Pages 1-13
Review
Ayush K. Kapila, Helena R. Watts, Tianlong Wang, Daqing Ma
The Impact of Surgery and Anesthesia on Post-Operative Cognitive Decline and Alzheimer’s Disease Development: Biomarkers and Preventive Strategies
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.
Pages 15-28
Review
Jiska Cohen-Mansfield, Kathleen Buckwalter, Elizabeth Beattie, Karen Rose, Christine Neville, Ann Kolanowski
Expanded Review Criteria: The Case of Nonpharmacological Interventions in Dementia
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 corresponding 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.
Pages 29-42
Review
Silvia Bolognin, Bruno Cozzi, Pamela Zambenedetti, Paolo Zatta
Metallothioneins and the Central Nervous System: From a Deregulation in Neurodegenerative Diseases to the Development of New Therapeutic Approaches
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.
Pages 43-60
Jade de Oliveira, Eduardo Luiz Gasnhar Moreira, Danúbia Bonfanti dos Santos, Tetsadê Camboim Piermartiri, Rafael Cypriano Dutra, Simone Pinton, Carla Inês Tasca, Marcelo Farina, Rui Daniel Schröder Prediger, Andreza Fabro de Bem
Increased Susceptibility to Amyloid-β-Induced Neurotoxicity in Mice Lacking the Low-Density Lipoprotein Receptor
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.
Pages 61-68
Tze Pin Ng, Liang Feng, Keng Bee Yap, Tih Shih Lee, Chay Hoon Tan, Bengt Winblad
Long-Term Metformin Usage and Cognitive Function among Older Adults with Diabetes
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.
Pages 69-83
Stefan J. Teipel, Michel J. Grothe, Massimo Filippi, Andreas Fellgiebel, Martin Dyrba, Giovanni B. Frisoni, Thomas Meindl, Arun L.W. Bokde, Harald Hampel, Stefan Klöppel, Karlheinz Hauenstein, and the EDSD study group (Handling Associate Editor: Marco Bozzali)
Fractional Anisotropy Changes in Alzheimer’s Disease Depend on the Underlying Fiber Tract Architecture: A Multiparametric DTI Study using Joint Independent Component Analysis
Abstract: Diffusion tensor imaging (DTI) allows the simultaneously 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.
Pages 85-99
Guoli Song, Zhonghao Zhang, Lei Wen, Chen Chen, Qingxue Shi, Yu Zhang, Jiazuan Ni, Qiong Liu
Selenomethionine Ameliorates Cognitive Decline, Reduces Tau Hyperphosphorylation, and Reverses Synaptic Deficit in the Triple Transgenic Mouse Model of Alzheimer’s Disease
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.
Pages 101-112
Sven Haller, Marie-Louise Montandon, Cristelle Rodriguez, Dominik Moser, Simona Toma, Jeremy Hofmeister, Indrit Sinanaj, Karl-Olof Lovblad, Panteleimon Giannakopoulos
Acute Caffeine Administration Effect on Brain Activation Patterns in Mild Cognitive Impairment
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.
Pages 113-127
Fabrizio Vecchio, Francesca Miraglia, Camillo Marra, Davide Quaranta, Maria Gabriella Vita, Placido Bramanti, Paolo Maria Rossini
Human Brain Networks in Cognitive Decline: A Graph Theoretical Analysis of Cortical Connectivity from EEG Data
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.
Pages 129-149
Gregory Hook, Jin Yu, Thomas Toneff, Mark Kindy, Vivian Hook
Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer’s Disease Therapeutic
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 (flAβ1-40/42) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ3-40/42. β-secretase cleavage of amyloid-β protein precursor (AβPP) produces flAβ1-40/42, 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 β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ3-40/42, flAβ1-40/42, 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-Aβ3-42, flAβ1-40/42, and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ3-40 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.
Pages 151-161
Mario Siervo*, Stephanie L. Harrison*, Carol Jagger, Louise Robinson, Blossom C.M. Stephan (Handling Associate Editor: Vincenza Frisardi) *These authors contributed equally to this manuscript.
Metabolic Syndrome and Longitudinal Changes in Cognitive Function: A Systematic Review and Meta-Analysis
Abstract: Background: Metabolic syndrome (MetS) is associated with an increased risk of coronary heart diseases and stroke. Results on the association of MetS with dementia and cognitive decline have been inconsistent. Objective: The aim of this study was to examine the association between MetS and longitudinal changes in cognitive function. Methods: Medline, EMBASE, and Scopus databases were searched from inception to June 2013. Longitudinal cohort studies that reported on the association between MetS and change in cognitive function (over two or more time points), were included. Results: Random-effects models were used to assess the pooled effect sizes of longitudinal changes in cognitive function associated with MetS. Thirteen studies were included. The total sample size was 19,522 subjects. Follow up duration ranged from 1 to 16 years. In the total sample, a small association of MetS with cognitive decline was observed (SDM 0.06, 95%CI: -0.001, 0.12; p=0.05). When age-stratified, a marginal significant association between MetS and cognitive decline was observed in the younger old group (≤70 years; SDM=0.09, 95%CI: -0.003, 0.19; p=0.05) but not in the older group (>70 years; SDM=0.03, 95%CI: -0.05, 0.11; p=0.48). The meta-regression showed that duration of follow up was not associated with changes in cognitive estimates (β=0.005; p=0.30). Conclusions: Age appears to modify the association between MetS and cognitive decline. These results emphasize the importance of age-stratified risk prediction models of dementia in subjects with chronic metabolic disorders.
Pages 163-167
Commentary
Vincenza Frisardi
Impact of Metabolic Syndrome on Cognitive Decline in Older Age: Protective or Harmful, Where is the Pitfall?
Abstract: Metabolic syndrome (MetS) has been found to be a risk factor for dementia, mild cognitive impairment, and its associated states. However, a definitive conclusion cannot be drawn from the available data. Discrepancies between the results are due to several factors, e.g., study design, heterogeneity of the population enrolled, reliability and sensitivity of detection tools for cognitive changes, cut-offs and criteria used to diagnose MetS, the outcome measures considered, MetS duration before the onset of cognitive decline, and also the analytical approach performed. Recently, a systematic review and meta-analysis including 19,522 subjects aged 59-85 years from 13 longitudinal population-based studies has been conducted to examine the association between MetS and longitudinal changes in cognitive functions. While a marginal significant association was found in the younger old group, this relationship was not observed in older group (> 70 years). It is not yet clear how age can influence this relationship. Apart from methodological issues, other biological factors are likely involved in this direction reversal.
Pages 169-178
Geon Ha Kim, Jung-Eun Kim, Kyoung-Gyu Choi, Soo Mee Lim, Jong-Min Lee, Duk L. Na, Jee-Hyang Jeong
T1-weighted Axial Visual Rating Scale for an Assessment of Medial Temporal Atrophy in Alzheimer’s Disease
Abstract: Background: The most-widely used visual rating scale (VRS) for medial temporal atrophy is the T1-weighted (T1W) coronal VRS developed by Scheltens et al. However, it is often difficult to use the T1W-coronal VRS in cases with limitations in obtaining T1W-coronal images. To overcome this issue, we modified the T1W-coronal VRS onto the axial plane. Objective: The purposes of this study were to validate our T1W-axial VRS by examining its compatibility with the original T1W-coronal VRS and by investigating the correlation with the cognitive functions and hippocampal volumes. Methods: Participants were 50 patients with Alzheimer’s disease dementia and 30 elderly with normal cognition. We transposed each component of the T1W-coronal VRS onto T1W-axial images (i.e., the largest height of the hippocampal formation into the width of the medial temporal lobe). The compatibility of T1W-axial VRS with T1W-coronal one was determined using the kappa value. The correlations of T1W-axial VRS with cognitive performance or the hippocampal volumes were analyzed with age, gender, and education as covariates. Results: The kappa value between the T1W-axial and T1W-coronal VRS was 0.772 (p < 0.045). The T1W-axial VRS showed a significant correlation with the scores of cognitive functions, including verbal memory tests (-0.601, p < 0.001 for the left). Furthermore, the T1W-axial VRS also correlated well with hippocampal volumes (-0.576, p < 0.001). Conclusions: The T1W-axial VRS showed good agreement with T1W-coronal VRS and correlated well with cognitive functions as well as hippocampal volumes, which suggests that the T1-axial VRS may replace the original T1W-coronal one.
Pages 179-192
Christopher J. Harris, Kellen Voss, Charles Murchison, Martina Ralle, Kate Frahler, Raina Carter, Allison Rhoads, Betty Lind, Emily Robinson, Joseph F. Quinn (Handling Associate Editor: Ashley Bush)
Oral Zinc Reduces Amyloid Burden in Tg2576 Mice
Abstract: The aggregation of amyloid-β in Alzheimer’s disease can be affected by free transition metals such as copper and zinc in the brain. Addition of copper and zinc with amyloid acts to increase aggregation and copper additionally promotes the formation of reactive oxygen species. We propose that reduction of brain copper by blocking uptake of copper from the diet is a viable strategy to regulate the formation of insoluble amyloid-β in the brain of Tg2576 mice. Mice were treated with regimens of zinc acetate, which acts with metallothionein to block copper uptake in the gut, at various times along their lifespan to model prevention and treatment paradigms. We found that the mice tolerated zinc acetate well over the six month course of study. While we did not observe significant changes in cognition and behavior, there was a reduction in insoluble amyloid-β in the brain. This observation coincided with a reduction in brain copper and interestingly no change in brain zinc. Our findings show that blocking copper uptake from the diet can redistribute copper from the brain and reduce amyloid-β aggregation.
Pages 193-202
Noora M. Scheinin, Kristina Wikman, Antti Jula, Markus Perola, Tero Vahlberg, Johanna Rokka, Kjell Någren, Matti Viitanen, Juha O. Rinne
Cortical 11C-PIB Uptake is Associated with Age, APOE Genotype, and Gender in “Healthy Aging”
Abstract: Background/Objective: Our aim was to elucidate factors that contribute to amyloid-β (Aβ) accumulation in the brains of the seemingly healthy elderly population, and whether there is interplay between those factors. Methods: We conducted a cross-sectional positron emission tomography (PET) study with the amyloid tracer 11C-PIB, in 64 cognitively healthy subjects (54-89 years). In addition to PET, magnetic resonance imaging, neuropsychological testing, and APOE genotyping was performed. The results were assessed with a statistical general linear model as well as with Statistical Parametric Mapping (SPM). Results: The effects of age (p<0.001), APOE ε4 carrier status (p=0.003), and gender (p=0.001) on composite cortical 11C-PIB uptake were all significant. The effect of educational level was non-significant (p=0.37). No significant interactions were found between any of the factors. Cortical 11C-PIB uptake increased, on the average, by 0.015 cortex/cerebellar cortical ratio unit, with every year of age. APOE ε4 positive subjects exhibited higher cortical 11C-PIB uptake than APOE ε4 negative subjects (unadjusted means 1.49±0.34 versus 1.29±0.26) and males had higher uptake than females (1.49±0.39 versus 1.29±0.22), irrespective of age. The results of the voxel-based (SPM) analysis were similar. In addition, SPM analysis showed that lower CERAD score was associated with higher 11C-PIB uptake in the frontal cortex. Conclusions: Age and APOE ε4 genotype were associated with higher 11C-PIB uptake. In this sample of cognitively healthy elderly individuals, men exhibited higher 11C-PIB uptake than women. Possible gender differences in Aβ accumulation have not been addressed in detail in previous studies, and deeper evaluation in the future is warranted.
Pages 203-211
Eman Al-khatee*, Ebaa Al-zayadneh, Osama Al-dalahmah, Zeinab Alawadi, Faisal khatib, Randa Naffa, Yanal Shafagoj* *These authors contributed equally to this manuscript.
Relation between Copper, Lipid Profile, and Cognition in Elderly Jordanians
Abstract: The purpose of the current study was to examine the association of serum copper and lipid concentrations with changes in cognitive function in elderly Jordanian individuals. The study population consisted of two groups: 52 dementia patients and 50 control subjects. All individuals were screened using the Mini-Mental State Examination and Clock Drawing Test. Serum copper and lipid profile were also assessed. Results were statistically evaluated at p < 0.05 level of significance. The dementia group had 10.1% higher copper level than control subjects that was not statistically significant. No significant differences could be found between the two groups in lipid profile levels. There was no significant correlation between serum copper, lipid profile, and cognitive decline in elderly Jordanians. Demographic variables indicated that educational level less than 12 years and illiterate demonstrated a 3.29 fold (p=0.026) and 6.29 fold (p=0.002) increase in risk of developing dementia, respectively. Coffee intake demonstrated a protective effect against cognitive decline with 6.25 fold lower risk with increased coffee intake.
Pages 213-221
Juan Pablo Romero, Julián Benito-León, Elan D. Louis, Félix Bermejo Pareja
Under Reporting of Dementia Deaths on Death Certificates: A Systematic Review of Population-based Cohort Studies
Abstract: The purpose of this review is to assess the extent to which dementia is omitted as a cause of death from the death certificates of patients with dementia. A systematic literature search was performed to identify population-based cohort studies in which all participants were examined or screened for symptoms of dementia with a validated instrument followed by confirmation of any suspected cases with a clinical examination (two-phase investigation). Data were extracted in a standardized manner and assessed through the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. Seven studies met the selection criteria. These were from the Americas (5 articles: 2 from Canada, 2 from the US, and 1 from Brazil) and Europe (2 articles: 1 from the UK and 1 from Spain). Each met at least 83% of the STROBE criteria. The reporting of dementia on death certificates was poor in these 7 studies, ranging from 7.2%-34%. Respiratory or circulatory-related problems were the most frequently reported causes of death among people who were demented but who were not reported as demented on death certificates. The use of death certificates for studying dementia grossly underestimates the occurrence of dementia in the population. The poor reporting of dementia on these certificates suggests a lack of awareness of the importance of dementia as a cause of death among medical personnel. There is an urgent need to provide better education on the importance of codification of dementia on death certificates in order to minimize errors in epidemiological studies on dementia.
Pages 223-232
María Lodeiro, Clara Ibáñez, Alejandro Cifuentes, Carolina Simó, Ángel Cedazo-Mínguez
Decreased Cerebrospinal Fluid Levels of L-Carnitine in Non-Apolipoprotein E4 Carriers at Early Stages of Alzheimer’s Disease
Abstract: Increasing evidence suggest that Alzheimer’s disease (AD) is a heterogeneous disorder that includes several subtypes with different etiology and progression. Cerebrospinal fluid (CSF) is being used to find new biomarkers reflecting the complexity of the pathological pathways within this disease. We used CSF and clinical data from patients to investigate the status of asymmetric dimethyl–L-arginine, creatine, suberylglycine, and L-carnitine along AD progression. These molecules play important roles in mitochondrial function and dysfunction in mitochondrial metabolism involved in AD pathology. We found that non-APOE4 carriers show lower levels of L-carnitine in CSF early in AD. L-carnitine levels correlate with amyloid-β (Aβ)42 levels and Mini-Mental State Examination score, but do not add to the specificity or sensitivity of the classical AD CSF biomarkers, Aβ42, phospho-tau, and total-tau. Our results suggest APOE genotype-dependent differences in L-carnitine synthesis or metabolism along AD, and insinuate that L-carnitine treatments would be more beneficial for AD patients not carrying the APOE4 isoform.
Pages 233-241
Minho Moon, Moon-Yong Cha, Inhee Mook-Jung
Impaired Hippocampal Neurogenesis and its Enhancement with Ghrelin in 5XFAD Mice
Abstract: Alzheimer’s disease (AD) is an age-related neurological disorder characterized by the deposition of amyloid-β (Aβ), cognitive deficits, and neuronal loss. The decline in neurogenic capacity could participate in neuronal vulnerability and contribute to memory impairment in AD. In our longitudinal study with AD model mice (5XFAD mice), we found that the number of doublecortin (neurogenesis marker)-positive cells in 5XFAD mice was significantly decreased compared to wild-type littermate mice. Using Aβ immunostaining with 4G8 antibody, we observed that impairment in neurogenesis might be associated with the deposits of amyloid plaques. To investigate the effect of the neurogenic hormone ghrelin on defective neurogenesis in the AD brain, 5XFAD mice were administered peripherally with ghrelin. We found that treatment with ghrelin increased the number of doublecortin-stained cells in the hippocampus of 5XFAD mice. In 5XFAD mice treated with ghrelin, the 4G8-positive area was not significantly different from the saline-treated 5XFAD mice. Together, these findings suggest that hippocampal neurogenesis is impaired in 5XFAD mice and that treatment with ghrelin successfully rescued the abnormality of neurogenesis in 5XFAD mice without affecting Aβ pathology.
Pages 243-260
Yun-Zhou Yu, Wen-Bin Wang, Ao Chen, Qing Chang, Si Liu, Meng Zhao, Shuang Wang, Wei-Yi Qiu, Xiao-Bin Pang, Qing Xu, Zhi-Wei Sun
Strikingly Reduced Amyloid Burden and Improved Behavioral Performance in Alzheimer’s Disease Mice Immunized with Recombinant Chimeric Vaccines by Hexavalent Foldable Aβ1-15 Fused to Toxin-Derived Carrier Proteins
Abstract: Targeting on the amyloid-β (Aβ) is a promising immunotherapeutic strategy for Alzheimer’s disease (AD). However, Aβ1-15 sequence alone induces low antibody response and poor protection against AD. We describe here the immunological characterization and protective efficacy of several recombinant chimeric vaccines with hexavalent foldable Aβ1-15 (6Aβ15) fused to PADRE or toxin-derived carrier proteins. Immunization with these chimeric antigens generated robust Th2 immune responses with high anti-Aβ42 antibody titers in different mice, which recognized neurotoxic Aβ42 oligomers, but did not stimulate Aβ42-specific T cell responses. These 6Aβ15 chimeric vaccines markedly reduced Aβ pathology and prevented development of behavioral deficits in immunized older AD mice. Importantly, toxin-derived carrier proteins as molecular adjuvants of chimeric vaccines could substantially boost immune responses and overcome Aβ- and old age-associated hypo-responsiveness, and elicit long-term Aβ-specific antibody response, which in turn inhibited Aβ-mediated pathology and improved acquisition and retention of spatial memory in immunized AD mice. These data indicate that toxin fragments as molecular adjuvants are promising new tools for the rational design and development of prototype chimeric vaccines for AD and this type of chimeric vaccine design has the added advantage of overcoming hypo-responsiveness in elderly AD patients with pre-existing memory Th cells from tetanus toxin.
Pages 261-271
Marcel G.M. Olde Rikkert, Frans R. Verhey, John W.C. Sijben, Femke H. Bouwman, Paul L.J. Dautzenberg, Mirian Lansink, Walther M.W. Sipers, Dieneke Z.B. van Asselt, Anneke M.J. van Hees, Martijn Stevens, Bruno Vellas, Philip Scheltens (Handling Associate Editor: Deborah Gustafson)
Differences in Nutritional Status between very Mild Alzheimer’s Disease Patients and Healthy Controls
Abstract: Background: Studies on the systemic availability of nutrients and nutritional status in Alzheimer’s disease (AD) are widely available, but the majority included patients in a moderate stage of AD. Objective: This study compares the nutritional status between mild AD outpatients and healthy controls. Methods: A subgroup of Dutch drug-naïve patients with mild AD (Mini-Mental State Examination (MMSE)≥20) from the Souvenir II randomized controlled study (NTR1975) and a group of Dutch healthy controls were included. Nutritional status was assessed by measuring levels of several nutrients, conducting the Mini Nutritional Assessment (MNA®) questionnaire and through anthropometric measures. Results: In total, data of 93 healthy cognitively intact controls (MMSE 29.0 [23.0-30.0]) and 79 very mild AD patients (MMSE=25.0 [20.0-30.0]) were included. Plasma selenium (p<0.001) and uridine (p=0.046) levels were significantly lower in AD patients, with a similar trend for plasma vitamin D (p=0.094) levels. In addition, the fatty acid profile in erythrocyte membranes was different between groups for several fatty acids. Mean MNA screening score was significantly lower in AD patients (p=0.008), but not indicative of malnutrition risk. No significant differences were observed for other micronutrient or anthropometric parameters. Conclusion: In non-malnourished patients with very mild AD, lower levels of some micronutrients, a different fatty acid profile in erythrocyte membranes and a slightly but significantly lower MNA screening score were observed. This suggests that subtle differences in nutrient status are present already in a very early stage of AD and in the absence of protein/energy malnutrition.
Pages 273-288
Marta Tajes, Abel Eraso-Pichot, Fanny Rubio-Moscardó, Biuse Guivernau, Eva Ramos-Fernández, Mònica Bosch-Morató, Francesc Xavier Guix, Jordi Clarimón, Gian Pietro Miscione, Mercé Boada, Gabriel Gil-Gómez, Toshiharu Suzuki, Henrik Molina, Jordi Villà-Freixa, Rubén Vicente, Francisco J. Muñoz
Methylglyoxal Produced by Amyloid-β Peptide-Induced Nitrotyrosination of Triosephosphate Isomerase Triggers Neuronal Death in Alzheimer’s Disease
Abstract: Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer’s disease (AD). One of the most strongly nitrotyrosinated proteins in AD, the triosephosphate isomerase (TPI) enzyme, regulates glycolytic flow, which decreases its efficiency. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center.
Pages 289-300
Elisa Evangelisti, Mariagioia Zampagni, Roberta Cascella, Matteo Becatti, Claudia Fiorillo, Anna Caselli, Silvia Bagnoli, Benedetta Nacmias, Cristina Cecchi
Plasma Membrane Injury Depends on Bilayer Lipid Composition in Alzheimer’s Disease
Abstract: Increasing evidence indicates that interaction of amyloid-β peptide (Aβ) with the cell membrane is a primary step in Alzheimer’s disease (AD) neurotoxicity. In particular, it has been demonstrated that lipid rafts are key sites of Aβ production, aggregation, and interaction with the cell membrane. In this study we show that Aβ42 oligomers are recruited to lipid rafts, leading to plasma membrane perturbation and Ca2+ dyshomeostasis in primary fibroblasts from familial AD patients bearing APPVal717Ile, PS-1Leu392Val, or PS-1Met146Leu gene mutations. In contrast, a moderate increase in membrane cholesterol content precluded the interaction of Aβ42 oligomers with the plasma membrane and resulting cell damage. Moreover, the recruitment of amyloid assemblies to lipid raft domains of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper increase in intracellular Ca2+ levels and plasma membrane permeabilization. Our findings suggest a protective role for raft cholesterol against amyloid toxicity in AD.
Pages 301-311
Ruth Alonso*, Diana Pisa*, Ana Isabel Marina, Esperanza Morato, Alberto Rábano, Luis Carrasco *These authors contributed equally to this work.
Fungal Infection in Patients with Alzheimer’s Disease
Abstract: Alzheimer’s disease is a progressive neurodegenerative disorder that leads to dementia mainly among the elderly. This disease is characterized by the presence in the brain of amyloid plaques and neurofibrillary tangles that provoke neuronal cell death, vascular dysfunction, and inflammatory processes. In the present work, we have analyzed the existence of fungal infection in Alzheimer’s disease patients. A proteomic analysis provides compelling evidence for the existence of fungal proteins in brain samples from Alzheimer’s disease patients. Furthermore, PCR analysis reveals a variety of fungal species in these samples, dependent on the patient and the tissue tested. DNA sequencing demonstrated that several fungal species can be found in brain samples. Together, these results show that fungal macromolecules can be detected in brain from Alzheimer’s disease patients. To our knowledge these findings represent the first evidence that fungal infection is detectable in brain samples from Alzheimer’s disease patients. The possibility that this may represent a risk factor or may contribute to the etiological cause of Alzheimer’s disease is discussed.
Pages 313-327
Spotlight
Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Niels Prins, Afina W. Lemstra, Femke H. Bouwman, Charlotte E. Teunissen, Bart N.M. van Berckel, Cornelis J. Stam, Frederik Barkhof, Pieter Jelle Visser, Evan van Egmond, Philip Scheltens
Optimizing Patient Care and Research: The Amsterdam Dementia Cohort
Abstract: Since its opening in 2000, patient care and research go hand in hand at the Alzheimer center of the VU University Medical Center, both organized in such a way that they mutually strengthen each other. Our mission is to give patients a voice by lifting the stigma on dementia, to find new diagnostic and treatment strategies, and, ultimately, to cure diseases that cause dementia. Our healthcare pathway is uniquely designed to accommodate all necessary investigations for the diagnostic work-up of dementia in one day (one-stop shop). A second unique feature is that research has been fully integrated in the healthcare pathway. The resulting Amsterdam Dementia Cohort now includes over 4000 patients, and for the majority of these, we have MRI, EEG, blood (serum, plasma), DNA, and CSF available. The Amsterdam Dementia Cohort forms the basis of much of our research, which focuses on four major research lines: 1) variability in manifestation, 2) early diagnosis, 3) vascular factors, and 4) interventions. By answering research questions closely related to clinical practice, the results of our research can be looped back to improve clinical work-up for our patients.
