Journal of Alzheimer's Disease - Volume 26, issue 1

Authors: Mielke, Michelle M. | Leoutsakos, Jeannie-Marie | Tschanz, JoAnn T. | Green, Robert C. | Tripodis, Yorghos | Corcoran, Chris D. | Norton, Maria C. | Lyketsos, Constantine G.

Article Type: Research Article

Abstract: Vascular factors have been shown to affect the rate of Alzheimer's disease (AD) progression. However, the effect of the APOE ε4 allele on rate of progression has been ambiguous. Little research to date has examined an interaction between vascular factors and the APOE ε4 allele in predicting decline among AD patients. 216 participants with incident AD from a population of elderly persons in Cache County, Utah, were followed for a mean of 3.3 years and 4.2 follow-up visits. A history of vascular risk factors and conditions and anti-hypertensive use was assessed at the diagnostic visit. Linear mixed effects models tested …interactions between the vascular factors, APOE ε4, and time as predictors of clinical progression on the Mini-Mental State Exam (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Multiple comparisons were corrected using the Holm-Bonferroni method. There was a 3-way interaction between stroke, APOE ε4 and time in predicting MMSE decline (LR χ2 = 10.32, 2 df, p = 0.006). For the CDR-SB, there were 3-way interactions between the APOE ε4, time and either myocardial infarction (LR χ2 = 17.83, 2 df, p = 0.0001) or stroke (LR χ2 = 11.48, 2 df, p = 0.003. Results suggest a complex relationship between the APOE ε4 and vascular factors in predicting cognitive and functional progression. Among individuals with a history of stroke or myocardial infarction at baseline, progression of AD is influenced by APOE ε4 carrier status and varies by time after AD diagnosis. Show more

Keywords: Alzheimer's disease, APOE, disease progression, myocardial infarction population-based, stroke, vascular factors

DOI: 10.3233/JAD-2011-110086

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 127-134, 2011

Authors: Rolstad, Sindre | Berg, Anne Ingeborg | Bjerke, Maria | Blennow, Kaj | Johansson, Boo | Zetterberg, Henrik | Wallin, Anders

Article Type: Research Article

Abstract: The aim of this study was to predict cognitive performance on the basis of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau) and amyloid-β42 (Aβ42 ) in controls and patients at various impairment levels. Previous studies have found an association of CSF T-tau levels with cognitive symptoms, but it has been difficult to relate Aβ to cognition, and it has thus been hypothesized that Aβ reaches a plateau level prior to cognitive symptoms. A comprehensive battery of neuropsychological tests was subjected to factor analysis to yield aggregated cognitive domains. Linear regression models were performed for the total sample of …the Gothenburg MCI study (n = 435) and for each level of impairment. Aβ42 and T-tau accounted for a significant proportion of performance in all cognitive domains in the total sample. In controls (n = 60) and patients with subjective cognitive impairment (n = 105), Aβ42 predicted a significant proportion of semantic and working memory performance. For patients with mild cognitive impairment (n = 170), T-tau had the most pronounced impact across cognitive domains, and more specifically on episodic memory, visuospatial, and speed/executive performance. For patients with dementia (n = 100), the most pronounced impacts of Aβ42 were found in episodic memory and visuospatial functioning, while T-tau was substantially associated with episodic memory. Our results suggest that cognition is related to CSF biomarkers regardless of impairment level. Aβ42 is associated with cognitive functions from a potentially early to a later disease phase, and T-tau is more indicative of performance in a later disease phase. Show more

Keywords: Aging, cerebrospinal fluid, dementia, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-2011-110038

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 135-142, 2011

Authors: Araujo, Joseph A. | Greig, Nigel H. | Ingram, Donald K. | Sandin, Johan | de Rivera, Christina | Milgram, Norton W.

Article Type: Research Article

Abstract: Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; …SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline. Show more

Keywords: Alzheimer's disease, cholinesterase inhibitor, dog, donepezil, learning, memory, phenserine

DOI: 10.3233/JAD-2011-110005

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 143-155, 2011

Authors: Deiber, Marie-Pierre | Ibáñez, Vicente | Herrmann, François | Rodriguez, Cristelle | Emch, Joan | Missonnier, Pascal | Millet, Philippe | Gold, Gabriel | Giannakopoulos, Panteleimon

Article Type: Research Article

Abstract: Amnestic mild cognitive impairment (aMCI) is characterized by memory deficits alone (single-domain, sd-aMCI) or associated with other cognitive disabilities (multi-domain, md-aMCI). The present study assessed the patterns of electroencephalographic (EEG) activity during the encoding and retrieval phases of short-term memory in these two aMCI subtypes, to identify potential functional differences according to the neuropsychological profile. Continuous EEG was recorded in 43 aMCI patients, whose 16 sd-aMCI and 27 md-aMCI, and 36 age-matched controls (EC) during delayed match-to-sample tasks for face and letter stimuli. At encoding, attended stimuli elicited parietal alpha (8–12 Hz) power decrease (desynchronization), whereas distracting stimuli were associated …with alpha power increase (synchronization) over right central sites. No difference was observed in parietal alpha desynchronization among the three groups. For attended faces, the alpha synchronization underlying suppression of distracting letters was reduced in both aMCI subgroups, but more severely in md-aMCI cases that differed significantly from EC. At retrieval, the early N250r recognition effect was significantly reduced for faces in md-aMCI as compared to both sd-aMCI and EC. The results suggest a differential alteration of working memory cerebral processes for faces in the two aMCI subtypes, face covert recognition processes being specifically altered in md-aMCI. Show more

Keywords: Alpha activity, amnestic MCI, EEG, face, N250r component, working memory

DOI: 10.3233/JAD-2011-110170

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 157-169, 2011

Authors: Maetzler, Walter | Berg, Daniela | Synofzik, Matthis | Brockmann, Kathrin | Godau, Jana | Melms, Arthur | Gasser, Thomas | Hörnig, Stephanie | Langkamp, Markus

Article Type: Research Article

Abstract: There is increasing evidence that in Lewy body-associated dementias (encompassing Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB)), the adaptive immune system is altered and the degenerative process includes glial cells in addition to neuronal structures. We therefore aimed to determine levels of autoantibodies against amyloid and glial-derived structures in these dementia types. Using a newly developed Enzyme-linked immunosorbent assay (ELISA), we measured levels of IgG autoantibodies against neuronal and glial structures in serum and cerebrospinal fluid of a total of 91 subjects (13 PDD, 14 DLB, 11 Alzheimer's disease (AD), 11 frontotemporal dementia (FTD), 11 vascular …dementia patients (VaD), and 31 healthy controls). Autoantibody levels against α-synuclein, amyloid-β42 (Aβ42 ), myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and S100B were determined. In all groups, autoantibody levels were about three magnitudes higher in serum than in CSF. Serum autoantibody levels against α-synuclein, Aβ42 , MOG, MBP, and S100B were higher in PDD/DLB compared to tau-associated dementias (AD, FTD), VaD, and controls, respectively, with most of them reaching highly significant p-values. In cerebrospinal fluid (CSF), levels of antibodies against oligodendrocyte-derived antigens (MOG, MBP) were significantly increased in PDD/DLB. Increased levels of autoantibodies against both neuronal- and glial-derived antigens in serum and CSF of Lewy body-associated dementias indicate an altered activity of the adaptive immune system in these dementia types. The potential of neural-derived IgG autoantibodies as part of a biomarker panel for the diagnosis of Lewy body-associated dementias should be further evaluated. Show more

Keywords: Astrocytes, autoantibodies, dementia with Lewy bodies, glial cells, Lewy body disease, oligodendrocytes, Parkinson's disease dementia

DOI: 10.3233/JAD-2011-110221

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 171-179, 2011

Authors: Koch, Giacomo | Esposito, Zaira | Kusayanagi, Hajime | Monteleone, Fabrizia | Codecá, Claudia | Di Lorenzo, Francesco | Caltagirone, Carlo | Bernardi, Giorgio | Martorana, Alessandro

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative process characterized by progressive neuronal degeneration, reduced levels of neurotransmitters, and altered forms of synaptic plasticity. In animal models of AD, amyloid-β (Aβ) and tau proteins are supposed to interfere with synaptic transmission. In the current study, we investigated the correlation between motor cortical plasticity, measured with 1 Hz repetitive transcranial magnetic stimulation (rTMS), and the levels of Aβ1-42 , total tau (t-Tau), and phosphorylated tau (p-Tau) detected in cerebrospinal fluid (CSF) of AD patients. We found that the overall rTMS after effects were milder in AD patients in comparison with controls. In AD …patients the amount of rTMS-induced inhibition correlated with CSF t-Tau, but not with Aβ1-42 CSF levels. Surprisingly, higher CSF t-Tau levels were associated to a stronger inhibition of the motor evoked potentials, implying that the expected effects of the 1 Hz rTMS protocol were more evident in patients with more pathological t-Tau CSF levels. These data could be interpreted as the consequence of CSF t-Tau mediated abnormal excitatory activity and could suggest that CSF t-Tau may impact mechanisms of cortical plasticity. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, cortical plasticity, tau, transcranial magnetic stimulation

DOI: 10.3233/JAD-2011-110116

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 181-186, 2011

Authors: Govindarajan, Nambirajan | Agis-Balboa, Roberto Carlos | Walter, Jonas | Sananbenesi, Farahnaz | Fischer, André

Article Type: Research Article

Abstract: Dysregulation of histone acetylation has been implicated in the onset of age-associated memory impairment and the pathogenesis of neurodegenerative diseases. Elevation of histone acetylation via administration of histone deacetylase (HDAC) inhibitors is currently being pursued as a novel therapeutic avenue to treat memory impairment linked to Alzheimer's disease (AD). Here we show that severe amyloid pathology correlates with a pronounced dysregulation of histone acetylation in the forebrain of APPPS1-21 mice. Importantly, prolonged treatment with the pan-HDAC inhibitor sodium butyrate improved associative memory in APPPS1-21 mice even when administered at a very advanced stage of pathology. The recovery of memory function …correlated with elevated hippocampal histone acetylation and increased expression of genes implicated in associative learning. These data advance our understanding of the potential applicability of HDAC inhibitors for the treatment of AD and suggest that HDAC inhibitors may have beneficial effects even when administered long after the onset of disease-associated symptoms. Show more

Keywords: Alzheimer's disease, gene expression, histone acetylation, histone deacetylases, memory impairment

DOI: 10.3233/JAD-2011-110080

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 187-197, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110081

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 199-200, 2011