Pages 1-17
Review
Charles T. Ambrose (Handling Associate Editor: Jack de la Torre)
A Therapeutic Approach for Senile Dementias: Neuroangiogenesis
Abstract: Alzheimer’s disease (AD) and related senile dementias (SDs) represent a growing medical and economic crisis in this country. Apart from cautioning persons about risk factors, no practical, effective therapy is currently available. Much of the recent research in AD has been based on the amyloid cascade theory. Another approach assumes a vascular basis for SDs. This paper presents evidence from a score of studies that cerebral capillary density (CCD) declines during old age in animals and people as well as in AD. Neuroangiogenic (NAG) factors initiate and maintain capillaries in the brain. Thus a waning level of these factors and the ensuing declining CCD would lead to local areas of reduced oxygen and glucose and result in impaired synaptic and neuronal function. The NAG hypothesis developed here proposes that the age-linked decline in CCD is a terminal condition in SDs, including many cases of AD. This age-linked decline is independent of any other of the various pathologies proposed as causing AD and listed in Table 1. Waning NAG factors would render the SDs a deficiency condition, somewhat like falling androgen levels in aging males. A logical corollary of this hypothesis is that chronic replacement therapy with recombinant forms of NAG factors may arrest the age-linked decline in CCD and prevent further loss of memory and mental deterioration. A transnasal route of therapy seems the most practical one for general use in the large aging populations.
Pages 19-22
Short Communication
Noga Oren*, Galit Yogev-Seligmann*, Elissa Ash, Talma Hendler, Nir Giladi, Yulia Lerner (Handling Associate Editor: Amos Korczyn) *These authors contributed equally to this work.
The Montreal Cognitive Assessment in Cognitively-intact Elderly: a Case for Age-adjusted Cutoffs
Abstract: The Montreal Cognitive Assessment (MoCA) is a widely used screening test for evaluation of mild cognitive impairment, with a single cutoff for all ages. We examined whether it is associated with age in a sample of cognitively-intact elderly (CIE). The average MoCA score was negatively correlated with age and was significantly higher for younger than older CIE. Additionally, 42% of the older elderly fell below the proposed mild cognitive impairment cutoff score, although all subjects were CIE. Thus, cognitive abilities captured by the MoCA test decrease with age, even in CIE. Therefore, cutoff scores by age for the MoCA are needed.
Pages 23-27
Short Communication
Apostolos Safouris, Anne-Sophie Hambye, Claudine Sculier, Sokratis G. Papageorgiou, Vasdekis N. Spyros, Marie-Dominique Gazagnes, Georgios Tsivgoulis
Chronic Brain Hypoperfusion due to Multi-Vessel Extracranial Atherosclerotic Disease: A Potentially Reversible Cause of Cognitive Impairment
Abstract: A 62-year-old patient presented with persistent cognitive deficits 3 months after a right temporal ischemic stroke due to ipsilateral carotid occlusion. Work-up disclosed hemodynamically significant contralateral carotid artery stenosis and left subclavian steal phenomenon. Brain SPECT imaging revealed bihemispheric chronic brain hypoperfusion that substantially improved on repeat imaging when the subclavian steal was temporarily diminished by inflating a cuff around the left arm. Carotid endarterectomy of the asymptomatic carotid stenosis substantially ameliorated bihemispheric brain perfusion and reversed cognitive impairment. This case highlights that multi-vessel, extracranial atherosclerotic disease may cause chronic diffuse brain hypoperfusion that can be associated with cognitive impairment.
Pages 29-35
Jian-Guo Li, Domenico Praticò (Handling Associate Editor: Patrizia Mecocci)
High Levels of Homocysteine Results in Cerebral Amyloid Angiopathy in Mice
Abstract: High levels of homocysteine is a risk factor for developing Alzheimer’s disease (AD), and the effect that this amino acid has on amyloid-β (Aβ) protein precursor metabolism is considered one of the potential mechanism(s) involved in this effect. However, despite consistent literature indicating that this condition results in brain parenchyma amyloidosis, no data are available on whether it may also influence the amount of Aβ deposited in the vasculature. To test this hypothesis, we implemented a model of diet-inducing high homocysteinemia in AD transgenic mice, 3xTg, and assessed them for the development of cerebral amyloid angiopathy (CAA). Compared with controls, mice with high homocysteine showed a significant increase in the amount of Aβ deposited in the brain vasculature, which was not associated with histological evidence of microhemorrhage occurrence. Mice with high homocysteine had a significant reduction in steady state level of the apolipoprotein E, which is a main Aβ chaperon protein, but no changes in its receptor, the low-density-lipoprotein-receptor-1. Our data demonstrate that a diet-induced high homocysteine level favors the development of CAA via a reduction of Aβ clearance and transport within the brain. Therapeutic approaches aimed at restoring brain apolipoprotein E levels should be considered in individuals carrying this environmental risk factor in order to reduce the incidence of homocysteine-dependent CAA.
Pages 37-45
Ram J. Bishnoi, Raymond F. Palmer, Donald R. Royall
Vitamin D Binding Protein as a Serum Biomarker of Alzheimer’s Disease
Abstract: Vitamin D binding protein (VDBP), a multifunctional protein, has been found to be elevated in the cerebrospinal fluid (CSF) of neurodegenerative disorder cases, implicating it in the pathogenesis of Alzheimer's disease (AD). However, the contribution of VDBP to AD has not been fully explored. We used a Multiple Indicators Multiple Causes (MIMIC) approach to examine the relationship between serum VDBP levels and cognitive performance in a well characterized AD cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used a latent dementia phenotype (d), which has been validated in several prior studies using this dataset. We found that serum VDBP levels are significantly positively associated with d scores, which in turn are inversely related to cognitive performance. This suggests that d mediates the adverse effects of serum VDB on cognition and therefore that its effects are specifically dementing. d scores are also specifically related to default mode network (DMN) structure. VDBP acts as an amyloid-β (Aβ) scavenger, and Aβ deposition in the DMN is seen in the pre-clinical stages of AD. We speculate then that serum effects of VDBP are mediated through changes in DMN structure or function, most probably via Aβ. Aβ affects the DMN early in the course of AD. Therefore, raised serum VDBP levels may be a useful indicator of future dementia and/or dementia conversion. This might be confirmed through longitudinal analysis of TARCC data.
Pages 47-56
Virginia Pérez-Grijalba, Pedro Pesini, José Antonio Allué, Leticia Sarasa, María Montañés, Ana-María Lacosta, Diego Casabona, Itziar San-José, Mercè Boada, Lluis Tárraga, Agustín Ruiz, Manuel Sarasa
Aβ1-17 is a Major Amyloid-β Fragment Isoform in Cerebrospinal Fluid and Blood with Possible Diagnostic Value in Alzheimer’s Disease
Abstract: This work was prompted by the finding that Aβ1-17 (Aβ17) appeared to be the second-most abundant cerebrospinal fluid (CSF) Aβ fragment, after Aβ40. We developed an ELISA to quantify levels of Aβ17 directly accessible in plasma (DA17), recovered from the proteomic plasma matrix (RP17) and associated with the cellular pellet (CP17) that remained after plasma collection. Then, we used a sample of 19 healthy control (HC), 27 mild cognitive impairment (MCI), and 17 mild Alzheimer’s disease (AD) patients to explore the association of the diagnostic groups with those direct markers, their ratios or the ratios with their Aβ40 or Aβ42 counterparts. After dichotomization (d) for the median of the sample population, logistic regression analysis showed that in the AD versus HC subgroup, subjects with a dDA/CP17 higher than the median had a significantly greater risk of being AD than those with marker levels equal to or below the median (odds ratio OR; 95% confidence interval; 17.21; 1.42-208.81). Subjects with dRP17/42 below the median had an increased likelihood of being MCI (20.00; 1.17-333.33) or AD (40.00; 1.87-1000) versus being HC, than those with dRP17/42 higher than the median. Although the confidence intervals are wide, these findings suggest that assessment of Aβ17 may increase the diagnostic performance of blood-based Aβ tests which might be developed into minimally invasive first-step screening tests for people with increased risk for AD.
Pages 57-65
Alex C. Hradek, Hyun-Pil Lee, Sandra L. Siedlak, Sandy L. Torres, Wooyoung Jung, Ashley H. Han, Hyoung-gon Lee
Distinct Chronology of Neuronal Cell Cycle Re-Entry and Tau Pathology in the 3xTg-AD Mouse Model and Alzheimer’s Disease Patients
Abstract: Cell cycle re-entry in Alzheimer’s disease (AD) has emerged as an important pathological mechanism in the progression of the disease. This appearance of cell cycle related proteins has been linked to tau pathology in AD, but the causal and temporal relationship between the two is not completely clear. In this study, we found that hyperphosphorylated retinoblastoma protein (ppRb), a key regulator for G1/S transition, is correlated with a late marker for hyperphosphorylation of tau but not with other early markers for tau alteration in the 3xTg-AD mouse model. However, in AD brains, ppRb can colocalize with both early and later markers for tau alterations, and can often be found singly in many degenerating neurons, indicating the distinct development of pathology between the 3xTg-AD mouse model and human AD patients. The conclusions of this study are two-fold. First, our findings clearly demonstrate the pathological link between the aberrant cell cycle re-entry and tau pathology. Second, the chronological pattern of cell cycle re-entry with tau pathology in the 3xTg-AD mouse is different compared to AD patients suggesting the distinct pathogenic mechanism between the animal AD model and human AD patients.
Pages 67-80
Sophie Poole, Sim K. Singhrao, Sasanka Chukkapalli, Mercedes Rivera, Irina Velsko, Lakshmyya Kesavalu*, StJohn Crean* *These authors contributed equally to this work.
Active Invasion of Porphyromonas gingivalis and Infection-Induced Complement Activation in ApoE-/- Mice Brains
Abstract: Periodontal disease is a polymicrobial inflammatory disease that leads to chronic systemic inflammation and direct infiltration of bacteria/bacterial components, which may contribute to the development of Alzheimer’s disease. ApoE-/- mice were orally infected (n = 12) with Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum as mono- and polymicrobial infections. ApoE-/- mice were sacrificed following 12 and 24 weeks of chronic infection. Bacterial genomic DNA was isolated from all brain tissues except for the F. nucleatum mono-infected group. Polymerase chain reaction was performed using universal 16s rDNA primers and species-specific primer sets for each organism to determine whether the infecting pathogens accessed the brain. Sequencing amplification products confirmed the invasion of bacteria into the brain during infection. The innate immune responses were detected using antibodies against complement activation products of C3 convertase stage and the membrane attack complex. Molecular methods demonstrated that 6 out of 12 ApoE-/- mice brains contained P. gingivalis genomic DNA at 12 weeks (p = 0.006), and 9 out of 12 at 24 weeks of infection (p = 0.0001). Microglia in both infected and control groups demonstrated strong intracellular labeling with C3 and C9, due to on-going biosynthesis. The pyramidal neurons of the hippocampus in 4 out of 12 infected mice brains demonstrated characteristic opsonization with C3 activation fragments (p = 0.032). These results show that the oral pathogen P. gingivalis was able to access the ApoE-/- mice brain and thereby contributed to complement activation with bystander neuronal injury.
Pages 81-91
Carla Manuela Crispim Nascimento, Jessica Rodrigues Pereira, Larissa Pires de Andrade, Marcelo Garuffi, Carlos Ayan, Daniel Shikanai Kerr, Leda Leme Talib, Márcia Regina Cominetti, Florindo Stella
Physical Exercise Improves Peripheral BDNF Levels and Cognitive Functions in Elderly Mild Cognitive Impairment Individuals with Different BDNF Val66Met Genotypes
Abstract: The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) levels and cognitive functioning have been reported in the literature. However, the variability of individual responses may be linked to genetic differences. BDNF is considered one of the most plausible factors involved in the cognitive benefits associated with physical activity practice. A single nucleotide polymorphism localized in the gene that codes BDNF results in a missense mutation that promotes an amino acid substitution (Val66Met) in the protein. This process has been associated with decreased levels of BDNF secretion, with corresponding impairments in specific cognitive functions. Therefore, the objective of this study was to analyze the effects of a multimodal physical exercise program on peripheral BDNF levels and cognitive functions in elderly individuals with mild cognitive impairment (MCI). The participants were genotyped for the BDNF Val66Met polymorphism. Cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA) prior to and after the intervention. Forty-five participants were assigned to the control and trained groups. The trained group participated in a multimodal physical training for a 16-week period. The results showed a significant between-subjects interaction (p<0.05), which indicates the beneficial contribution of training on cognitive functions independent of the BDNF genotype. However, only participants with wild-type genotypes (BDNF-Met) exhibited significant improvements in peripheral BDNF levels. The BDNF genotype appears to modulate the effects of physical exercise on BDNF secretion, but it does not influence cognition. This is the first study that evaluated the influence of a BDNF polymorphism on physical activity and cognition performance in elderly MCI individuals.
Pages 93-108
Bartholomew J. Naughton, F. Jason Duncan, Darren A. Murrey, Aaron S. Meadows, David E. Newsom, Nicoleta Stoicea, Peter White, Douglas W. Scharre, Douglas M. Mccarty, Haiyan Fu
Blood Genome-Wide Transcriptional Profiles Reflect Broad Molecular Impairments and Strong Blood-Brain Links in Alzheimer’s Disease
Abstract: To date, little is known regarding the etiology and disease mechanisms of Alzheimer’s disease (AD). There is a general urgency for novel approaches to advance AD research. In this study, we analyzed blood RNA from female patients with advanced AD and matched healthy controls using genome-wide gene expression microarrays. Our data showed significant alterations in 3,944 genes (≥2-fold, FDR≤1%) in AD whole blood, including 2,932 genes that are involved in broad biological functions. Importantly, we observed abnormal transcripts of numerous tissue-specific genes in AD blood involving virtually all tissues, especially the brain. Of altered genes, 157 are known to be essential in neurological functions, such as neuronal plasticity, synaptic transmission and neurogenesis. More importantly, 205 dysregulated genes in AD blood have been linked to neurological disease, including AD/dementia and Parkinson’s disease, and 43 are known to be the causative genes of 42 inherited mental retardation and neurodegenerative diseases. The detected transcriptional abnormalities also support robust inflammation, profound extracellular matrix impairments, broad metabolic dysfunction, aberrant oxidative stress, DNA damage, and cell death. While the mechanisms are currently unclear, this study demonstrates strong blood-brain correlations in AD. The blood transcriptional profiles reflect the complex neuropathological status in AD, including neuropathological changes and broad somatic impairments. The majority of genes altered in AD blood have not previously been linked to AD. We believe that blood genome-wide transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tauopathy for AD research.
Pages 109-119
Erika Olsson, Brita Karlström, Lena Kilander, Liisa Byberg, Tommy Cederholm, Per Sjögren (Handling Associate Editor: Pascale Barberger-Gateau)
Dietary Patterns and Cognitive Dysfunction in a 12-Year Follow-Up Study of 70 Year Old Men
Abstract: Background: Adherence to dietary patterns has been associated with cognitive decline and dementia, but studies are inconsistent. Objective: Dietary patterns, i.e., WHO recommendations (Healthy Diet Indicator), a Mediterranean-like diet (modified Mediterranean Diet Score, mMDS), and a low carbohydrate high protein diet (LCHP), were related to incident cognitive dysfunction, as indicated by Alzheimer's disease (AD), all-type dementia, and all-type cognitive impairment, in a cohort of 1,138 elderly Swedish men. Methods: Dietary patterns were derived from 7-day records. Risk relations were calculated by Cox and logistic regression analyses, adjusted for potential confounders. Sensitivity analysis was performed in a subpopulation (n=564) with energy intake according to the Goldberg cut-off. Results: During a mean follow-up of 12 years, 84, 143, and 198 men developed AD, all-type dementia, and all-type cognitive impairment, respectively. There was no association between Healthy Diet Indicator and any of the outcomes. Hazard ratios associated with 1 standard deviation (SD) increment in the LCHP score were 1.16 (95% confidence interval [CI]: 0.95, 1.43) for AD and 1.16 (95% CI: 0.99, 1.37) for all-type dementia. mMDS was not associated with dementia diagnosis. Odds ratio (OR)/1 SD increase for mMDS and all-type cognitive impairment was 0.82 (95% CI: 0.65, 1.05). In the subpopulation OR for mMDS and all-type cognitive impairment was 0.32 (95% CI: 0.11, 0.89). Conclusion: We found no strong associations with development of cognitive dysfunction for any of the dietary patterns investigated. However, there was a potentially beneficial association for a Mediterranean-like diet on the development of cognitive dysfunction in the subpopulation.
Pages 121-132
Katherine A. Gifford, Dandan Liu, Hugo Carmona, Zengqi Lu, Raymond Romano, Yorghos Tripodis, Brett Martin, Neil Kowall, Angela L. Jefferson (Handling Associate Editor: Frank Jessen)
Inclusion of an Informant Yields Strong Associations between Cognitive Complaint and Longitudinal Cognitive Outcomes in Non-Demented Elders
Abstract: Background: The relation between the source of cognitive complaint and objective cognitive performance is not well understood. Objective: To examine self and informant cognitive complaint as predictors of objective cognitive and functional trajectory in non-demented elders. Methods: Participants from the National Alzheimer’s Coordinating Center had a baseline diagnosis of normal cognition (NC; n=6,133, 72±8 years, 68% female) or mild cognitive impairment (MCI; n=3,040, 74±8 years, 55% female). Four independent groups defined cognitive complaint: no-complaint, self-only complaint, informant-only complaint, or mutual-complaint (both self and informant complaint). Linear mixed model regression analyses related complaint status (referent was no-complaint) to cognitive and functional trajectories, adjusting for age, gender, race, education, and follow-up period. Results: Among NC participants, mutual-complaint related to faster decline in global cognition (p<0.0001), language (all p-values<0.0001), processing speed (p=0.0002), and executive functioning (p=0.0006). Informant-only complaint related to faster decline in global cognition (p=0.0001) and processing speed (p=0.0001). Self-only complaint related to greater decline in immediate (p<0.0001) and delayed (p=0.0005) episodic memory. In MCI, mutual-complaint related to faster decline in global cognition (p<0.0001), verbal episodic memory (all p-values<0.0001), language (all p-values<0.0001), and processing speed (all p-values<0.0006). Informant-only or self-only complaint associations with cognitive trajectory did not survive correction factor for multiple comparisons. Conclusion: Cognitive complaint appears to have clinical significance, as it is related to declines in objective cognitive performance over time. Mutual complaint was associated with the worst cognitive trajectory in both NC and MCI elders, highlighting the importance of incorporating an informant into evaluation of elders whenever feasible.
Pages 133-142
Teng Chen, Ruihua Hou, Chao Li, Chengyuan Wu, Shujun Xu (Handling Associate Editor: Paulo Agostinho)
MPTP/MPP+ Suppresses Activation of Protein C in Parkinson’s Disease
Abstract: Endothelial dysfunction and disruption of the blood-brain barrier have been found to be associated with Parkinson’s disease (PD). However, the mechanisms underlying these effects have yet to be elucidated. It has also been found that activated protein C (APC) displays neuroprotective properties. Presently, the effects of APC on PD remain unknown. Using a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxin rodent model of PD, we found that administration of MPTP can reduce expression of endothelial protein C receptor (EPCR), an N-glycosylated type I membrane protein that has the ability to enhance protein C activation. However, the use of MPTP does not alter levels of thrombomodulin. These findings were verified in an in vitro study showing that 1-methyl-4-phenylpyridinium (MPP+) treatment leads to suppression of EPCR along with reduction of protein C activation in human primary endothelial cells. Importantly, our results display that activation of the transcriptional factor SP1 is involved in the inhibitory effects of MPTP/MPP+ on EPCR expression. We found that using 300 nM of the SP1 inhibitor MIT can abolish the effects of MPP+ on EPCR expression. Consistently, SP1 silencing using small RNA interference was able to prevent the inhibitory effects of MPTP/MPP+ on the reduction of EPCR expression and impairment of protein C activation. Importantly, our results indicate that overexpression of SP1 inhibits EPCR promoter activity. Our study suggests that EPCR-APC may be a potential therapeutic target for endothelial dysfunction in PD.
Pages 143-152
Byoung Seok Ye, Juhee Chin, Seung Yoon Kim, Jung-Sun Lee, Eun-Joo Kim, Yunhwan Lee, Chang Hyung Hong, Seung Hye Choi, Kyung Won Park, Bon D. Ku, So Young Moon, SangYun Kim, Seol-Hee Han, Jae-Hong Lee, Hae-Kwan Cheong, Sun Ah Park, Jee Hyang Jeong, Duk L. Na, Sang Won Seo (Handling Associate Editor: Yong Jeong)
The Heterogeneity and Natural History of Mild Cognitive Impairment of Visual Memory Predominant Type
Abstract: We evaluate the longitudinal outcomes of amnestic mild cognitive impairment (aMCI) according to the modality of memory impairment involved. We recruited 788 aMCI patients and followed them up. aMCI patients were categorized into three groups according to the modality of memory impairment: Visual-aMCI, only visual memory impaired; Verbal-aMCI, only verbal memory impaired; and Both-aMCI, both visual and verbal memory impaired. Each aMCI group was further categorized according to the presence or absence of recognition failure. Risk of progression to dementia was compared with pooled logistic regression analyses while controlling for age, gender, education, and interval from baseline. Of the sample, 219 (27.8%) aMCI patients progressed to dementia. Compared to the Visual-aMCI group, Verbal-aMCI (OR = 1.98, 95% CI = 1.19-3.28, p = 0.009) and Both-aMCI (OR = 3.05, 95% CI = 1.97-4.71, p < 0.001) groups exhibited higher risks of progression to dementia. Memory recognition failure was associated with increased risk of progression to dementia only in the Visual-aMCI group, but not in the Verbal-aMCI and Both-aMCI groups. The Visual-aMCI without recognition failure group were subcategorized into aMCI with depression, small vessel disease, or accelerated aging, and these subgroups showed a variety of progression rates. Our findings underlined the importance of heterogeneous longitudinal outcomes of aMCI, especially Visual-aMCI, for designing and interpreting future treatment trials in aMCI.
Pages 153-165
Wang Xiu-Lian*, Zeng Ji*, Yang Yang, Xiong Yan, Zhang Zhi-Hua, Qiu Mei, Yan Xiong, Sun Xu-Ying, Tuo Qing-Zhang, Liu Rong, Wang Jian-Zhi *These authors contribute equally to this work.
Helicobacter pylori Filtrate Induces Alzheimer-Like Tau Hyperphosphorylation by Activating Glycogen Synthase Kinase-3β
Abstract: Abnormal hyperphosphorylation of microtubule-associated protein tau is involved in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Helicobacter pylori (H. pylori) infection has been reported to be related with a high risk of AD, but the direct laboratory evidence is lacking. Here we explored the effect of H. pylori infection on tau phosphorylation. The results showed that H. pylori filtrate induced significant tau hyperphosphorylation at several AD-related tau phosphorylation sites, such as Thr205, Thr231, and Ser404, both in mouse neuroblastoma N2a cells and rat brains with activation of glycogen synthase kinase-3β (GSK-3β). Application of GSK-3 inhibitors efficiently attenuated the H. pylori-induced tau hyperphosphorylation. Our data provide evidence supporting the role of H. pylori infection in AD-like tau pathology, suggesting that H. pylori eradication may be beneficial in the prevention of tauopathy.
Pages 167-176
Hélène Villars, Charlotte Dupuy, Amélie Perrin, Bruno Vellas, Fati Nourhashemi
Impact of a Therapeutic Educational Program on Quality of Life in Alzheimer’s Disease: Results of a Pilot Study
Abstract: Background: Therapeutic patient education is expanding in the field of Alzheimer’s disease (AD). Objective: To evaluate the impact of a therapeutic educational program, on AD-affected patients and their caregivers, living in the community, on the patient’s quality of life. Methods: Non experimental before and after study. Patient/caregiver dyads were recruited in the geriatric department of the Toulouse University Hospital. The intervention consisted of an educational program, designed for both patients and caregivers. It included two individual sessions (at baseline (M0) and two months later (M2)) and four group sessions for caregivers only, one per week between M0 and M2. The primary outcome was the patient’s quality of life at two months, hetero-evaluated by the caregiver. We compared the QoL-AD score between M0 and M2 with a paired Student’s test. The secondary outcomes were patient’s autonomy (activities of daily living) and caregiver’s burden (Zarit Burden interview). Results: 29 patient/caregiver dyads were recruited. The QoL-AD score was 24.6 ± 5.1 at M0 versus 27.2 ± 6.0 at M2 (p=0.038). This difference is statistically significant. There was no difference in the secondary outcomes. Conclusion: This study revealed a significant positive impact of a therapeutic educational program on patients’ quality of life. Our results led us to design a randomized controlled trial called the THERAD study (THERapeutic education in Alzheimer’s disease). It started in January 2013, and the results will be available in 2015. If the efficacy of this approach is proven, it will be important to implement educational programs in the care plan of these patients.
Pages 177-181
María J. Perez de Lara, Jesús Pintor (Handling Associate Editor: Miguel Diaz-Hernandez)
Presence and Release of ATP from the Retina in an Alzheimer’s Disease Model
Abstract: The aim of this study was to assess the changes of extracellular ATP levels during the progress of Alzheimer’s disease by using a murine model of the disease. Retinal nucleotide release was measured from flattened whole-mounts stimulated with 59 mM KCl or non-stimulated maintained in Ringer solution. Mice exhibited an increase in retinal ATP release as long as the pathology progressed up to 14 months. This value decreased to normal values by 18 months of age. Changes occurred also when comparing to non-pathological mice. The increase in the presence of ATP levels may contribute, together with other factors, to the changes in the functionality of the retina and the concomitant death of retinal cells.
Pages 183-191
Piotr Lewczuk, Natalia Lelental, Philipp Spitzer, Juan Manuel Maler, Johannes Kornhuber
Amyloid-β 42/40 Cerebrospinal Fluid Concentration Ratio in the Diagnostics of Alzheimer's Disease: Validation of Two Novel Assays
Abstract: Background: The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer's disease (AD) is reflected in recently published diagnostic and/or research criteria. A growing body of evidence suggests better diagnostic performance of the amyloid-β (Aβ)42/40 CSF concentration ratio compared to the Aβ42 concentration alone. Objective: (a) to analytically validate two novel ELISAs capable to measure Aβ1-40 and Aβ1-42 in the CSF, and (b) to compare the diagnostic accuracies of Aβ1-42 and Aβ42/40 ratio. Methods: In this study, (a) the novel Aβ1-40 and Aβ1-42 ELISAs (IBL International GmbH, Hamburg, Germany) have been analytically validated, and (b) a clinical study has been performed comparing the diagnostic performance of the CSF Aβ42/40 concentration ratio and the CSF Aβ42 concentration. Results: In the analytical part of the study, only marginal cross-reactivity (Aβ1-42 versus Aβ1-40) was observed; recoveries were in the range of 85-100% for the samples diluted 1:20-1:640 (Aβ1-40), and 92-104% for the samples diluted 1:20-1:320 (Aβ1-42). For Aβ1-40, the intra-assay imprecision was 2.1%, the inter-assay imprecision was 4.4%, and the inter-lot imprecision was 5.4 %. For Aβ1-42, the numbers were 3.1%, 6.2%, and 6.9%, respectively. The goodness of the fit of the average standard curves was > 0.99 for both assays, and the imprecision of the optical densities in ten repetitions of the standard curves was ≤ 5% for all standards. In the clinical part, at the cut off value 691 pg/mL, Aβ1-42 showed sensitivity and specificity of 69.3% and 88.9%, respectively, whereas at the cut off value 0.06, the Aβ42/40 ratio showed significantly improved performance with sensitivity and specificity of 93.3% and 100%, respectively. The area under the ROC curve for Aβ42/40 (0.974) was highly significantly larger compared to Aβ1-42 concentration ROC curve (0.827, p<0.0001). Conclusions: (a) the novel Aβ1-40 and Aβ1-42 ELISA assays characterize with very good analytical performance; (b) we reconfirm that the CSF Aβ42/40 concentration ratio shows significantly better diagnostic performance compared to the CSF Aβ1-42 concentration alone.
Pages 193-199
Manuel Montero-Odasso, Susan W. Muir-Hunter, Afua Oteng-Amoako, Karen Gopaul, Anam Islam, Michael Borrie, Jennie Wells, Mark Speechley
Donepezil Improves Gait Performance in Older Adults with Mild Alzheimer’s Disease: A Phase II Clinical Trial
Abstract: Background: Gait deficits are prevalent in people with dementia and increase their fall risk and future disability. Few treatments exist for gait impairment in Alzheimer’s disease (AD) but preliminary studies have shown that cognitive enhancers may improve gait in this population. Objective: To determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic activity, on gait in older adults newly diagnosed with AD. Methods: Phase II clinical trial in 43 seniors with mild AD received donepezil. Participants had not previously received treatment with cognitive enhancers. Primary outcome variables were gait velocity (GV) and stride time variability (STV) under single and dual-task conditions measured using an electronic walkway. Secondary outcomes included attention and executive function. Results: After four months of treatment, participants with mild AD improved their GV from 108.4±18.6 to 113.3±19.5 cm/s, p=0.01; dual-task GV from 80.6±23.0 to 85.3±22.3 cm/s, p=0.03. Changes in STV were in the expected direction although not statistically significant. Participants also showed improvements in Trail Making Tests A (p=0.030), B (p=0.001), and B-A (p=0.042). Conclusion: Donepezil improved gait in participants with mild AD. The enhancement of dual-task gait suggests that the positive changes achieved in executive function as a possible causal mechanism. This study yielded a clinically significant estimate of effect size; as well, the findings are relevant to the feasibility and ethics considerations for the design of a Phase III clinical trial.
Pages 201-212
Ailton Andrade de Oliveira, Maria Teresa Carthery-Goulart, Pedro Paulo de Magalhães Oliveira Júnior, Daniel Carneiro Carrettiero, João Ricardo Sato, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: J. Wesson Ashford)
Defining Multivariate Normative Rules for Healthy Aging using Neuroimaging and Machine Learning: An Application to Alzheimer’s Disease
Abstract: Background: Neuroimaging techniques combined with computational neuroanatomy have been playing a role in the investigation of healthy aging and Alzheimer’s disease (AD). The definition of normative rules for brain features is a crucial step to establish typical and atypical aging trajectories. Objective: To introduce an unsupervised pattern recognition method; to define multivariate normative rules of neuroanatomical measures; and to propose a brain abnormality index. Methods: This study was based on a machine learning approach (one class classification or novelty detection) to neuroanatomical measures (brain regions, volume, and cortical thickness) extracted from the Alzheimer’s Disease Neuroimaging Initiative (ADNI)’s database. We applied a ν-One-Class Support Vector Machine (ν-OC-SVM) trained with data from healthy subjects to build an abnormality index, which was compared with subjects diagnosed with mild cognitive impairment and AD. Results: The method was able to classify AD subjects as outliers with an accuracy of 84.3% at a false alarm rate of 32.5%. The proposed brain abnormality index was found to be significantly associated with group diagnosis, clinical data, biomarkers, and future conversion to AD. Conclusion: These results suggest that one-class classification may be a promising approach to help in the detection of disease conditions. Our findings support a framework considering the continuum of brain abnormalities from healthy aging to AD, which is correlated with cognitive impairment and biomarkers measurements.
Pages 213-226
Ianire Maté, Julia Cruces, Lydia Giménez-Llort, Mónica De la Fuente
Function and Redox State of Peritoneal Leukocytes as Preclinical and Prodromic Markers in a Longitudinal Study of Triple-Transgenic Mice for Alzheimer’s Disease
Abstract: The aging process involves the impairment of the immune system (immunosenescence), based on the imbalance of the redox status, as occurs in neurodegenerative diseases such as Alzheimer’s disease (AD). Since in AD there is a systemic disorder, we aimed to assess longitudinally, from before the onset until the complete establishment of AD, cell populations, several functions, and oxidative stress parameters in peritoneal leukocytes of triple transgenic mice for AD (3xTgAD). These animals mimic the human AD pathophysiology. The results indicate a premature immunosenescence in 3xTgAD at 4 months of age, when the immunoreactivity against intracellular amyloid-β fibrils appears. Thus, decreases in functions such as chemotaxis, phagocytosis, and lymphoproliferation, as well as a lower reduced glutathione content and higher xanthine oxidase activity, appear in leukocytes. Moreover, NK percentage and cytotoxic activity, CD25+ B and naïve CD8 T cells percentage, GSSG/GSH ratio, and GSH content were already changed before the onset of AD, at the age of 2 months. Furthermore, the changes in some parameters such as CD5+ B1 cells, phagocytosis, lymphoproliferation, and xanthine oxidase activity continue at 15 months of age, when AD pathophysiology is completely established. Because the immune system parameters studied are markers of health and longevity, the premature immunosenescence could explain the shorter life span shown by 3xTgAD observed in the present work. These results suggest that peripheral immune cell functions and their oxidative stress status could be good early peripheral markers of the preclinical and prodromal stages and progression of AD.
Pages 227-242
Lei Peng*, Yang Yu*, Jin Liu, Shuqin Li, Huiqiong He, Ni Cheng, Richard D. Ye (Handling Associate Editor: Chengxin Gong) *These authors contributed equally to this work.
The Chemerin Receptor CMKLR1 is a Functional Receptor for Amyloid-β Peptide
Abstract: Amyloid-β peptides such as Aβ1-42 (Aβ42) play a pivotal role in the progression of Alzheimer’s disease (AD). Aβ42 is neurotoxic and can activate microglial cells. These cells in turn migrate toward senile (neuritic) plaques and help to clear Aβ deposits through an endocytotic mechanism. It is of potential significance to characterize the Aβ42 receptors that mediate microglia chemotaxis and Aβ42 uptake. We found that the transcript of the chemerin receptor CMKLR1 was upregulated in the brain of AD patients and in mouse brain tissue following systemic LPS administration. CMKLR1 and Aβ42 colocalized in hippocampus and cortex of AβPP/PS1 transgenic mice. Moreover, Aβ42 bound specifically to CMKLR1 in stably transfected rat basophilic leukemia (RBL) cells (CMKLR1-RBL), suggesting that CMKLR1 is a receptor for Aβ42. Aβ42 induced migration of primary microglia, the mouse microglial cell line N9, and CMKLR1-RBL cells, but not untransfected RBL-2H3 cells. Mechanistic studies showed that Aβ42 induced CMKLR1-dependent cell migration through activation of the ERK1/2, PKA, and Akt pathways, but not Ca2+ mobilization. Aβ42 stimulation of CMKLR1-RBL cells and primary glial cells led to internalization of the Aβ42-CMKLR1 complex, suggesting a potential role for CMKLR1 in Aβ42 clearance. Taken together, these results indicate that Aβ42 activates CMKLR1, leading to glia cell migration and clearance of Aβ42. CMKLR1 is a new addition to the repertoire of cell surface molecules that are responsible for Aβ processing and clearance.
Pages 243-257
Kyung-Ok Uhm*, Mi-Jeong Kim*, Makoto Kawaguchi, Hiroyasu Akatsu, Yutaka Miura, Sachiyo Misumi, Hideki Hida, Eun-Kyoung Choi, Yong-Sun Kim, Makoto Michikawa, Cha-Gyun Jung *These authors contributed equally to this work.
ATBF1 is a Novel Amyloid-β Protein Precursor (AβPP) Binding Protein that Affects AβPP Expression
Abstract: The cytoplasmic C-terminal domain of amyloid-β protein precursor (AβPP) binds to several proteins that regulate the trafficking and processing of AβPP and affects amyloid-β (Aβ) production. We previously reported that levels of AT-motif binding factor 1 (ATBF1) are increased in the brains of 17-month-old Tg2576 mice compared with wild-type controls, and that Aβ42 increases ATBF1 expression, inducing death in primary rat cortical neurons. Here, we show that ATBF1 levels are increased in the cytoplasm of hippocampal neurons in Alzheimer’s disease (AD) brains compared with non-AD brains. Furthermore, cotransfection of human embryonic kidney (HEK293T) and human neuroblastoma (SH-SY5Y) cells with ATBF1 and AβPP695 increased steady-state levels of AβPP via the binding of ATBF1 to the AβPP cytoplasmic domain (amino acids 666–690), resulting in increased Aβ production and cellular and soluble AβPP (sAβPP) levels without affecting the activity or levels of AβPP processing enzymes (α-, β-, or γ-secretase). Conversely, knockdown of endogenous ATBF1 reduced levels of cellular AβPP, sAβPP, and Aβ in HEK293 cells overexpressing human AβPP695. Our findings provide insight into the dynamics of AβPP processing and Aβ production, and suggest that ATBF1 is a novel AβPP binding protein that may be a suitable therapeutic target for AD.
Pages 259-273
Pablo Cuesta, Ana Barabash, Sara Aurtenetxe, Pilar Garcés, María Eugenia López, Ricardo Bajo, Marcos Llanero-Luque, Inés Ancín, José Antonio Cabranes, Alberto Marcos, Miguel Sancho, Akinori Nakamura, Fernando Maestú, Alberto Fernandez (Handling Associate Editor: Susana Cid Fernández)
Source Analysis of Spontaneous Magnetoencephalograpic Activity in Healthy Aging and Mild Cognitive Impairment: Influence of Apolipoprotein E Polymorphism
Abstract: The apolipoprotein E (APOE) ɛ4 allele is a genetic risk factor for the development of late-onset Alzheimer’s disease (AD), which affects cholinergic system functioning. The association between reduced cholinergic levels and increase of magnetoencephalographic (MEG) low-frequency has been used to explain spectral changes found in AD patients. However, the investigation in predementia stages is scarce. We obtained MEG recordings from 25 aged controls and 36 mild cognitive impairment (MCI) patients during a resting-state condition. According to their APOE genotype, MCIs and controls were subdivided in carriers and non-carriers of the ɛ4 allele. Sources of spectral variations in these groups were calculated through beamforming. MCI patients exhibited a significant increase of relative power within the low-frequency domain, accompanied by a power decrease within the high-frequency range. APOEɛ4 carriers showed an increased relative power in the 4.5-6.5 Hz frequency range over frontal lobes. The power increase observed in controls carrying ε4 was significantly higher as compared with MCI non-carriers, while MCI carriers exhibited the highest relative power within the 4.5-6.5 Hz range. Higher power values within the low-frequency ranges correlated with a poorer cognitive performance in MCIs and controls. Our investigation demonstrates that APOEɛ4 affects resting-state activity to an extent that makes it more proximate to the pattern observed in early stages of AD. Therefore, a combination of genetic and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD, and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.
Pages 275-287
Donald R. Royall, Raymond F. Palmer for the Texas Alzheimer’s Research and Care Consortium
Ethnicity Moderates Dementia’s Biomarkers
Abstract: We have employed structural equation models to explicitly distinguish functional status, and therefore "dementia-relevant" variance in cognitive task performance (i.e., “δ”). We previously associated δ with cytokines and other serum biomarkers in a well characterized Alzheimer’s disease cohort, the Texas Alzheimer’s Research and Care Consortium. However, that δ homolog did not exhibit factor equivalence across ethnicity. In this study, we construct a δ homolog that exhibits mean and factor equivalence across ethnicity [i.e., “d(=)”]. d(=) is associated significantly with ten of the twelve previously selected biomarkers. Most of these associations are again specific to Non-Hispanic White participants. These findings have yet to be validated in other cohorts, but may suggest cross-ethnic differences in dementia’s pathobiological mechanisms between Hispanic Mexican-Americans and Non-Hispanic White.
Pages 289-290
Commentary
Steve Balsis, Deborah A. Lowe
A Fresh Perspective Revealed by Powerful Trends in Alzheimer’s Disease Research
Pages 291-302
Dan Yu*, Bang-Bao Tao*, Yun-Yun Yang, Li-Sha Du, Shuang-Shuang Yang, Xiao-Jie He, Yu-Wen Zhu, Jun-Kai Yan, Qing Yang (Handling Associate Editor: Irina Alafuzoff) *These authors contributed equally to this work
The IDO Inhibitor Coptisine Ameliorates Cognitive Impairment in a Mouse Model of Alzheimer’s Disease
Abstract: Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer’s disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT’s action on AD. Here, we characterized the effects of coptisine in an AD mouse model on the basis of its IDO inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM. In AβPP/PS1 transgenic mice, oral administration of coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-β peptide 1-42 and interferon-γ showed reduction of cell viability and enhancement of IDO activity, while coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment.
Pages 303-314
Justin Tao Wen Chiam, Richard James Butler Dobson, Steven John Kiddle*, Martina Sattlecker* (Handling Associate Editor: Gary Arendash) *These authors contributed equally to this work.
Are Blood-Based Protein Biomarkers for Alzheimer’s Disease also Involved in Other Brain Disorders? A Systematic Review
Abstract: Background: Alzheimer’s disease (AD) biomarkers are urgently needed for both early and accurate diagnosis and prediction of disease progression. Past research has studied blood-based proteins as potential AD biomarkers, revealing many candidate proteins. To date only limited effort has been made to investigate the disease specificity of AD candidate proteins and whether these proteins are also involved in other neurodegenerative or psychiatric conditions. Objective: This review seeks to determine if blood-based AD candidate protein biomarkers are disease specific. Methods: A two-stage systematic literature search was conducted. Firstly, the most consistently identified AD protein biomarkers in blood were determined from a list of published discovery or panel-based (>100 proteins) blood proteomics studies in AD. Secondly, an online database search was conducted using the 10 most consistently identified proteins to determine if they were involved in other brain disorders, namely frontotemporal lobe dementia, vascular dementia, Lewy body disease, Parkinson’s disease, schizophrenia, depression, and autism. Results: Among the reviewed candidate proteins, plasma protease C1 inhibitor, pancreatic prohormone, and fibrinogen γ chain were found to have the least evidence for non-specificity to AD. All other candidates were found to be affected by other brain disorders. Conclusion: Since we found evidence that the majority of AD candidate proteins might also be involved in other brain disorders, more research into the disease specificity of AD protein biomarkers is required.
Pages 315-324
Alon Seifan, Karen S. Marder, Jesse Mez, James M. Noble, Etty P. Cortes, Jean Paul Vonsattel, Lawrence S. Honig
Hippocampal Laminar Distribution of Tau Relates to Alzheimer’s Disease and Age of Onset
Abstract: Background: Cerebral deposition of phospho-tau in Alzheimer’s disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. Objective: To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. Methods: 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n=44; High OML Only (n=35); High IML Only (n=5); and Low IML&OML (n=14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. Results: High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p<0.01) and to have higher median Braak stage (6 versus 5, p<0.01) and earlier mean age of onset (65.9 versus 73.7 y, p=0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI -6.7 to -0.7, p<0.01), after adjustment for demographics and symptom duration. Conclusions: Phospho-tau pathology, when prominent within both IML and OML, is associated with CERAD diagnosis of Definite AD and earlier age of onset in AD. Laminar patterns of tau deposition reflect regional involvements during disease course.
Pages 325-334
Isabel Hernández, Maitée Rosende-Roca, Montserrat Alegret, Ana Mauleón, Ana Espinosa, Liliana Vargas, Oscar Sotolongo-Grau, Lluís Tárraga, Mercè Boada, Agustín Ruiz (Handling Associate Editor: Benedetta Nacmias)
Association of TMEM106B rs1990622 Marker and Frontotemporal Dementia: Evidence for a Recessive Effect and Meta-Analysis
Abstract: Transmembrane Protein 106B SNP rs1990622 was recently shown to modify the risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTD-TDP). An independent replication study of this genetic variant was performed in 381 individuals from Catalonia (Spain). By applying a recessive model, a tendency toward an association with FTD risk was observed in our case-control study (age- and gender-adjusted odds ratio=0.57; p=0.082). Importantly, meta-analysis of available studies also supports a recessive effect for rs1990622 CC genotype (OR=0.70; CI 95% [0.57-0.85]; p=0.0003) and demonstrates the existence of statistical heterogeneity due to an inherent pathological heterogeneity between series (p=0.00014). We conclude that TMEM106B is associated with FTD, although the extent of this effect is difficult to be estimated by using clinical FTD series.
