Journal of Alzheimer's Disease - Volume 24, issue 2

Authors: Roher, Alex E. | Maarouf, Chera L. | Daugs, Ian D. | Kokjohn, Tyler A. | Hunter, Jesse M. | Sabbagh, Marwan N. | Beach, Thomas G.

Article Type: Research Article

Abstract: The field of Alzheimer's disease (AD) research eagerly awaits the results of a large number of Phase III clinical trials that are underway to investigate the effectiveness of anti-amyloid-β (Aβ) immunotherapy for AD. In this case report, we review the pertinent clinical history, examine the neuropathology, and characterize the Aβ profile of an AD patient who received bapineuzumab immunotherapy. The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed …that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of Aβ due to immunotherapy. The Aβ species profile of this case was compared with non-immunized AD cases and non-demented controls and found to be similar to non-immunized AD cases. SELDI-TOF mass spectrometric analysis revealed the presence of full-length Aβ1-42 and truncated Aβ peptides demonstrating species with and without bapineuzumab specific epitopes. These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment. Show more

Keywords: Active immunotherapy, Alzheimer's disease, amyloid-β, amyloid plaques, bapineuzumab, cerebral amyloid angiopathy, neurofibrillary tangles, passive immunotherapy

DOI: 10.3233/JAD-2011-101809

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 315-325, 2011

Authors: Smith, Edward R. | Nilforooshan, Ramin | Weaving, Gary | Tabet, Naji

Article Type: Research Article

Abstract: The significance of vascular risk factors in the development and progression of Alzheimer's disease (AD) is now widely recognized. Fetuin-A is an abundant plasma protein that predicts vascular risk in a variety of clinical settings. In the context of cerebral ischemia, fetuin-A appears to be anti-inflammatory. Given the apparent importance of neuroinflammation in cognitive decline, we analyzed fetuin-A concentrations and pro-inflammatory cytokine levels in a cohort of 34 patients with mild-to-moderate AD, and compared these to age-matched controls. Further, we analyzed the relationship between plasma fetuin-A concentration and a measure of cognitive impairment using multivariate regression modeling. Plasma fetuin-A concentrations …were lower in the patient group (p = 0.006) compared with controls and were significantly correlated with Mini-Mental State Examination (MMSE) score (r = 0.504, p = 0.002). Fetuin-A concentration was also significantly and inversely correlated with plasma TNF-α concentration (r = −0.496, p = 0.003). The association between MMSE performance and fetuin-A was maintained even after multivariate adjustment for other risk factors including TNF-α (adjusted R2 total = 0.371). Using this model, plasma fetuin-A concentration explained 21% of the variance in MMSE scores. Further studies are needed to evaluate whether fetuin-A is related to the progression and pathogenesis of AD. Show more

Keywords: Alpha2HS glycoprotein, Alzheimer's disease, inflammation, tumor necrosis factor-alpha

DOI: 10.3233/JAD-2011-101872

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 327-333, 2011

Authors: Prà, Ilaria Dal | Whitfileld, James F. | Pacchiana, Raffaella | Bonafini, Clara | Talacchi, Andrea | Chakravarthy, Balu | Armato, Ubaldo | Chiarini, Anna

Article Type: Research Article

Abstract: Astrocytes in amyloid-β (Aβ)42 -accumulating human brains afflicted with Alzheimer's disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and also become loaded with Aβ42 . We have already shown that Aβ25-35 (surrogate of Aβ42 )-induced VEGF-A production in ‘normoxic’ cultures of early passage normal human cerebral astrocytes (NAHAs) is mediated by the stabilization of VEGF gene-stimulating hypoxia-inducible factor (HIF)-1α and nuclear translocation of HIF-1α•HIF-1β complexes. We have now found that treating these NAHAs with Aβ25-35 also stimulates them to make Aβ42 (appearing in immunoblots as several bands with Mr 's from 8 kDa upwards), whose levels …peak at 48 h (2.8-fold versus 0 h, p < 0.001) and then start falling slowly. This rise of Aβ42 peptide production coincides with a transiently increased flow of HIF-1α (therefore HIF-1α•HIF-1β complexes; at 24 h, 1.5-fold versus 0 h, p < 0.001) into the nucleus and transient surges first of β-secretase (BACE-1/β-S) mRNA expression (1.2-fold versus 0 h, p = 0.013) and activity peaking at 24-h (1.4-fold versus 0 h, p = 0.001), and then of γ-secretase (γ-S) activity cresting at 48 h (1.6-fold versus 0 h, p < 0.001) that cleave the Aβ42 peptides from amyloid-β protein precursor. Since the genes encoding components of these two secretases have the same HIF-1α•HIF-1β-responsive elements in their promoters as the VEGF gene, these observations suggest that the Aβ42 released from neurons in the AD brain can recruit associated astrocytes via HIF-1α•HIF-1β signaling into the pool of Aβ42 -producing cells. In other words, Aβ42 begets Aβ42 in NAHAs. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, β-secretase/BACE-1, γ-secretase, HIF, normal adult human astrocytes

DOI: 10.3233/JAD-2011-101626

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 335-347, 2011

Authors: Chigurupati, Srinivasulu | Madan, Meenu | Okun, Eitan | Wei, Zelan | Pattisapu, Jogi V. | Mughal, Mohamed R. | Mattson, Mark P. | Chan, Sic L.

Article Type: Research Article

Abstract: The cell fate determinant Numb exists in four alternatively spliced variants that differ in the length of their PTB (phosphotyrosine-binding domain, either lacking or containing an 11 amino acid insertion) and PRR (proline-rich region, either lacking or containing a 48 amino acid insertion). We previously reported that Numb switches from isoforms containing the PTB insertion to isoforms lacking this insertion in neural cultures subjected to stress induced by trophic factor withdrawal. The switch in Numb isoforms enhances the generation of amyloid-β peptide (Aβ), the principle component of senile plaques in Alzheimer's disease (AD). Here we examine the expression of the …Numb isoforms in brains from AD patients and triple transgenic (3xTg) AD mice. We found that levels of the Numb isoforms lacking the PTB insertion are significantly elevated in the parietal cortex but not in the cerebellum of AD patients when compared to control subjects. Levels of Numb isoforms lacking the PTB insertion were also elevated in the cortex but not cerebellum of 12 month-old 3xTg AD mice with Aβ deposits compared to younger 3xTg-AD mice and to non-transgenic mice. Exposure of cultured neurons to Aβ resulted in an increase in the levels of Numb isoforms lacking the PTB domain, consistent with a role for Aβ in the aberrant expression of Numb in vulnerable brain regions of AD patients and mice. Collectively, the data show that altered expression of Numb isoforms in vulnerable neurons occurs during AD pathogenesis and suggest a role for Numb in the disease process. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, endocytosis, endosomes, protein trafficking

DOI: 10.3233/JAD-2011-101797

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 349-361, 2011

Authors: Frölich, Lutz | Ashwood, Tim | Nilsson, Jonas | Eckerwall, Göran | on behalf of the Sirocco Investigators

Article Type: Research Article

Abstract: AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12–26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21–26). Mean age was 74 (range 58–85) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at …Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 25–26) indicated improvement versus placebo for AZD3480 20 mg (−1.4, 95% CI: −3.0; 0.2) and donepezil (−1.0, 95% CI: −2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria: since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating α4β2 receptors with NNRs in AD patients. Show more

Keywords: Alzheimer's disease, AZD3480, cognitive impairment, NNR agonist, randomized controlled trial

DOI: 10.3233/JAD-2011-101554

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 363-374, 2011

Authors: Railey, Angela M. | Groeber, Caitlin M. | Flinn, Jane M.

Article Type: Research Article

Abstract: The amyloid-β protein (Aβ) is a metalloprotein with affinity for the metal ions zinc (Zn), copper (Cu), and iron (Fe), which are found in high concentrations in the plaques of Alzheimer's disease (AD). Increasing attention is focused on the role of these metals in AD, and much of the evidence suggests a dyshomeostasis between these metal ions may significantly affect Aβ aggregation and deposition in the brain. While the effect of these metals on Aβ has been shown in vitro, there is less behavioral data supporting a direct role in cognitive impairment. In order to investigate the cognitive consequences of …metal dyshomeostasis, we sought to directly increase metal levels in the brain by dietary means in a transgenic mouse model (Tg2576). We have now examined the effect of increased Zn (10 ppm) and Fe (10 ppm) levels in the drinking water in the Tg2576 mouse. Since increased dietary Zn can lead to Cu deficiency, a Zn group supplemented with copper was also examined (Zn (10 ppm)+Cu (0.025 ppm)). Significant increases in latency and fewer platform crossings on probe trials, which are considered measures of spatial memory impairment, were seen in both Fe and Zn supplemented transgenic mice, compared to those raised on lab water. No significant differences were seen between the Zn + Cu group and in transgenic mice raised on lab water. These data suggest that the negative consequences of Zn may be due to a reduction in copper levels and, therefore, an imbalance between these metal ions rather than a direct effect of increased Zn. Show more

Keywords: Alzheimer's disease, copper, iron, maze learning, metal ions, spatial memory disorder, transgenic mice, zinc

DOI: 10.3233/JAD-2011-101452

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 375-381, 2011

Authors: Mollenhauer, Brit | Esselmann, Herrmann | Trenkwalder, Claudia | Schulz-Schaeffer, Walter | Kretzschmar, Hans | Otto, Markus | Wiltfang, Jens | Bibl, Mirko

Article Type: Research Article

Abstract: Appropriate treatment of dementia requires biomarkers that provide an exact and differential diagnosis. We recently presented differentially expressed amyloid-β (Aβ) peptide patterns in cerebrospinal fluid (CSF) as biomarker candidates for neurochemical diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The objective of the present study was to investigate CSF Aβ peptide patterns in both neuropathologically and clinically defined diagnostic groups of AD and DLB. Using the quantitative Aβ-SDS-PAGE/immunoblot, we analyzed CSF samples of neuropathologically defined patients with AD (definite AD, dAD; n = 11) and DLB (definite, dDLB; n = 12). We compared absolute and relative quantities …of CSF Aβ-peptides with a larger cohort of clinically diagnosed patients with probable AD (pAD; n = 71), probable DLB (pDLB; n = 32), and non-demented controls (NDC; n = 71). Each neuropathologically and clinically defined diagnostic group showed a similar relative distribution of CSF Aβ-peptides (Aβ1-X% . Aβ1-42% was lowered in dAD compared to NDC (p = 1.6 × 10−7 , but did not differ between dAD and pAD. Aβ1-40ox% was elevated in dDLB as compared to NDC (p = 1.8 × 10−5 , but did not differ between dDLB and pDLB. Thus, we were able to confirm previous results on Aβ peptide patterns in neuropathologically characterized patients with AD and DLB. Our results underline the usefulness of the CSF Aβ1-42% and Aβ1-40ox% as diagnostic biomarkers for AD and DLB, respectively. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrospinal fluid, dementia with Lewy bodies, neuropathologically confirmed diagnosis

DOI: 10.3233/JAD-2011-101551

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 383-391, 2011

Authors: Kim, SangYun | Park, Moon Ho | Han, Seol-Heui | Na, Hae Ri | Cho, SungJin | Choi, Mun Seong | Lee, Jae-Hong | Na, Duk L. | Kim, Jung Eun | Park, Kun Woo

Article Type: Research Article

Abstract: Screening tests that briefly measure early signs of cognitive dysfunction in Alzheimer's disease (AD) are lacking. We devised a new scale focused on early detecting cognitive dysfunction: the Attention Questionnaire Scale (AQS). We prospectively studied the AQS in 268 subjects with varying degrees of cognitive dysfunction and compared it with the Mini-Mental Status Examination (MMSE), digit span test, trail making test part B, letter cancellation test, Instrumental ADL, Geriatric Depression Scale, and Clinical Dementia Rating Scale. The internal consistency was excellent with the AQS (Cronbach's α = 0.945). There were significant differences in the overall AQS scores across varying degree …of cognitive dysfunction (26.80 ± 3.43 in normal elderly, 20.78 ± 4.83 in patients with mild cognitive impairment (MCI), 19.01 ± 4.49 in early AD, 16.00 ± 5.03 in mild AD, and 12.02 ± 6.28 in moderate AD), and subjects with the early stage of cognitive dysfunction could be further distinguished using the AQS than MMSE. The area under the receiver operating characteristic curve was estimated to be 0.93 (95% confidence interval 0.89–0.97) in screening for normal elderly versus patients with MCI or various stages of AD. The AQS provides greater screening ability for early stage cognitive dysfunction, used not only as a screening tool but also an appropriate simple questionnaire. Show more

Keywords: Alzheimer's disease, attention, dementia, questionnaire

DOI: 10.3233/JAD-2011-100660

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 393-402, 2011

Authors: Small, David H.

Article Type: Book Review

DOI: 10.3233/JAD-2010-110004

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 403-404, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-101552

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 405-407, 2011