Journal of Alzheimer's Disease - Volume 36, issue 4

Authors: Leoni, Valerio | Solomon, Alina | Lövgren-Sandblom, Anita | Minthon, Lennart | Blennow, Kaj | Hansson, Oskar | Wahlund, Lars-Olof | Kivipelto, Miia | Björkhem, Ingemar

Article Type: Research Article

Abstract: We evaluated the diagnostic potential of 24S-hydroxycholesterol (24OHC) in cerebrospinal fluid. At a memory clinic, we investigated subjects with subjective cognitive impairment (SCI, n = 33), mild cognitive impairment (MCI) patients (n = 27), MCI patients with later progression into Alzheimer dementia at follow up (n = 10), and patients with AD (n = 24). We also had a control group of healthy volunteers who did not later develop cognitive problems (n = 13). The fraction of the population with pathological levels of 24OHC was 8% in controls, 34% in SCI, 37% in MCI, 80% in MCI with progression, and …42% in AD. The corresponding fractions for T-tau, P-tau, and Aβ42 were lower in the case of SCI and MCI but higher in the case of controls and AD. In case of MCI with progression, the fraction of pathological levels of 24OHC and Aβ42 were 80% and 63% respectively. We also studied a population of old healthy subjects age 75–99 years (n = 25). The fraction of individuals in this population with pathological levels of 24OHC was 0% whereas the fraction of individuals with pathological level of at least one of the other three biomarkers was 40%. The diagnostic power of 24OHC in cerebrospinal fluid seems to be similar to or lower than that of the established biomarkers T-tau, P-tau, and Aβ42 in the diagnosis of established AD. Our data suggest that 24OHC may be more sensitive than the classical biomarkers in an early phase of the neurodegenerative process and a better marker for “brain health” in old age. Show more

Keywords: Aging, ApoE, biomarker, cholesterol, cognitive decline, mass spectrometry, neurodegenerative diseases, oxysterols

DOI: 10.3233/JAD-130035

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 739-747, 2013

Authors: Engelman, Corinne D. | Koscik, Rebecca L. | Jonaitis, Erin M. | Okonkwo, Ozioma C. | Hermann, Bruce P. | La Rue, Asenath | Sager, Mark A.

Article Type: Research Article

Abstract: The strongest genetic factor for late-onset Alzheimer's disease (AD) is APOE; nine additional susceptibility genes have recently been identified. The effect of these genes is often assumed to be additive and polygenic scores are formed as a summary measure of risk. However, interactions between these genes are likely to be important. We sought to examine the role of interactions between the nine recently identified AD susceptibility genes and APOE in cognitive function and decline in 1,153 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Participants underwent extensive …cognitive testing at baseline and up to two additional visits approximately 4 and 6 years later. The influence of the interaction between APOE and each of 14 single nucleotide polymorphisms (SNPs) in the nine recently identified genes on three cognitive factor scores (Verbal Learning and Memory, Working Memory, and Immediate Memory) was examined using linear mixed models adjusting for age, gender, and ancestry. Interactions between the APOE ε4 allele and both of the genotyped ABCA7 SNPs, rs3764650 and rs3752246, were associated with all three cognitive factor scores (p-values ≤ 0.01). Both of these genes are in the cholesterol metabolism pathway leading to AD. This research supports the importance of considering non-additive effects of AD susceptibility genes. Show more

Keywords: Alzheimer's disease, cholesterol, cognition, gene-gene interaction, memory

DOI: 10.3233/JAD-130482

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 749-757, 2013

Authors: Slaets, Sylvie | Le Bastard, Nathalie | Martin, Jean-Jacques | Sleegers, Kristel | Van Broeckhoven, Christine | De Deyn, Peter Paul | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: It is assumed that the concentration of amyloid-β1-40 (Aβ1-40 ) in cerebrospinal fluid (CSF) reflects the total amount of Aβ protein in the brain and thus allows a better interpretation of inter-individual differences in Aβ quantity than the Aβ1-42 concentration. In this study, Aβ1-40 was added to the existing CSF biomarker panel of Aβ1-42 , total tau (T-tau), and phosphorylated tau (P-tau181P ) in order to test whether the accuracy of the differential dementia diagnosis improved. The concentration of Aβ1-40 (INNOTEST® β-amyloid(1–40) prototype version, Innogenetics NV, Belgium) and the other biomarkers (INNOTEST®) was determined in CSF …samples from 80 Alzheimer's disease (AD) patients, 75 non-AD dementia patients, and 30 controls. A large proportion of the study population had autopsy-confirmed neurodegeneration (AD: 73/80 = 91%; non-AD: 38/75 = 51%). The levels of Aβ1-40 were decreased in AD (10856 ± 4745 pg/mL) and non-AD patients (10519 ± 4491 pg/mL) when compared to controls (14760 ± 7846 pg/mL) (p = 0.002 and p = 0.001). The Aβ1-42 /Aβ1-40 ratio was significantly decreased in AD (0.043 ± 0.021) as compared to non-AD patients (0.064 ± 0.027; p < 0.001) and controls (0.053 ± 0.023; p < 0.001). In order to differentiate AD from non-AD patients, a decision tree was constructed. The diagnostic accuracy of the decision tree that contained Aβ1-42 , Aβ1-40 , P-tau181P , and the Aβ1-42 /Aβ1-40 ratio was significantly better than the diagnostic accuracy (80% versus 74%) of the decision tree without Aβ1-40 and the Aβ1-42 /Aβ1-40 ratio (p < 0.001). In conclusion, no difference in Aβ1-40 CSF levels was found between AD and non-AD patients, but adding CSF Aβ1-40 and the CSF Aβ1-42 /Aβ1-40 ratio to a biomarker-based decision tree, might have an added value for discriminating AD from non-AD patients in case of intermediate CSF P-tau181P values. Show more

Keywords: Alzheimer's disease, amyloid-β1-40, autopsy-confirmed, biological markers, dementia, differential dementia diagnosis

DOI: 10.3233/JAD-130107

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 759-767, 2013

Authors: Ravona-Springer, Ramit | Beeri, Michal Schnaider | Goldbourt, Uri

Article Type: Research Article

Abstract: The present study aimed to assess the relationship of midlife Motivation to Improve Status at work (MIS) with dementia more than three decades later. In 1963, 9,920 out of 10,059 male participants of the Israel Ischemic Heart disease (IIHD) study, aged 40–65 years, were questioned about their MIS as follows: “Do you want to improve your status at work and do you believe it is possible?”. One of four answers was possible: trying to change status and believe it is possible (MIS1) (n = 3,060); trying but unsure of success (MIS2) (n = 2,618); not trying, unlikely to succeed (MIS3) …(n = 2,020); not trying, satisfied (MIS4) (n = 2,222). Dementia was assessed over three decades later in 1,714 survivors of the original cohort, including 1,691 who responded in 1963 to the questionnaire regarding MIS. Controlling for age, the estimated odds for dementia relative to MIS1 were 1.45 (95% CI 1.06–2.01) in MIS2, 1.52 (95% CI 1.04–2.23) in MIS3, and 1.96 (95% CI 1.38–2.81) in MIS4. Further adjustment for age and socioeconomic status index resulted in adjusted estimated odds for dementia relative to MIS1 were 1.26 (95% CI 0.90–1.75) in MIS2, 1.10 (95% CI 0.74–1.64) in MIS3, and 1.78 (95% CI 1.23–2.56) in MIS4. These results were not attenuated when midlife diabetes, blood pressure values, serum-cholesterol levels, and coronary heart disease were controlled for in the analysis. Among tenured working men, lack of MIS together with satisfaction with current status was associated with higher risk for dementia among survivors several decades later. This association was partially attenuated by socioeconomic status. Show more

Keywords: Dementia, midlife, motivation to improve status, risk factor, work

DOI: 10.3233/JAD-122422

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 769-780, 2013

Authors: Bhat, Narayan R. | Thirumangalakudi, Lakshmi

Article Type: Research Article

Abstract: Previous studies demonstrated that a high fat/high cholesterol (HFC) diet results in a loss of working memory in mice correlated with neuroinflammatory changes and increased AβPP processing (Thirumangalakudi et al. (2008) J Neurochem 106, 475–485). To further explore the nature of the molecular correlates of cognitive impairment, in this study, we examined changes in tau phosphorylation, insulin/IGF-1 signaling (IIS) including GSK3, and levels of specific synaptic proteins. Immunoblot analysis of hippocampal tissue from C57BL/6 mice fed HFC for 2 months with anti-phospho-tau (i.e., PHF1 and phospho-Thr-231 tau) antibodies demonstrated the presence of hyperphosphorylated tau. The tau phosphorylation correlated with activated …GSK3, a prominent tau kinase normally kept inactive under the control of IIS. That IIS itself was impaired due to the hyperlipidemic diet was confirmed by a down-regulation of insulin receptor substrate-1 and phospho-Akt levels. Although no significant changes in the levels of the pre-synaptic protein (i.e., synaptophysin) in response to HFC were apparent in immunoblot analysis, there was a clear down-regulation of the post-synaptic protein, PSD95, and drebrin, a dendritic spine-specific protein, indicative of altered synaptic plasticity. The results, in concert with previous findings with the same model, suggest that high dietary fat/cholesterol elicits brain insulin resistance and altered IIS leading to Alzheimer's disease-like cognitive impairment in ‘normal’ mice. Show more

Keywords: Brain insulin resistance, dietary fat, hippocampus, insulin/IGF signaling, synaptic plasticity, tau phosphorylation

DOI: 10.3233/JAD-2012-121030

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 781-789, 2013

Authors: Lazzeroni, Laura C. | Halbauer, Joshua D. | Ashford, J. Wesson | Noda, Art | Hernandez, Beatriz | Azor, Virgina | Hozack, Nikki | Hasson, Noelle | Henderson, Victor W. | Yesavage, Jerome A. | Tinklenberg, Jared R.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans …aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study. Show more

Keywords: Alzheimer's disease, anticholinesterase drugs, database, donepezil, life-expectancy, memantine, mortality, pharmacy, survival analysis

DOI: 10.3233/JAD-130662

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 791-798, 2013

Authors: Magnin, Eloi | Chopard, Gilles | Ferreira, Sabrina | Sylvestre, Geraldine | Dariel, Elfried | Ryff, Ilham | Mertz, Catherine | Lamidieu, Charlie | Hidalgo, Julie | Tio, Gregory | Haffen, Sophie | Galmiche, Jean | Moulin, Thierry | Vandel, Pierre | Rumbach, Lucien

Article Type: Research Article

Abstract: Background: Logopenic variant of primary progressive aphasia (LPPA) is classically considered as an isolated language disorder, but verbal short-term memory deficit induces difficulties in neuropsychological tests that are not intended to evaluate language. Objective: The aim of this study is to describe the initial symptoms and neuropsychological profiles of LPPA. Methods: A retrospective study was conducted with a series of 20 consecutive patients diagnosed with LPPA. Clinical, neuroimaging, neuropsychological, and linguistic examinations are reported. The first neuropsychological examinations (mean time between neuropsychological assessment and diagnosis: 11 months) were then compared to 20 patients with mild cognitive …impairment (MCI) and 20 patients with Alzheimer’s disease (AD) matched by age, gender, and education level. Results: A recent onset or aggravation of anxiety disorders was frequently reported. An unusual neuropsychological profile, different from that of AD or MCI, was observed: dissociation between verbal and visual memory performances, poor encoding performances on verbal memory tests, and preserved orientation to time, difficulties with mental calculation and fluency tasks. Biparetal abnormality and left hippocampal diaschisis was frequently observed. Asymptomatic dopaminergic depletion was observed in four patients. Conclusion: Our study identifies that de novo or recently worsening anxiety and specific neuropsychological profiles call for screening for LPPA, including a linguistic examination. Sometimes, there may be a continuum between LPPA and corticobasal syndrome. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, neuropsychology, primary progressive aphasia, screening

DOI: 10.3233/JAD-122335

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 799-808, 2013

Article Type: Correction

DOI: 10.3233/JAD-139904

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 809-809, 2013

Article Type: Other

DOI: 10.3233/JAD-130636

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 811-812, 2013

Article Type: Other

DOI: 10.3233/JAD-2013-36420

Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 813-822, 2013