Journal of Alzheimer's Disease - Volume 22, issue 3

Authors: Ebenezer, Philip J. | Weidner, Adam M. | LeVine III, Harry | Markesbery, William R. | Murphy, M. Paul | Zhang, Le | Dasuri, Kalavathi | Fernandez-Kim, Sun Ok | Bruce-Keller, Annadora J. | Gavilán, Elena | Keller, Jeffrey N.

Article Type: Research Article

Abstract: Recent studies have demonstrated a potential role for oligomeric forms of amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aβ. In the present study, we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aβ oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aβ. The neuron death induced by oligomer treatment was associated with an increase …in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aβ toxicity in neurons. These data indicate that oligomeric Aβ is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aβ as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, neurotoxicity, protein oxidation

DOI: 10.3233/JAD-2010-101161

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 839-848, 2010

Authors: Candela, Pietra | Gosselet, Fabien | Saint-Pol, Julien | Sevin, Emmanuel | Boucau, Marie-Christine | Boulanger, Eric | Cecchelli, Roméo | Fenart, Laurence

Article Type: Research Article

Abstract: Several studies have highlighted the close relationship between Alzheimer's disease (AD) and alterations in the bidirectional transport of amyloid-β (Aβ) peptides across the blood-brain barrier (BBB). The brain capillary endothelial cells (BCECs) that compose the BBB express the receptors and transporters that enable this transport process. There is significant in vivo evidence to suggest that P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restrict Aβ peptides entry into the brain, whereas the receptor for advanced glycation end-products (RAGE) seems to mediate apical-to-basolateral passage across the BBB. However, deciphering the molecular mechanisms underlying these in vivo processes requires further in vitro …characterization. Using an in vitro BBB model and specific competition experiments against RAGE, we have observed a significant decrease in apical-to-basolateral (but not basolateral-to-apical) transport of Aβ1–40 and Aβ1–42 peptides through BCECs. This transport is a caveolae-dependent process and fits with the apical location of RAGE observed in confocal microscopy experiments. Inhibition of P-gp and BCRP using different inhibitors increases transport of Aβ peptides suggesting that these efflux pumps are involved in Aβ peptide transport at the BCECs level. Taken as a whole, these results demonstrate the involvement of the caveolae-dependent transcytosis of Aβ peptides through the BBB in a RAGE-mediated transport process, reinforcing the hypothesis whereby this receptor is a potential drug target in AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, BCRP, blood-brain barrier, brain capillary endothelial cells, caveolae, P-gp, RAGE

DOI: 10.3233/JAD-2010-100462

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 849-859, 2010

Authors: Motawaj, Mouhammad | Peoc'h, Katell | Callebert, Jacques | Arrang, Jean-Michel

Article Type: Research Article

Abstract: Neuropathological studies have reported a strong neurofibrillary degeneration of the tuberomamillary nucleus, the region of origin of histamine neurons, in Alzheimer's disease (AD). Histaminergic neurons enhance cognition and memory, suggesting that their degeneration may contribute to the cognitive decline of AD. Besides neurons, the brain histaminergic system comprises mast cells and microglia that can also produce histamine. The level of activity of this histaminergic system in AD remained unknown. In the present study, we have measured the levels of the main histamine metabolite in brain, tele-methylhistamine (t-MeHA), an index of histaminergic system activity, in the cerebrospinal fluid (CSF) of 97 …non-AD (controls) and 91 AD patients, males or females. t-MeHA levels in CSF of controls tended to be higher, although non-significantly, in females than in males. t-MeHA levels of controls and AD significantly increased with age (1.66 ± 0.13, 2.04 ± 0.12, and 2.76 ± 0.12 pmol/ml at 40, 60 and 80 years, respectively). In spite of the strong degeneration of histamine neurons in the disease, t-MeHA levels in CSF were only slightly decreased in AD compared to controls (2.14 ± 0.10 vs 2.76 ± 0.13 pmol/ml, –22%, p < 0.01). This decrease was similar whatever the age, and was slightly higher in females than in males. The increase observed with age, and the limited magnitude of the decrease in AD even at late stages may result from the compensatory activation of spared neurons, as well as the neuroinflammation-induced activation of microglia occurring in senescence and AD. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, cognitive deficits, histaminergic system activity, mast cells, microglia, neuroinflammation, neurons, tele-methylhistamine

DOI: 10.3233/JAD-2010-100381

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 861-871, 2010

Authors: Jyoti, Amar | Plano, Andrea | Riedel, Gernot | Platt, Bettina

Article Type: Research Article

Abstract: Since sleep and electroencephalogram (EEG) disturbances are endophenotypes of Alzheimer's disease (AD) patients alongside cognitive dysfunction, we here characterized these parameters in transgenic mice carrying transgenes for amyloid-β protein precursor (AβPPswe ) and presenilin 1 (PSEN1A246E ) at 5 (pre-plaque) and 20 months, relative to PSEN1 and wild-type (WT) mice, using a novel wireless microchip device. While circadian rhythms were not affected, we obtained significantly higher overall activity at 5 months in the AβPP/PSEN1 strain (p < 0.001) compared to both PSEN1 and WT animals. Vigilance staging revealed that AβPP/PSEN1 animals present with an age-independent increase in wakefulness (p < …0.001) and a decrease in non rapid-eye movement (NREM) sleep (p < 0.01). These changes were age- and genotype-dependent only during the light phase, while dark phase activity pattern were equally affected at both ages. In all genotypes, the amount of REM sleep was lower at 20 months indicating a general age-related profile. Spectral power of qEEG changed in AβPP/PSEN1 mice at 5 months during wakefulness and REM sleep; during wakefulness hippocampal delta (0.5–5 Hz) was reduced and theta (5–9 Hz) power enhanced. By contrast, NREM EEG spectra were affected by age and genotype. Interestingly, PSEN1 animals also showed spectral EEG changes, these differed from both WT and AβPP/PSEN1 animals. Our results indicate that AβPP/PSEN1 mice exhibit abnormalities in activity and sleep architecture preceding amyloid plaque deposition as well as age-related changes in cortical EEG power. Though not fully recapitulating the profile of AD patients, this suggests activity and EEG recordings as sensitive and translational biomarkers in murine models. Show more

Keywords: Alzheimer's disease, amyloid, circadian activity, EEG, FFT, power spectrum, presenilin, sleep

DOI: 10.3233/JAD-2010-100879

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 873-887, 2010

Authors: Cacho, Jesús | Benito-León, Julián | García-García, Ricardo | Fernández-Calvo, Bernardino | Vicente-Villardón, José Luis | Mitchell, Alex J.

Article Type: Research Article

Abstract: There is currently a need to develop tools to identify patients with mild AD and mild cognitive impairment (MCI). We determined the validity and reliability of a brief, easily administered cognitive screening battery consisting of fusion of two well-known brief tests (Mini-Mental Status Examination [MMSE] and Clock Drawing Test [CDT]) (Mini-clock) to differentiate between patients with mild AD, MCI, and healthy control subjects. 66 consecutive patients with mild AD, 21 with MCI, and 66 healthy controls seen in a memory clinic setting were compared. Receiver operating characteristic (ROC) curve analysis was used to calculate the cut-off value permitting discrimination between …mild AD, MCI, and healthy control subjects. Interrater and test-retest reliability were also assessed. Mean cognitive scores for patients with AD, MCI, and control subjects on all two individual tests were significantly different (for each, p < 0.001). The mean area under the ROC curve for Mini-clock was higher than that obtained with MMSE or CDT in differentiating mild AD from controls (0.973 vs. 0.952 and 0.881, respectively) and MCI from controls (0.855 vs. 0.821 and 0.779, respectively). Test-retest reliability for the Mini-clock was 0.99, meanwhile interrater reliability was 0.87. The mean time to complete the test for all subjects was 8 min and 50 s. The Mini-clock is highly sensitive and specific in the detection of mild AD and reasonably accurate when attempting to separate MCI from health controls. It has a high interrater and test-retest reliability, can be quickly administered, and does not require major training. Show more

Keywords: Alzheimer's disease, diagnosis, screening

DOI: 10.3233/JAD-2010-101182

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 889-896, 2010

Authors: Collette, Fabienne | Van der Linden, Martial | Salmon, Eric

Article Type: Research Article

Abstract: A decline of cognitive functioning affecting several cognitive domains was frequently reported in patients with frontotemporal dementia. We were interested in determining if these deficits can be interpreted as reflecting an impairment of controlled cognitive processes by using an assessment tool specifically developed to explore the distinction between automatic and controlled processes, namely the process dissociation procedure (PDP) developed by Jacoby [1]. The PDP was applied to a word stem completion task to determine the contribution of automatic and controlled processes to episodic memory performance and was administered to a group of 12 patients with the behavioral variant of frontotemporal …dementia (bv-FTD) and 20 control subjects (CS). Bv-FTD patients obtained a lower performance than CS for the estimates of controlled processes, but no group differences was observed for estimates of automatic processes. The between-groups comparison of the estimates of controlled and automatic processes showed a larger contribution of automatic processes to performance in bv-FTD, while a slightly more important contribution of controlled processes was observed in control subjects. These results are clearly indicative of an alteration of controlled memory processes in bv-FTD. Show more

Keywords: Behavior, controlled processes, dementia, executive functions, frontotemporal

DOI: 10.3233/JAD-2010-100042

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 897-907, 2010

Authors: Fortea, Juan | Sala-Llonch, Roser | Bartrés-Faz, David | Bosch, Beatriz | Lladó, Albert | Bargalló, Nuria | Molinuevo, José Luis | Sánchez-Valle, Raquel

Article Type: Research Article

Abstract: Neuroimaging studies of familial Alzheimer's disease allow investigation of the disease process before clinical onset. We performed semi-automated MRI analysis to evaluate cortical thickness (CTh), grey matter (GM) volumes, and GM diffusivity indexes in PSEN1 mutation carriers (MC). We recruited 11 MC from 4 families with PSEN1 mutations (L286P, M139T, K239N) and 6 familial and 12 non-familial healthy controls. MC were classified as either asymptomatic (n = 6) or symptomatic (n = 5). Subjects underwent structural and diffusion-weighted 3-Tesla MRI scanning. CTh and GM volumes of subcortical structures and diffusivity indexes were calculated and group comparisons were performed. Structural images …were reanalyzed with voxel-based morphometry methodology. Cerebrospinal fluid amyloid-β1–42 levels (Aβ) were measured. We found that symptomatic MC presented widespread cortical thinning, especially in precuneus and parietotemporal areas (p < 0.01) and increased mean diffusivity (MD) in these areas compared to controls. Unexpectedly, asymptomatic MC, 9.9 years prior to the predicted age of disease onset, presented increased CTh in the precuneus and parietotemporal areas (p < 0.01), increased caudate volumes (p < 0.01), and decreased MD (p < 0.05) in these areas compared to HC. In MC, CTh correlated with adjusted age. Aβ values were within normal limits in AMC. In conclusion, at early preclinical stages, CTh in the precuneus and parietotemporal regions and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. The different trends in MD in asymptomatic and symptomatic MC suggest that different microstructural changes underlie the contrasting morphometric findings. Reactive neuronal hypertrophy or/and inflammation may account for increased CTh and decreased MD in asymptomatic MC. Show more

Keywords: Alzheimer disease, amyloid, cerebrospinal fluid, magnetic resonance imaging, presenilin 1

DOI: 10.3233/JAD-2010-100678

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 909-922, 2010

Authors: Padovani, Alessandro | Cosseddu, Maura | Premi, Enrico | Archetti, Silvana | Papetti, Alice | Agosti, Chiara | Bigni, Barbara | Cerini, Carlo | Paghera, Barbara | Bellelli, Giuseppe | Borroni, Barbara

Article Type: Research Article

Abstract: The FOXP2 gene is mutated in a severe monogenic form of speech and language deficits, but no study on the influence of genetic variations within FOXP2 in neurological disorders characterized by language impairment is available yet. In the present study, we investigated the impact of common FOXP2 polymorphisms with regard to frontotemporal lobar degeneration (FTLD). Two-hundred ten FTLD patients underwent clinical and a wide standardized neuropsychological examination as well as brain imaging. In all patients, and in 200 age-matched healthy controls, four FOXP2 polymorphisms were evaluated, namely rs2396753, rs1456031, rs17137124 and rs1852469. SPECT images were analyzed by Statistical Parametric Mapping …(SPM5). No significant differences of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls were observed. A significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores was reported. The two polymorphisms showed an addictive effect. When the analysis was computed on the number of observations over time, and 391 assessments considered, comparable results were obtained. FTLD patients carrying at-risk polymorphisms showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers (p < 0.005). Genetic variations within FOXP2 do not represent a genetic risk to FTLD per se, but modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas. Show more

Keywords: FOXP2, frontotemporal dementia, frontotemporal lobar degeneration, genetics, SPECT

DOI: 10.3233/JAD-2010-101206

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 923-931, 2010

Authors: Maetzler, Walter | Stoycheva, Velichka | Schmid, Benjamin | Schulte, Claudia | Hauser, Ann-Kathrin | Brockmann, Kathrin | Melms, Arthur | Gasser, Thomas | Berg, Daniela

Article Type: Research Article

Abstract: Lewy body disease, defined by the occurrence of α-synuclein aggregates as fibrils in Lewy bodies and Lewy neurites, is associated with increased probabilities for both co-occurrence of dementia, and co-occurrence of Alzheimer's disease (AD)-like pathology, in particular amyloid-β (Aβ) plaques and lowered cerebrospinal fluid (CSF) Aβ42 levels. Not surprisingly, in patients with Lewy body disease patients, there is a strong association between dementia and Aβ42 pathology. Neprilysin (NEP) is an Aβ-degrading protein found at presynaptic terminals and in body fluids. Reduced CSF NEP activity levels have been shown to occur in early AD, suggesting that altered CSF NEP …activity levels may also be associated with dementia and lowered CSF Aβ42 levels in Lewy body disease. Hypothesizing a relation between CSF NEP activity and dementia in Lewy body disease, we determined CSF and serum NEP activity, and Aβ42 levels of 41 demented Lewy body disease patients, 38 non-demented Lewy body disease patients, and of 23 elderly controls. Demented Lewy body disease patients had lowered CSF NEP activity levels (0.3 pmol/min*ml, 0.2–81.5), compared to both non-demented Lewy body disease subjects (8.5 pmol/min*ml, 0.2–87.2; p = 0.004) and controls (21.5 pmol/ml*min, 0.15–413.4; p = 0.02). In addition, CSF NEP activity levels correlated positively with CSF Aβ42 levels (Rho = 0.28, p = 0.008) which was not explained by the presence or absence of ApoE4. Serum NEP activity levels were not significantly different between the groups. We conclude that, in Lewy body disease, CSF NEP activity levels are associated with dementia, probably via the Aβ pathway. Show more

Keywords: Alzheimer's disease, enzyme, Lewy body disease, metalloendopeptidase, Parkinson's disease, spinal puncture

DOI: 10.3233/JAD-2010-101197

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 933-938, 2010

Authors: Virta, Jyri J. | Järvenpää, Tarja | Heikkilä, Kauko | Perola, Markus | Koskenvuo, Markku | Räihä, Ismo | Rinne, Juha O. | Kaprio, Jaakko

Article Type: Research Article

Abstract: In this prospective follow-up study, we monitored the effects of midlife alcohol consumption and drinking patterns on cognitive impairment risks in late life. 1,486 subjects recruited from the Finnish Twin Cohort were included in the analyses. Alcohol consumption data was obtained with structured questionnaires in 1975 and 1981, and subjects were contacted between 1999 and 2007 to conduct a telephone interview evaluating cognitive function. The mean follow-up period was 22.8 years (standard deviation 2.1 years). Both abstainers and heavy drinkers were found to have an increased risk of cognitive impairment in comparison to light drinkers (relative risk ratios 1.44; 95% …confidence interval: 1.02–2.10 and 1.94, 1.10–3.44, respectively. Also, binge drinking at least monthly in 1975 and 1981, as well as more than two pass-outs due to excess drinking in 1981 were associated with an increased risk of cognitive impairment (1.98, 1.08–3.64 and 3.85, 1.51–9.83, respectively), even when excluding abstainers and controlling for total alcohol consumption. Subgroup analyses based on apolipoprotein E ε4 status suggest that the increased risk of cognitive impairment associated with being an abstainer is limited to subjects without an ε4 allele. Our results add to the evidence that light to moderate alcohol use is associated with a lower risk of cognitive impairment compared with higher levels of consumption. In addition, binge drinking was found to be an independent risk factor for cognitive impairment. Show more

Keywords: Alcohol drinking, Alzheimer's disease, cohort studies, dementia, risk factors

DOI: 10.3233/JAD-2010-100870

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 939-948, 2010