Journal of Alzheimer's Disease - Volume 41, issue 1

Authors: Kapila, Ayush K. | Watts, Helena R. | Wang, Tianlong | Ma, Daqing

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a major social and clinical burden in the elderly, affecting 5% of people aged over 65 and 20% aged over 80. Despite improved management, a cure has not been found and hence analysis of predisposing factors to identify preventive strategies has become increasingly important. Surgery and anesthesia have been proposed to increase the incidence of post-operative cognitive decline (POCD) and AD. This is hypothesized to be the result of a malignant neuroinflammatory response and subsequent synaptic impairment in the elderly and susceptible individuals. As a result, strategies are being explored to prevent surgery and anesthesia induced …cognitive impairment. Whereas previously the diagnosis of AD was primarily dependent on clinical examination, biomarkers such as inflammatory cytokines, amyloid-β, and tau deposition in the cerebrospinal fluid have received increased attention. Nonetheless, AD is currently still treated symptomatically with acetylcholinesterase inhibitors and NMDA antagonists to improve cholinergic transmission and prevent glutamatergic excitotoxicity. Therapeutic success is, however, often not achieved, since these treatment methods do not address the ongoing neuroinflammatory processes and hence novel therapeutic and protective strategies are urgently needed. This review provides an insight into the current understanding of age-related cognitive impairment post-surgery and reflects on novel markers of AD pathogeneses exploring their use as targets for treatment. It gives a summary of recent efforts in preventing and treating POCD or AD with regards to the choice and depth of anesthesia, surgical strategy, and peri-operative medication, and discusses the mechanism of action and therapeutic prospects of novel agents. Show more

Keywords: Alzheimer's disease, anesthesia, cognitive decline, neuroinflammation, surgery

DOI: 10.3233/JAD-132258

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 1-13, 2014

Authors: Cohen-Mansfield, Jiska | Buckwalter, Kathleen | Beattie, Elizabeth | Rose, Karen | Neville, Christine | Kolanowski, Ann

Article Type: Review Article

Abstract: This paper challenges the assumptions underlying many reviews and offers alternative criteria for examining evidence for nonpharmacological interventions. We evaluated 27 reviews examining interventions for persons with dementia as they relate to the issues of selection based on randomized controlled trial (RCT) design. Reviews were described by type of intervention, level of cognitive function, and criteria for inclusion. Of the 27 reviews, 46% required RCTs for inclusion and most had stringent inclusion criteria. This resulted in poor utilization of the literature and low ecological validity. Eliminating most of the available data poses a critical problem to clinical and research development. …Studies meeting strict methodological criteria may not generalize to the greater population or may exclude sub-populations and interventions. Limitations of double-blind RCTs and potential design solutions are set forth based on appropriate populations, problems, interventions, and settings characteristics. Show more

Keywords: dementia, interventions, older persons, randomized controlled trials, research designs, review

DOI: 10.3233/JAD-132357

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 15-28, 2014

Authors: Bolognin, Silvia | Cozzi, Bruno | Zambenedetti, Pamela | Zatta, Paolo

Article Type: Review Article

Abstract: Metallothioneins (MT) are a family of proteins actively involved in metal detoxification and storage as well as in prevention of free-radical damage. Changes in the levels of MT have been described in a number of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, prion protein disease, Binswanger type of subcortical vascular dementia, and amyotrophic lateral sclerosis. This suggests that MT functions might be more complex and vast than what was initially thought. In this review, we summarize the current knowledge on the potential involvement of MT in the mentioned neurodegenerative diseases while also discussing the emerging evidence proposing MT modulation as …a feasible therapeutic approach. Enhancing repair mechanisms after neurological damage and/or protection against oxidative stress through a proper modulation of this family of protein might indeed represent an important avenue to cope neurodegeneration. Show more

Keywords: Brain development, metal ions, metallothioneins, neurodegenerative diseases

DOI: 10.3233/JAD-130290

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 29-42, 2014

Authors: de Oliveira, Jade | Moreira, Eduardo Luiz Gasnhar | dos Santos, Danúbia Bonfanti | Piermartiri, Tetsadê Camboim | Dutra, Rafael Cypriano | Pinton, Simone | Tasca, Carla Inês | Farina, Marcelo | Prediger, Rui Daniel Schröder | de Bem, Andreza Fabro

Article Type: Research Article

Abstract: Familial hypercholesterolemia is caused by inherited genetic abnormalities that directly or indirectly affect the function of the low-density lipoprotein (LDL) receptor. This condition is characterized by defective catabolism of LDL which results in increased plasma cholesterol concentrations and premature coronary artery disease. Nevertheless, there is increasing preclinical and clinical evidence indicating that familial hypercholesterolemia subjects show a particularly high incidence of mild cognitive impairment. Moreover, the LDL receptor (LDLr) has been implicated as the main central nervous system apolipoprotein E receptor that regulates amyloid deposition in distinct mouse models of β-amyloidosis. In this regard, herein we hypothesized that the lack …of LDLr would enhance the susceptibility to amyloid-β-(Aβ)-induced neurotoxicity in mice. Using the acute intracerebroventricular injection of aggregated Aβ1-40 peptide (400 pmol/mouse), a useful approach for the investigation of molecular mechanisms involved in Aβ toxicity, we observed oxidative stress, neuroinflammation, and neuronal membrane damage within the hippocampus of C57BL/6 wild-type mice, which were associated with spatial reference memory and working memory impairments. In addition, our data show that LDLr knockout (LDLr−/− ) mice, regardless of Aβ treatment, displayed memory deficits and increased blood-brain barrier permeability. Nonetheless, LDLr−/− mice treated with Aβ1-40 peptide presented increased acetylcholinesterase activity, astrogliosis, oxidative imbalance, and cell permeability within the hippocampus in comparison with Aβ1-40 -treated C57BL/6 wild-type mice. Overall, the present study shows that the lack of LDLr increases the susceptibility to Aβ-induced neurotoxicity in mice providing new evidence about the crosslink between familial hypercholesterolemia and cognitive impairment. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, hypercholesterolemia, LDL receptor, learning and memory, oxidative stress

DOI: 10.3233/JAD-132228

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 43-60, 2014

Authors: Ng, Tze Pin | Feng, Liang | Yap, Keng Bee | Lee, Tih Shih | Tan, Chay Hoon | Winblad, Bengt

Article Type: Research Article

Abstract: Evidence strongly supports the important role of insulin resistance in cognitive decline and dementia and suggests that insulin sensitizers may protect against cognitive decline in diabetic and pre-diabetic individuals. Inconclusive results have been reported in clinical trials of rosiglitazone, an insulin sensitizer that also increases cardiovascular mortality risks. No study has yet reported a protective cognitive effect of metformin, an insulin-sensitizing biguanide widely used in diabetic patients. We studied 365 older persons aged 55 and over in the population-based Singapore Longitudinal Aging Study with diabetes who were followed up over 4 years. The odds ratios (OR) of association of metformin …use (n = 204) versus non-use (n = 161) with cognitive impairment (Mini-Mental State Exam ≤ 23), and by duration: up to 6 years (n = 114) and more than 6 years (n = 90) were evaluated in cross-sectional and longitudinal multivariate analyses. Controlling for age, education, diabetes duration, fasting blood glucose, vascular and non-vascular risk factors, metformin use showed a significant inverse association with cognitive impairment in longitudinal analysis (OR = 0.49, 95% CI 0.25–0.95). Metformin use showed significant linear trends of association across duration of use in cross-sectional and longitudinal analyses (p = 0.018 and p = 0.002, respectively), with use for more than 6 years significantly associated with lowest risk of cognitive impairment in both cross-sectional analysis (OR = 0.30, 95% CI 0.11–0.80) and in longitudinal analysis (OR = 0.27, 95% CI 0.12–0.60). No significant interactive effects of metformin use with APOE-ε4, depression, or fasting glucose level were observed. Among individuals with diabetes, long-term treatment with metformin may reduce the risk of cognitive decline. Further studies should establish the role of hyperglycemia and insulin resistance, and the protective role of metformin in the risk of cognitive decline and dementia. Show more

Keywords: Cognition, dementia, diabetes, insulin resistance, metformin

DOI: 10.3233/JAD-131901

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 61-68, 2014

Authors: Teipel, Stefan J. | Grothe, Michel J. | Filippi, Massimo | Fellgiebel, Andreas | Dyrba, Martin | Frisoni, Giovanni B. | Meindl, Thomas | Bokde, Arun L.W. | Hampel, Harald | Klöppel, Stefan | Hauenstein, Karlheinz | the EDSD study group

Article Type: Research Article

Abstract: Diffusion tensor imaging (DTI) allows the simultaneous measurement of several diffusion indices that provide complementary information on the substrate of white matter alterations in neurodegenerative diseases. These indices include fractional anisotropy (FA) as measure of fiber tract integrity, and the mode of anisotropy (Mode) reflecting differences in the shape of the diffusion tensor. We used a multivariate approach based on joint independent component analysis of FA and Mode in a large sample of 138 subjects with Alzheimer's disease (AD) dementia, 37 subjects with cerebrospinal fluid biomarker positive mild cognitive impairment (MCI-AD), and 153 healthy elderly controls from the European DTI …Study on Dementia to comprehensively study alterations of microstructural white matter integrity in AD dementia and predementia AD. We found a parallel decrease of FA and Mode in intracortically projecting fiber tracts, and a parallel increase of FA and Mode in the corticospinal tract in AD patients compared to controls. Subjects with MCI-AD showed a similar, but spatially more restricted pattern of diffusion changes. Our findings suggest an early axonal degeneration in intracortical projecting fiber tracts in dementia and predementia stages of AD. An increase of Mode, parallel to an increase of FA, in the corticospinal tract suggests a more linear shape of diffusion due to loss of crossing fibers along relatively preserved cortico-petal and cortico-fugal fiber tracts in AD. Supporting this interpretation, we found three populations of fiber tracts, namely cortico-petal and cortico-fugal, commissural, and intrahemispherically projecting fiber tracts, in the peak area of parallel FA and Mode increase. Show more

Keywords: Crossing fibers, diffusion spectrum imaging, diffusion tensor imaging, early diagnosis, fractional anisotropy, mode of anisotropy, predementia Alzheimer's disease

DOI: 10.3233/JAD-131829

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 69-83, 2014

Authors: Song, Guoli | Zhang, Zhonghao | Wen, Lei | Chen, Chen | Shi, Qingxue | Zhang, Yu | Ni, Jiazuan | Liu, Qiong

Article Type: Research Article

Abstract: Disruption of the intracellular balance between free radicals and the antioxidant system is a prominent and early feature in the neuropathology of Alzheimer's disease (AD). Selenium, a vital trace element with known antioxidant potential, has been reported to provide neuroprotection through resisting oxidative damage but its therapeutic effect on AD remains to be investigated. The objective of our study was to investigate the potential of selenomethionine (Se-Met), an organic form of selenium, in the treatment of cognitive dysfunction and neuropathology of triple transgenic AD (3 × Tg-AD) mice. 3 × Tg-AD mice, which were four months old, were treated with …Se-Met for 3 months and demonstrated significant improvements in cognitive deficit along with an increased selenium level compared with the untreated control mice. Se-Met treatment significantly reduced the level of total tau and phosphorylated tau, mitigated the decrease of synaptic proteins including synaptophysin and postsynaptic density protein 95 in the hippocampus and cortex of the 3 × Tg-AD mice. Meanwhile, glial activation in AD mice was inhibited and the level of reduced glutathione was increased in the treated mice compared with control mice. Additionally, the expression and activity of glycogen synthase kinase 3β and protein phosphatase 2A, two important enzymes involved in tau phosphorylation, were markedly decreased and increased respectively by Se-Met treatment. Thus Se-Met improves cognitive deficit in a murine model of AD, which is associated with reduction in tau expression and hyperphosphorylation, amelioration of inflammation, and restoration of synaptic proteins and antioxidants. This study provides a novel therapeutic approach for the prevention of AD. Show more

Keywords: Alzheimer's disease, selenomethionine, tau, transgenic mouse model

DOI: 10.3233/JAD-131805

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 85-99, 2014

Authors: Haller, Sven | Montandon, Marie-Louise | Rodriguez, Cristelle | Moser, Dominik | Toma, Simona | Hofmeister, Jeremy | Sinanaj, Indrit | Lovblad, Karl-Olof | Giannakopoulos, Panteleimon

Article Type: Research Article

Abstract: Previous studies showed that acute caffeine administration enhances task-related brain activation in elderly individuals with preserved cognition. To explore the effects of this widely used agent on cognition and brain activation in early phases of cognitive decline, we performed a double-blinded, placebo-controlled functional magnetic resonance imaging (fMRI) study during an n-back working memory task in 17 individuals with mild cognitive impairment (MCI) compared to 17 age-matched healthy controls (HC). All individuals were regular caffeine consumers with an overnight abstinence and given 200 mg caffeine versus placebo tablets 30 minutes before testing. Analyses included assessment of task-related activation (general linear model), …functional connectivity (tensorial-independent component analysis, TICA), baseline perfusion (arterial spin labeling, ASL), grey matter density (voxel-based morphometry, VBM), and white matter microstructure (tract-based spatial statistics, TBSS). Acute caffeine administration induced a focal activation of the prefrontal areas in HC with a more diffuse and posteromedial activation pattern in MCI individuals. In MCI, TICA documented a significant caffeine-related enhancement in the prefrontal cortex, supplementary motor area, ventral premotor and parietal cortex as well as the basal ganglia and cerebellum. The absence of significant group differences in baseline ASL perfusion patterns supports a neuronal rather than a purely vascular origin of these differences. The VBM and TBSS analyses excluded potentially confounding differences in grey matter density and white matter microstructure between MCI and HC. The present findings suggest a posterior displacement of working memory-related brain activation patterns after caffeine administration in MCI that may represent a compensatory mechanism to counterbalance a frontal lobe dysfunction. Show more

Keywords: Blood oxygenation level dependent, caffeine, functional magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-132360

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 101-112, 2014

Authors: Vecchio, Fabrizio | Miraglia, Francesca | Marra, Camillo | Quaranta, Davide | Vita, Maria Gabriella | Bramanti, Placido | Rossini, Paolo Maria

Article Type: Research Article

Abstract: The aim of this study was to investigate the neuronal network characteristics in physiological and pathological brain aging. A database of 378 participants divided in three groups was analyzed: Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal elderly (Nold) subjects. Through EEG recordings, cortical sources were evaluated by sLORETA software, while graph theory parameters (Characteristic Path Length λ, Clustering coefficient γ, and small-world network σ) were computed to the undirected and weighted networks, obtained by the lagged linear coherence evaluated by eLORETA software. EEG cortical sources from spectral analysis showed significant differences in delta, theta, and alpha 1 bands. …Furthermore, the analysis of eLORETA cortical connectivity suggested that for the normalized Characteristic Path Length (λ) the pattern differences between normal cognition and dementia were observed in the theta band (MCI subjects are find similar to healthy subjects), while for the normalized Clustering coefficient (γ) a significant increment was found for AD group in delta, theta, and alpha 1 bands; finally, the small world (σ) parameter presented a significant interaction between AD and MCI groups showing a theta increase in MCI. The fact that AD patients respect the MCI subjects were significantly impaired in theta but not in alpha bands connectivity are in line with the hypothesis of an intermediate status of MCI between normal condition and overt dementia. Show more

Keywords: Alzheimer's disease, delta and alpha bands, EEG, functional connectivity, graph theory, mild cognitive impairment, sLORETA/eLORETA

DOI: 10.3233/JAD-132087

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 113-127, 2014

Authors: Hook, Gregory | Yu, Jin | Toneff, Thomas | Kindy, Mark | Hook, Vivian

Article Type: Research Article

Abstract: Pyroglutamate amyloid-β peptides (pGlu-Aβ) are particularly pernicious forms of amyloid-β peptides (Aβ) present in Alzheimer's disease (AD) brains. pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42) ) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42) . β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42) , but it is not yet known whether the β-secretase BACE1 or the alternative β-secretase cathepsin B (CatB) participate in the production of pGlu-Aβ. Therefore, this study examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform …695 and have the wild-type (wt) β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42) , flAβ(1-40/42) , and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. Treatment of AβPPLon mice with E64d, a cysteine protease inhibitor of CatB, also reduced brain pGlu-Aβ(3-42) , flAβ(1-40/42) , and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ(3-40) released from the activity-dependent, regulated secretory pathway. Moreover, CatB knockout and E64d treatment has been previously shown to improve memory deficits in the AβPPLon mice. These data illustrate the role of CatB in producing pGlu-Aβ and flAβ that participate as key factors in the development of AD. The advantages of CatB inhibitors, especially E64d and its derivatives, as alternatives to BACE1 inhibitors in treating AD patients are discussed. Show more

Keywords: Pyroglutamate amyloid-β, cathepsin B, BACE1, AβPP, protease, transgenic AD mice, inhibitor, cysteine protease, secretion

DOI: 10.3233/JAD-131370

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 129-149, 2014