Journal of Alzheimer's Disease - Volume 25, issue 2

Authors: Neufang, Susanne | Akhrif, Atae | Riedl, Valentin | Förstl, Hans | Kurz, Alexander | Zimmer, Claus | Sorg, Christian | Wohlschläger, Afra M.

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), the loss of cerebral connectivity has been evidenced by numerous studies. There is growing evidence of attention related failures already in prodromal stages of AD; however, connectivity changes within attention networks have been rarely reported. Here we focused on effective connectivity of top-down attention control in patients with prodromal Alzheimer's disease (pAD). We scanned 15 pAD patients and 16 healthy elderly using the Attentional Network Task and determined effective connectivity within a cingulo-fronto-parietal network using Dynamic Causal Modeling. We related connectivity parameters to structural and behavioral parameters (gray matter volume as well as reaction time) to …examine the relation between affected domains. Our analyses revealed that effective connectivity from the right middle frontal gyrus to the left superior parietal cortex as well as from the right to the left superior parietal gyrus was reduced in pAD patients. Furthermore, we found that, effective connectivity varied as a function of GM volume in the patient group: right middle frontal gray matter volume significantly correlated with connectivity from the right parietal cortex to the right middle frontal gyrus as well as from the middle frontal gyrus to the anterior cingulate cortex. In addition, inter-parietal connectivity was correlated to right and left parietal gray matter volume. We conclude that, at very early stages of AD, the reduction of effective connectivity in fronto-parietal circuits is related to regional gray matter volume and contributes to impairments in top-down attentional control. Show more

Keywords: Effective connectivity, prodromal Alzheimer's disease, regional gray matter volume, top down attentional control

DOI: 10.3233/JAD-2011-102154

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 309-321, 2011

Authors: Cao, Chuanhai | Wang, Li | Lin, Xiaoyang | Mamcarz, Malgorzata | Zhang, Chi | Bai, Ge | Nong, Jasson | Sussman, Sam | Arendash, Gary

Article Type: Research Article

Abstract: Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer's disease (AD). Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-β levels/deposition through suppression of both β- and γ-secretase. Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone. In both AβPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma …levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6. Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines. The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines. Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine's established ability to suppress Aβ production. We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD. Show more

Keywords: AD mice, Alzheimer's disease, caffeine, coffee, cognitive benefits, cytokines, GCSF

DOI: 10.3233/JAD-2011-110110

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 323-335, 2011

Authors: Yin, Gang | Li, Ling-Yun | Qu, Min | Luo, Hong-Bin | Wang, Jian-Zhi | Zhou, Xin-Wen

Article Type: Research Article

Abstract: Overproduction and accumulation of amyloid-β (Aβ) have been proposed to be an initiating factor of neuron loss in Alzheimer's disease (AD). AKT is a pivotal molecule in regulating neuronal survival, however, it is still not known whether upregulation of AKT can protect the cells from the Aβ-induced apoptosis. By using cell viability assay and flow cytometry, we demonstrated in the present study that overexpression of AKT could significantly attenuate the cell apoptosis induced by Aβ1-42 , whereas simultaneous inhibition of PI3 K, the immediate upstream stimulator of AKT, abolished the protective effect of AKT in HEK293 cells. Upregulation of AKT …restored the Aβ-induced alterations of the mitochondria-related Bcl-2 family members (including Bcl-xL, Bcl-w, Bad, and Bax) and suppressed the activation of caspase-3 and JNK. Our data suggest that upregulation of AKT could be a promising therapeutic strategy for arresting Aβ toxicity in AD patients. Show more

Keywords: Alzheimer's disease, AKT, amyloid-β, apoptosis, JNK

DOI: 10.3233/JAD-2011-110104

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 337-345, 2011

Authors: Derflinger, Sabine | Sorg, Christian | Gaser, Christian | Myers, Nicholas | Arsic, Milan | Kurz, Alexander | Zimmer, Claus | Wohlschläger, Afra | Mühlau, Mark

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), brain atrophy has been proposed to be left lateralized. Here, we reinvestigated the asymmetry and lateralization (i.e., asymmetry directed toward one hemisphere) of grey-matter (GM) distribution in 35 patients with AD, 24 patients with amnestic mild cognitive impairment (aMCI, a state of increased risk for AD), and 30 age-matched healthy controls (HC). We analyzed GM distribution by applying voxel-based morphometry (VBM) including analyses for asymmetry and lateralization. When comparing MCI with AD patients, VBM revealed GM loss in the entorhinal, temporoparietal, dorsofrontal, and occipital cortices as well as in the precuneus; when comparing HCs with MCI …patients, we found similar differences, which were less pronounced especially within the temporoparietal cortex and precuneus. Analyses of regional asymmetry and regional lateralization as well as global lateralization did not yield significant results. However, lobar asymmetry of the temporal, parietal, and occipital lobes increased from HC to AD. Moreover, in aMCI and AD patients, performance of language-based neuropsychological tests correlated with lateralization of GM loss to the left hemisphere. We conclude that, in principle, brain atrophy in AD is asymmetric rather than lateralized. At the individual level however, asymmetry contributes to cognitive deficits. Show more

Keywords: Alzheimer's disease, asymmetry, CERAD, lateralization, voxel-based morphometry

DOI: 10.3233/JAD-2011-110041

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 347-357, 2011

Authors: Wharton, Stephen B. | Brayne, Carol | Savva, George M. | Matthews, Fiona E. | Forster, Gill | Simpson, Julie | Lace, Gemma | Ince, Paul G. | on behalf of the Medical Research Council Cognitive Function and Aging Study

Article Type: Research Article

Abstract: We here describe the study-design major findings from the neuropathological component of the Medical Research Council Cognitive Function and Aging Study (MRC CFAS). MRC CFAS is a population-representative study of aging and health including more than 18000 participants at baseline. More than 500 brain donations were accrued to date and have been subjected to comprehensive pathological assessment. This resource enables a thorough epidemiological description of the neuropathology associated with dementia in the UK. Results to date reveal a high prevalence of mixed Alzheimer and vascular pathology, a significant population who die with dementia but with a more limited pathological burden …than is traditionally associated with dementia, and a group who die with a significant pathological burden yet remained cognitively intact until death. This dissociation between pathology and dementia increases with increasing age. Further studies have described the distribution and etiology of neurodegenerative disease in the population, and determined pathological correlates of cognitive impairment and dementia. Brain donation programs linked to epidemiological studies provide an invaluable resource for describing the pathological correlates of dementia in a way that is representative of the population, thereby identifying targets for and assessing the likely effect of therapeutic and preventive interventions. Show more

Keywords: Alzheimer's disease, cerebrovascular disease, epidemiology, dementia, Lewy bodies, longitudinal studies, neurofibrillary tangles

DOI: 10.3233/JAD-2011-091402

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 359-372, 2011

Authors: Ewers, Michael | Cheng, Xin | Zhong, Zhenyu | Nural, Hikmet F. | Walsh, Cathal | Meindl, Thomas | Teipel, Stefan J. | Buerger, Katharina | He, Ping | Shen, Yong | Hampel, Harald

Article Type: Research Article

Abstract: The enzyme β-secretase (BACE1) is essentially involved in the production of cerebral amyloidogenic pathology in Alzheimer's disease (AD). The measurement of BACE1 activity in cerebrospinal fluid (CSF) has been reported, which may render CSF measurement of BACE1 a potential biomarker candidate of AD. In order to investigate whether BACE1 protein activity is correlated with regional brain atrophy in AD, we investigated the association between CSF levels of BACE1 and MRI-assessed hippocampus volume in patients with AD (n = 30). An increase in CSF-BACE1 activity was associated with decreased left and right hippocampus volume corrected for global head volume in the …AD patients. Boot-strapped regression analysis showed that increased CSF levels of BACE1 activity were associated with increased CSF concentration of total tau but not amyloid-β1-42 in AD. White matter hyperintensities did not influence the results. BACE1 activity and protein levels were significantly increased in AD compared to 19 elderly healthy controls. Thus, the CSF biomarker candidate of BACE1 activity was associated with hippocampus atrophy in AD in a robust manner and may reflect neurotoxic amyloid-β-related processes. Show more

Keywords: BACE1, β-secretase, cerebrospinal fluid, hippocampus

DOI: 10.3233/JAD-2011-091153

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 373-381, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110042

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 383-384, 2011