Journal of Alzheimer's Disease - Volume 21, issue 2

Authors: van Eijk, Jeroen J.J. | van Everbroeck, Bart | Abdo, W. Farid | Kremer, Berry P.H. | Verbeek, Marcel M.

Article Type: Research Article

Abstract: In this study we investigated the cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and heavy chain (NFHp35), total tau (t-tau), and glial fibrillary acidic protein (GFAP) to detect disease specific profiles in sporadic Creutzfeldt Jakob disease (sCJD) patients and Alzheimer's disease (AD) patients. CSF levels of NFL, NFHp35, t-tau, and GFAP of 23 sCJD patients and 55 AD patients were analyzed and compared to non-demented controls. Median NFL, NFHp35, GFAP, and t-tau levels were significantly increased in sCJD patients and AD patients versus controls (p < 0.0001 in all). NFL, NFHp35, and t-tau levels were significantly increased in sCJD …patients versus AD patients (p < 0.005), but GFAP concentrations did not differ between sCJD and AD. The results suggest that neuroaxonal damage, reflected by higher CSF levels of NFL, NFHp35, and t-tau, is more pronounced in the pathophysiology of sCJD than in AD. The comparable CSF GFAP concentrations suggest that astroglial damage or astrocytosis is equally pronounced in the pathophysiology of AD and sCJD. Prospective studies are needed to determine whether NFL and NFHp35 may be additional tools in the differential diagnosis of rapidly progressive dementias. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, Creutzfeldt-Jakob disease, diagnosis, prion disease

DOI: 10.3233/JAD-2010-090649

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 569-576, 2010

Authors: Eriksson, Ulrika K. | Sjöberg, Beatrice G. | Bennet, Anna M. | de Faire, Ulf | Pedersen, Nancy L. | Frostegård, Johan

Article Type: Research Article

Abstract: Phosphorylcholine (PC) may play an important role in the atherogenic and pro-inflammatory effects of oxidized low density lipoproteins. We recently demonstrated that low levels of IgM antibodies against PC (anti-PC) are associated with development of myocardial infarction and stroke. We here evaluate the association between anti-PC and dementia and Alzheimer's disease (AD). We conducted a nested case-control study of 182 incident dementia cases (serum collected before onset of dementia) matched to 366 controls and a case-control study of 97 prevalent dementia cases (serum collected after dementia onset) matched to 205 controls. Controls were matched on gender and age at blood …draw (± 1 year). Participants were from the Swedish Twin Registry. Anti-PC levels were measured by ELISA. The odds ratio (OR) of dementia was modeled using conditional logistic regression. Patients with dementia had significantly lower mean anti-PC levels than controls (39.1 versus 49.5 U/ml). The likelihood of having dementia or AD was doubled for individuals with the lowest 25% anti-PC levels (OR=2.04 and 2.70, respectively). The results were similar after adjustments for potential confounders. There was no association between anti-PC levels and incident dementia. Low levels of atheroprotective anti-PC could play a role in AD and dementia. Potential mechanisms include decreased anti-inflammatory potential and effects on the vasculature. Further attention is merited to elucidate the role of anti-PC in AD development and the usefulness of anti-PC as a part of risk prediction, prognosis, diagnosis, or treatment. Show more

Keywords: Alzheimer's disease, dementia, natural antibodies, oxidized LDL, phosphorylcholine

DOI: 10.3233/JAD-2010-091705

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 577-584, 2010

Authors: Güntert, Andreas | Campbell, James | Saleem, Muzamil | O'Brien, Darragh P. | Thompson, Andrew J. | Byers, Helen L. | Ward, Malcolm A. | Lovestone, Simon

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder where definite diagnosis can only be made postmortem, and for which the most promising peripheral markers of disease state and severity have been found in the cerebrospinal fluid. However, recent results suggest that differences in the levels of certain plasma proteins do exist between AD patients and non-demented controls (NDC). Herein, we undertook an untargeted discovery study using isobaric mass tagging to compare the plasma protein levels between slow cognitive declining AD patients, rapid cognitive declining AD patients (RCD) and NDC subjects. Subsequent relative quantification and statistical analysis identified a list of …candidate proteins able to distinguish RCD from NDC groups based on multivariate analysis. Selected proteins were then validated by western blot analysis in an independent sample set of 60 AD and 35 NDC subjects. In this cohort, AD patients displayed significantly lower plasma gelsolin levels compared to NDC subjects. Additionally, gelsolin levels correlated with disease progression rate estimated by Mini-Mental Status Examination decline per year. In order to further investigate gelsolin expression, three different brain regions from an additional cohort of 23 subjects and their respective plasma samples were analysed. No significant change in brain gelsolin levels could be established between AD and control subjects. Interestingly, this study reveals yet another condition where plasma gelsolin levels are decreased and our findings, together with the reported interaction of gelsolin and amyloid-β, makes plasma gelsolin an attractive candidate for further studies targeted at better understanding disease progression in AD. Show more

Keywords: Alzheimer's disease, biomarker, disease progression, mass spectrometry, plasma gelsolin

DOI: 10.3233/JAD-2010-100279

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 585-596, 2010

Authors: Wang, Hongmei | Ma, Jianfang | Tan, Yuyan | Wang, Zhiquan | Sheng, Chengyu | Chen, Shengdi | Ding, Jianqing

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder initiated by the aggregation of amyloid-β peptide (Aβ). Macroautophagy, which is essential for cell survival as well as the promotion of cell death, has been observed extensively in AD brains or transgenic mice overexpressing Aβ protein precursor. However, the role of macroautophagy in the pathogenesis of AD is unclear. In this study, we showed that Aβ1-42 triggered autophagic cell death in both human glioma cell line (U87 cell) and human neuroblastoma cell line (SH-SY5Y cell). Aβ1-42 -induced cytotoxicity and autophagic cell death were blocked by the autophagy inhibitor 3-methyladenine (3-MA) or by …small interfering RNA against the autophagy gene Beclin-1. Reactive oxygen species (ROS) accumulation was also detected in both Aβ1-42 treated cell lines and this accumulation was not affected by 3-MA. Moreover, pretreatment with the ROS scavenger N-acetylcysteine inhibited ROS accumulation and autophagic cell death induced by Aβ1-42 , suggesting that Aβ1-42 -induced ROS accumulation might trigger the onset of autophagy and subsequent autophagic cell death. These findings provide further insights into the mechanisms underlying Aβ-induced cytotoxicity. Show more

Keywords: Apoptosis, autophagic cell death, Beclin-1, N-acetylcysteine, reactive oxygen species

DOI: 10.3233/JAD-2010-091207

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 597-610, 2010

Authors: Hyttinen, Laura | Tuulio-Henriksson, Annamari | Vuorio, Alpo F. | Kuosmanen, Noora | Härkänen, Tommi | Koskinen, Seppo | Strandberg, Timo E.

Article Type: Research Article

Abstract: The cognitive status of aged familial hypercholesterolemia (FH) patients treated with long-term statin therapy was compared with that of population controls. A comprehensive cohort of 43 elderly (age ⩾ 65 years) patients all with the same FH North Karelia mutation living in North Karelia (eastern Finland) was identified, 37 of whom (aged 65 to 84 years) agreed to participate. All but one of these FH patients had been using statins for approximately 15 years. Population-based controls (aged 65 to 84 years, n= 309) were the participants of the Health 2000 Survey living in eastern Finland. The cognitive assessment was conducted …with tests for verbal fluency, Word List Learning (WLL) and Word List Delayed Recall (WLDR) subtests in the Consortium to Establish a Registry for Alzheimer's disease test battery. After adjustment for age, gender, education, diabetes mellitus, and coronary heart disease, FH patients were more likely to be in the top tertile of the WLDR (Odds ratio (OR) 3.40, 95% confidence interval (CI) 1.52–7.63) and WLL3 (OR 2.83, 95% CI 1.28–6.25) subtests. When the FH patients were subdivided according to the median length of their statin therapy, the ORs to be in the top tertile in the WLDR subtest were 1.65 (95% CI 0.52–5.25) for those with less and 5.40 (95% CI 1.74–17.72) in those individuals with more than median length of statin therapy. In conclusion, aged FH patients receiving long-term statin therapy exhibited better episodic memory than population controls, and this association became even more pronounced with longer statin therapy. Show more

Keywords: Aged, CERAD, familial hypercholesterolemia, statins

DOI: 10.3233/JAD-2010-091381

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 611-617, 2010

Authors: Rodrıguez-Rodrıguez, Eloy | Vázquez-Higuera, José Luis | Sánchez-Juan, Pascual | Mateo, Ignacio | Pozueta, Ana | Martínez-García, Ana | Frank, Ana | Valdivieso, Fernando | Berciano, José | Bullido, María J. | Combarros, Onofre

Article Type: Research Article

Abstract: Aberrant cholesterol metabolism has been implicated in Alzheimer's disease (AD). Recent findings have suggested an interaction of Niemann-Pick C1 (NPC1) and ATP-binding cassette transporter A1 (ABCA1) proteins in intracellular cholesterol transport and in maintaining cell cholesterol balance. Underexpression of NPC1 in concert with under-expression of ABCA1 would result in increased cholesterol accumulation and increased AD risk. We examined a functional polymorphism in the ABCA1 promoter region (-477, rs2422493), and four NPC1 polymorphisms in exon 6 (rs18050810), intron 20 (rs4800488), intron 22 (rs2236707), and intron 24 (rs2510344) capturing 85% of genetic variability in the Hap Map Caucasian (CEU) population, in a …group of 631 Spanish AD patients and 731 controls. Subjects carrying both the ABCA1 (-477) TT genotype and the NPC1 (exon 6) GG genotype (OR=1.89; 95% CI 1.04–3.41), NPC1 (intron 20) AA genotype (OR=2.05; 95% CI 1.26–3.33), NPC1 (intron 22) AA genotype (OR=2.05; 95% or NPC1 (intron 24) GG genotype (OR=1.89; 95% higher risk of developing AD than subjects without these risk genotypes. Testing for epistatic interaction between genes in the pathway of cholesterol metabolism might be useful for predicting AD risk. Show more

Keywords: ABCA1, Alzheimer's disease, cholesterol, epistasis, NPC1, polymorphism

DOI: 10.3233/JAD-2010-100432

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 619-625, 2010

Authors: Serra, Laura | Perri, Roberta | Cercignani, Mara | Spanò, Barbara | Fadda, Lucia | Marra, Camillo | Carlesimo, Giovanni A. | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: Behavioral and psychological symptoms of dementia (BPSD) are commonly observed over the course of Alzheimer's disease (AD). However, it is unclear whether BPSD are part of AD neuropathology or rather represent a psychological reaction to cognitive disabilities. Using voxel-based-morphometry (VBM), we aimed to clarify this issue by investigating patients with AD at different clinical stages. Twenty-seven patients with AD (12 early [ADe] and 15 moderate [ADm]), 19 with amnestic mild cognitive impairment (a-MCI), and 23 healthy controls underwent MRI scanning at 3T. Assessment of BPSD was done in each patient using the Neuropsychiatric Inventory-12 (NPI-12). VBM was used to investigate …changes in grey matter (GM) atrophy across groups, and associations between regional GM volumes and occurrence and severity of BPSD in patients. Mood disorders, anxiety, and agitation were present in both a-MCI and AD, while psychotic symptoms were observed mainly in AD. As expected, VBM showed only limited areas of GM atrophy in a-MCI patients, with a progressive extension in ADe and ADm patients (PFWE -corrected-values < 0.05). Disinhibition was strongly associated with GM volume in bilateral cingulate and right middle frontal gyri, while delusions were associated with GM volume in right hippocampus (PFWE -corrected-values < 0.05). This study confirms that BPSD are present since the earliest AD stages. Interesting associations were found in regions traditionally implicated by AD neuropathology. This suggests that BPSD are likely to represent clinical features of AD and should be regarded for their diagnostic and prognostic value. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, behavioral and psychological symptoms of dementia (BPSD), neurodegeneration, NPI-12, voxel-based morphometry

DOI: 10.3233/JAD-2010-100048

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 627-639, 2010

Authors: Sedaghat, Fereshteh | Dedousi, Eleni | Baloyannis, Ioannis | Tegos, Thomas | Costa, Vasiliki | Dimitriadis, Athanasios S. | Baloyannis, Stavros J.

Article Type: Research Article

Abstract: Anosognosia is a common symptom of dementia. The aim of this study was to evaluate the contribution of different regions of the brain to anosognosia in Alzheimer's disease (AD) brains using single photon emission computed tomography (SPECT). Forty-two patients with AD were included in this study. After clinical interviews with the patients and their relatives, the patients were divided into two groups: Anosognosia and No-anosognosia. The patients were studied regarding the severity of dementia. They underwent SPECT with HMPAO and regional cerebral blood flow (rCBF) was measured. Regional CBF significantly differed between Anosognosia and No-anosognosia groups in right prefrontal (P …⩽ 0.02), right inferior parietal (P ⩽ 0.00), and right (P ⩽ 0.01) and left (P ⩽ 0.01) medial temporal cortex. There was a significant correlation between the severity of dementia and rCBF in medial temporal regions. When comparisons were made between mild and moderate stages separately, the 'right inferior parietal region' was the common region which showed hypoperfusion in both anosognosia subgroups. We conclude that anosognosia may be a reflection of functional impairment in right prefrontal, right frontal and especially right inferior parietal regions in AD. Show more

Keywords: Alzheimer, anosognosia, brain SPECT, disease unawareness, right parietal, right prefrontal

DOI: 10.3233/JAD-2010-090631

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 641-647, 2010

Authors: Arrieta-Cruz, Isabel | Wang, Jun | Pavlides, Constantine | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: In this study, we examined acute effects of carvedilol, a nonselective α/β-adrenergic receptor blocker, on neuronal transmission and long-term potentiation (LTP) in six month-old TgCRND8 mice and their wild-type age-matched controls. Field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus from carvedilol- or vehicle dimethyl sulfoxide-treated slices, and differences in basal synaptic transmission and LTP were assessed. Carvedilol treatment produced a significant increase in basal synaptic transmission and LTP in TgCRND8 mice, as compared to their vehicle-treated slices, in which basal neuronal transmission and LTP decreased. Interestingly, carvedilol significantly suppressed spontaneous seizure activity in TgCRND8 mice …as measured by the number of slices showing epileptic discharges as well as the number of spikes within these and the amplitude of the second spike, measured at baseline and end of recording. In contrast, vehicle-treated slices in TgCRND8 mice did not show a significant decrease in epileptic discharges. These results suggest that carvedilol reestablishes basal synaptic transmission, enhances neuronal plasticity and suppresses neuronal hyperexcitability in TgCRND8 mice. Show more

Keywords: Alzheimer's disease, carvedilol, epileptic discharges, hippocampus, LTP, neuronal transmission, synaptic plasticity, TgCRND8 mice

DOI: 10.3233/JAD-2010-100225

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 649-654, 2010

Authors: Liu, Shi-Jie | Gasperini, Robert | Foa, Lisa | Small, David Henry

Article Type: Research Article

Abstract: α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are key regulators of synaptic function and cognition. In Alzheimer's disease (AD), cell-surface AMPARs are downregulated, however the reason for this downregulation is not clear. In the present study, we found that Aβ significantly decreased levels of the cell-surface AMPA-type glutamate receptor subunit 2 (GluR2), and increased the concentration of free cytosolic calcium ion ([Ca2+ ]i ) in hippocampal neurons. Ion channel blockers (nifedipine, tetrodotoxin, SKF96365) decreased [Ca2+ i and increased the level of cell-surface GluR2, whereas Bay K 8644, an activator of L-type voltage-gated calcium channels increased [Ca2+ ]i and decreased cell-surface GluR2. …Aβ and Bay K 8644 increased phosphorylation of serine-880 (S880) on GluR2, whereas the nifedipine. tetrodotoxin and SKF96365 decreased S880 phosphorylation. Finally, we found that bisindolylmeimide I (GF 109203X, GFX), an inhibitor of protein kinase C (PKC) blocked both the decrease in cell-surface GluR2 and the increase in phospho-S880 induced by Aβ and Bay K 8644. Taken together, these results demonstrate that Aβ decreases cell-surface GluR2 by increasing PKC-mediated phosphorylation of S880. Our study supports the view that a rise in cytosolic [Ca2+ ]i induced by Aβ could impair synaptic function by decreasing the availability of AMPARs at the synapse. This decrease in AMPARs may contribute to the decline in cognitive function seen in AD. Show more

Keywords: Alzheimer's disease, AMPA, amyloid-β, calcium, GluR2, phospho-GluR2, PKC

DOI: 10.3233/JAD-2010-091654

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 655-666, 2010

Authors: Fagan, Tom

Article Type: Research Article

DOI: 10.3233/JAD-2010-101340

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 667-671, 2010