without …dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42 /Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42 /t-tau and Aβ1-42 /p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42 /p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = −0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42 /p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70–80%; specificity 96%, 95%CI: 94–98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients. Show more

Keywords: Alzheimer's disease, amyloid-β 1-40, amyloid-β 1-42, biomarker, cerebrospinal fluid, dementia, mild cognitive impairment, phosphorylated tau, total tau

DOI: 10.3233/JAD-2011-111349

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 229-238, 2012