Pages 1-12
Review
Dharma Singh Khalsa (Handling Associate Editor: J. Wesson Ashford)
Stress, Meditation, and Alzheimer’s Disease Prevention: Where The Evidence Stands
Abstract: Although meditation is believed to be over five thousand years old, scientific research on it is in its infancy. Mitigating the extensive negative biochemical effects of stress is a superficially discussed target of Alzheimer’s disease (AD) prevention, yet may be critically important. This paper reviews lifestyle and stress as possible factors contributing to AD and meditation’s effects on cognition and well-being for reduction of neurodegeneration and prevention of AD. This review highlights Kirtan Kriya (KK), an easy, cost effective meditation technique requiring only 12 minutes a day, which has been successfully employed to improve memory in studies of people with subjective cognitive decline, mild cognitive impairment, and highly stressed caregivers, all of whom are at increased risk for subsequent development of AD. KK has also been shown to improve sleep, decrease depression, reduce anxiety, down regulate inflammatory genes, upregulate immune system genes, improve insulin and glucose regulatory genes, and increase telomerase by 43%; the largest ever recorded. KK also improves psycho-spiritual well-being or spiritual fitness, important for maintenance of cognitive function and prevention of AD. KK is easy to learn and practice by aging individuals. It is the premise of this review that meditation in general, and KK specifically, along with other modalities such as dietary modification, physical exercise, mental stimulation, and socialization, may be beneficial as part of an AD prevention program.
Pages 13-14
Commentary
J. Wesson Ashford, Louise Mahoney, Tim Burkett
A Role for Complementary and Integrative Medicine in Alzheimer’s Disease PreventionAbstract:Complementary and Integrative Medicine has been maturing as a field to support treatment for a variety of medical conditions. The approaches, including yoga, meditation, acupuncture, and dietary supplements, may assist patients in a variety of ways, though clear explanations for their mechanisms of action or measurements of their possible benefit are in most cases elusive. In this issue of the Journal of Alzheimer’s Disease, Khalsa examines the use of meditation as a stress-reduction technique and provides an argument that with a specific technique such stress reduction can be provided efficiently, with relatively little interference in daily activities, and might decrease Alzheimer risk. This thorough review provides some evidence of physiological benefit of meditation to brain function. While any actual effect of meditation on Alzheimer pathophysiology is only conjectural, meditation has received considerable attention as a tool that may have positive psychological and medical benefits. Consequently, this review is welcome. What is less certain is whether the recommended meditation approach is of specific benefit for Alzheimer’s disease or any other condition above and beyond what might be provided by many other types of exercises (like singing in a chorus or doing cross-word puzzles) or physical activities (like swimming or yoga).
Pages 15-34
Review
Kostas T. Siarkos, Everina A. Katirtzoglou, Antonios M. Politis (Handling Associate Editor: Gwenn Smith)
A Review of Pharmacological Treatments for Depression in Alzheimer’s Disease
Abstract: Depression in Alzheimer’s disease (dAD) is one of the most common behavioral and psychological symptoms of dementia, with devastating consequences not only for the affected individuals, but for caregivers as well. So far, pharmacological treatment of dAD has been based on the “monoamine hypothesis’’. However, the reported moderate effects of approved antidepressants, as well as an increasing body of research evidence, suggest a more complex pathophysiologic mechanism. In the present paper, a systematic review of different treatments for dAD is presented that can inform the study of alternative neuropathological and neurobiological aspects of the disease aimed at the development of more effective treatment targets.
Pages 35-53
Hypothesis
Bryna Shatenstein, Pascale Barberger-Gateau (Handling Associate Editor: Patrizia Mecocci)
Prevention of Age-Related Cognitive Decline: Which Strategies, When, and for Whom?
Abstract: Brain aging is characterized by the progressive and gradual accumulation of detrimental changes in structure and function, which increase risk of age-related cognitive decline and dementia. This devastating chronic condition generates a huge social and economic burden and accounts for 11.2% of years of disability. The increase in lifespan has contributed to the increase in dementia prevalence; however, there is currently no curative treatment for most causes of dementias. This paper reviews evidence-based strategies to build, enhance, and preserve cognition over the lifespan by examining approaches that work best, proposing when in the life course they should be implemented, and in which population group(s). Recent work shows a tendency to decreased age-specific prevalence and incidence of cognitive problems and dementia among people born later in the first half of the 20th century, citing higher educational levels, improvements in lifestyle, and better handling of vascular risk factors. This implies that we can target modifiable environmental, lifestyle, and health risk factors to modify the trajectory of cognitive decline before the onset of irreversible dementia. Because building cognitive reserve and prevention of cognitive decline are of critical importance, interventions are needed at every stage of the life course to foster cognitive stimulation, and enable healthy eating habits and physical activity throughout the lifespan. Preventive interventions to decrease and delay cognitive decline and its consequences in old age will also require collaboration and action on the part of policy-makers at the political and social level.
Pages 55-58
Short Communication
Jia Liu, Ming-wei Zhu, Thomas Arzberger, Lu-ning Wang
Frontotemporal Lobar Degeneration with Accumulation of Argyrophilic Grains and Lewy Bodies: A Clinicopathological Report
Abstract: A clinicopathological investigation was conducted on a case of an 89-year-old man with a 10-year history of progressive dementia who also suffered strokes, apathy, aphasia, dysarthria, weakness of both legs, and walking difficulties. At autopsy, we found an obvious atrophy of the frontal and temporal cortex. Lewy bodies (LBs) could be seen in brain stem, amygdala, and neocortex. Argyrophilic grains were observed in hippocampus, entorhinal cortex, neocortex, amygdala, and pons, as well as neurofibrillary tangles in the entorhinal cortex and hippocampus. The case presented here is a rare case of frontotemporal lobar degeneration with accumulation of argyrophilic grains and Lewy bodies.
Pages 59-61
Editorial
Joseph J. Fins
The Reagan Diaries Reconsidered
Pages 63-72
Sofia Söllvander, Frida Ekholm-Pettersson, Rose-Marie Brundin, Gabriel Westman, Lena Kilander, Staffan Paulie, Lars Lannfelt, Dag Sehlin (Handling Associate Editor: Fabrizio Piazza)
Increased Number of Plasma B Cells Producing Autoantibodies Against Aβ42 Protofibril in Alzheimer’s Disease
Abstract: The Alzheimer’s disease (AD)-related peptide amyloid-β (Aβ) has a propensity to aggregate into various assemblies including toxic soluble Aβ protofibrils. Several studies have reported the existence of anti-Aβ antibodies in humans. However, it is still debated whether levels of anti-Aβ antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma Aβ makes it difficult to reliably measure the concentration of circulating anti-Aβ antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-Aβ antibody production on a cellular level by measuring the amount of anti-Aβ antibody producing cells instead of the plasma level of anti-Aβ antibodies. To our knowledge, this is the first time the anti-Aβ antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding Aβ40 monomers, whereas the number of cells producing antibodies toward Aβ42 protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic Aβ protofibrils, which is significantly increased in AD patients.
Pages 73-87
Jonatan A. Snir, Mojmir Suchy, Keith St. Lawrence, Robert H.E. Hudson, Stephen H. Pasternak, Robert Barth
Prolonged In Vivo Retention of a Cathepsin D Targeted Optical Contrast Agent in a Mouse Model of Alzheimer’s DiseaseAbstract: Background: Cathepsin D (CatD) is a lysosomal protease that is elevated early in Alzheimer’s disease (AD). We have previously developed a contrast agent (CA) to detect CatD activity in vivo, consisting of a magnetic resonance imaging/fluorescent moiety linked to a cell penetrating peptide (CPP) by means of a CatD cleavage site and have demonstrated its uptake in the brain of an AD mouse model. Objective: The purpose of this study was to characterize the in vivo retention of a near infra-red fluorescent dye labeled version of this CA. Methods: Six adult C57Bl/6 wild-type mice and six adult 5XFAD transgenic AD mice were studied using a small animal imaging system at five and twelve months of age using our novel CA, or two different control CAs; a Non-Targeted (lacking the CatD cleavage site) and a Non-Penetrating (lacking the CPP). Following intravenous CA administration, the optical signal was recorded within the brain and uptake and washout curves were measured and fitted to a one-phase exponential decay curve. Results: In all wild-type and 5XFAD mice, the washout of the CA that included a CPP domain was significantly slower than the washout of the Non-Penetrating and Non-Targeted CA. Furthermore, the washout of the CatD Targeted CA was significantly slower in the 5XFAD mice compared to the age matched wild-type controls (p<0.05) at 5 and 12 months of age. Control CAs showed no differences in washout. Conclusions: The prolonged retention of the CatD targeted CA in 5XFAD mice suggests this agent may be useful for AD detection.
Pages 89-104
Xiao-Fang Zhang, Yan-Feng Zhao, Shun-Wei Zhu, Wei-Jie Huang, Yan Luo, Qing-Ying Chen, Li-Jun Ge, Run-Sheng Li, Jian-Fei Wang, Mu Sun, Zhi-Cheng Xiao, Guo-Huang Fan
CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer’s Disease
Abstract: Truncation of tau protein is considered an early event in Alzheimer’s disease (AD) and is believed to play a major pathogenic role in sporadic AD. However, causative factors that trigger tau truncation in AD remain poorly understood. In the present study, we demonstrate that CXCL1 (C-X-C motif ligand 1), a specific ligand for the chemokine receptor CXCR2, induced cleavage of tau at ASP421 in a caspase-3-dependent manner in long-term but not short-term cultured neurons. The cleaved tau formed varicosities or bead-like structures along the neurites, an abnormal distribution of tau induced by CXCL1 that has not been observed previously. CXCL1-induced activation of GSK3β and the subsequent phosphorylation of tau preceded and were required for caspase-3 activation and tau cleavage. Moreover, intrahippocampal microinjection of lentiviral CXCL1 induced tau cleavage in hippocampal neurons in aged (15-18 months of age) but not adult mice (5-10 months of age). Our data highlight a new role of CXCR2 in tau cleavage and suggest that targeting CXCR2 may offer therapeutic benefits to patients with AD and potentially other tauopathies.
Pages 105-114
Zdena Kristofikova, Jan Ricny, Martin Vyhnalek, Jakub Hort, Jan Laczo, Jana Sirova, Jan Klaschka, Daniela Ripova
Levels of 17β-Hydroxysteroid Dehydrogenase Type 10 in Cerebrospinal Fluid of People with Mild Cognitive Impairment and Various Types of Dementias
Abstract: Background: Overexpression of the mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10, which is also known as the intracellular amyloid-β peptide (Aβ) binding protein) is observed in cortical or hippocampal regions of patients with Alzheimer’s disease (AD). It appears that 17β-HSD10 may play a role in the pathogenesis of AD. Objective: We investigated the possibility that levels of 17β-HSD10 in cerebrospinal fluid could be a prospective biomarker of AD. Methods: We estimated the enzyme levels in 161 people (15 non-demented controls, 52 people with mild cognitive impairment (MCI), 35 people with probable AD, or 59 people with other types of dementia) and compared them with those of Aβ1-42, tau, and phospho-tau. Results: We found significantly higher levels of 17β-HSD10 in people with MCI due to AD (to 109.9%), with AD (to 120.0%), or with other types of dementia (to 110.9%) when compared to the control group. The sensitivity of the new biomarker to AD was 80.0%, and the specificity was 73.3% (compared to controls) or 52.5-59.1% (compared to other types of dementia). Results of multiple linear regression and of correlation analysis revealed AD-mediated changes in links between 17β-HSD10 and Mini Mental State Examination score. Conclusion: It seems that changes in 17β-HSD10 start many years before symptom onset, analogous to those in Aβ1-42, tau, or phospho-tau and that the levels are a relatively highly sensitive but unfortunately less specific biomarker of AD. A role of 17β-HSD10 overexpression in AD is discussed.
Pages 115-121
Ewa Papuć, Ewa Kurys-Denis, Witold Krupski, Marcin Tatara, Konrad Rejdak Handling Associate Editor: Paula Agostinho)
Can Antibodies against Glial Derived Antigens be Early Biomarkers of Hippocampal Demyelination and Memory Loss in Alzheimer’s Disease?
Abstract: Background: Alzheimer’s disease (AD) is known to exhibit well characterized pathologies including the extracellular accumulation of amyloid plaques, intra-axonal presence of neurofibrillary tangles, and glial hypertrophy. Nevertheless, the nature of myelin pathology in AD has not been well studied. Recent studies on animal models of AD, however, revealed focal demyelination within amyloid-β plaques in hippocampus. Objectives: In a view of this finding, we decided to assess humoral response against proteins of myelin sheath in AD, in the hope of identifying early biomarkers of memory loss and neuropathological process characteristic of AD. Methods: We assessed antibodies levels against proteins of the myelin sheath: myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and proteolipoprotein (PLP) in sera of 26 AD patients and 26 healthy controls, using commercially available ELISA system (Mediagnost, Germany). Results: In the AD patient subgroup, significantly higher titers were observed for all types of assessed IgG autoantibodies compared to healthy control subjects (anti-MOG, anti-MAG, anti-MBP, anti-PLP). The titers of most of the investigated IgM antibodies were also higher in AD patients (p<0.05), with the exception of anti-MAG IgM antibodies (p>0.05). Conclusion: The study provides the evidence for the significantly increased production of autoantibodies against proteins of myelin sheath in AD. These results can be of importance in the light of emerging data from animal models of AD, indicating early demyelination of hippocampal region. Further studies on larger population are necessary to confirm whether these autoantibodies could serve as early biomarkers of AD in humans.
Pages 123-133
Nina Kemppainen, Juho Joutsa, Jarkko Johansson, Noora M Scheinin, Kjell Någren, Johanna Rokka, Riitta Parkkola, Juha O Rinne (Handling Associate Editor: Henryk Barthel)
Long-Term Interrelationship between Brain Metabolism and Amyloid Deposition in Mild Cognitive Impairment
Abstract: The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.
Pages 135-147
Rosalind Hutchings, John R. Hodges, Olivier Piguet, Fiona Kumfor (Handling Associate Editor: Claire Boutoleau-Bretonnière)
Why Should I Care? Dimensions of Socio-Emotional Cognition in Younger-Onset Dementia
Abstract: Background: Skills such as empathy and emotion recognition rely on a multi-dimensional socio-emotional system. Increasingly, evidence suggests that socio-emotional cognition is affected in frontotemporal dementia and Alzheimer’s disease (AD), to varying degrees. However, the specific dimensions of socio-emotional behavior and their neuroanatomical correlates have been relatively unexplored. Objective: The current study aimed to: (i) determine how different dimensions of socio-emotional cognition are affected in behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SD), and AD; (ii) investigate insight into socio-emotional cognition; (iii) identify the neural correlates subserving dimensions of socio-emotional cognition. Methods: Sixteen bvFTD, 15 SD, 10 AD patients, and 17 controls were included. Each participant and a nominated ‘informant’ completed the socio-emotional questionnaire; a 30-item rating scale assessing five dimensions of socio-emotional cognition (empathy, emotion recognition, social conformity, antisocial behavior, sociability). Results: SD and bvFTD participants were rated lower on measures of empathy and emotion recognition compared to AD participants and Controls, while other dimensions were relatively intact. In contrast, participants with AD were rated similarly to Controls across all dimensions. SD and bvFTD groups demonstrated reduced insight into socio-emotional dysfunction. Grey matter intensity in the temporal regions correlated with empathy and emotion recognition. Social conformity was associated with the orbitofrontal cortex and amygdala. Conclusion: Distinct profiles in typically presenting bvFTD, SD, and AD illustrate preliminary evidence of the utility of socio-emotional cognition in diagnostic clarification. This is an important starting point in understanding socio-emotional functioning in younger-onset dementia, paving the way for targeted management and interventions.
Pages 149-162
Takashi Hosono, Akihiro Mouri, Kazuchika Nishitsuji, Cha-Gyun Jung, Masanori Kontani, Hisanori Tokuda, Hiroshi Kawashima, Hiroshi Shibata, Toshiharu Suzuki, Toshitaka Nabehsima, Makoto Michikawa
Arachidonic or Docosahexaenoic Acid Diet Prevents Memory Impairment in Tg2576 Mice
Abstract: It is believed that the amyloid β-protein (Aβ) plays a causative role in the development of Alzheimer’s disease (AD). The amyloid-β protein precursor (AβPP), a substrate of Aβ, and β-secretase and γ-secretase complex proteins, which process AβPP to generate Aβ, are all membrane proteins. Thus, it is reasonable to assume that alterations in brain lipid metabolism modulate AβPP and/or Aβ metabolism. However, the role of cellular polyunsaturated fatty acids in AβPP processing has not been completely understood yet. We report here that 4 months of treatment of Tg2576 mice with an arachidonic acid (ARA)- or a docosahexaenoic acid (DHA)-containing (ARA+ or DHA+) diet prevented memory impairment at 13 months of age. Although, AβPP processing to generate soluble AβPP and induce Aβ synthesis was enhanced, Aβ1-42/Aβ1-40 ratio decreased in 14-month-old Tg2576 mice fed with the ARA+ or DHA+ diet. The ARA+ or DHA+ diet did not alter the AβPP levels and the expression levels of Aβ-degrading enzymes. In cortical primary neuron cultures, ARA or DHA treatment also increased soluble AβPP and Aβ1-40 levels, and decreased Aβ1-42/Aβ1-40 ratio, which are similar to what were observed in Tg2576 mice fed with ARA+ or DHA+ diet. These findings suggest that not only the DHA+ diet, but also the ARA+ diet could prevent cognitive dysfunction in Tg2576 mice through the alteration of AβPP processing.
Pages 163-173
Adriana Serna, Israel Contador, Félix Bermejo-Pareja, Alex J. Mitchell, Bernardino Fernández-Calvo, Francisco Ramos, Alberto Villarejo, Julián Benito-León
Accuracy of a Brief Neuropsychological Battery for the Diagnosis of Dementia and Mild Cognitive Impairment: An Analysis of the NEDICES Cohort
Abstract: Early separation of mild cognitive impairment (MCI) from normal aging and mild cases of dementia remains a challenge, especially in the general population. We aimed to analyze the diagnostic accuracy of a brief neuropsychological battery (BNB) in dementia and MCI cases from the Neurological Disorders in Central Spain (NEDICES) population-based cohort study. We screened 3,891 participants into dementia and non-dementia groups using a two-phase procedure: screening (MMSE-37 and Pfeffer-11) and clinical diagnosis by specialists (DSM-IV criteria). We selected subsequently a subsample of dementia (n=98), MCI (n=71), and cognitively healthy (n=123) participants matched in socio-demographic characteristics. The clinical validity of each test of the BNB was determined by the area under the ROC curve. We determined the best combination of tests to classify individuals into the diagnostic groups by logistic regression analyses. The results indicated that dementia and MCI groups could be best discriminated from the healthy control group on the basis of their scores on the semantic verbal fluency and delayed recall subtests of the BNB. As for discriminating the MCI group from the dementia group, immediate recall tasks (stories and pictures) yielded the highest level of accuracy. Probably the most interesting finding is that the verbal fluency task consistently allowed discrimination among the diagnostic groups. Overall, subtests of the BNB are more accurate in differentiating dementia patients than MCI patients from healthy controls. In this population-based sample, a more fine-grained discrimination that includes MCI patients should follow a systematic subtest-wise analysis and decision.
Pages 175-187
Qiao-Xin Li, Victor L. Villemagne, James D. Doecke, Alan Rembach, Shannon Sarros, Shiji Varghese, Amelia McGlade, Katrina M. Laughton, Kelly K. Pertile, Christopher J. Fowler, Rebecca L. Rumble, Brett O. Trounson, Kevin Taddei, Stephanie R. Rainey-Smith, Simon M. Laws, Joanne S. Robertson, Lisbeth A. Evered, Brendan Silbert, Kathryn A. Ellis, Christopher C. Rowe, S. Lance Macaulay, David Darby, Ralph N. Martins, David Ames, Colin L. Masters, Steven Collins, for the AIBL Research Group
Alzheimer’s Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study
Abstract: Background: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer’s disease (AD). Objective: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Methods: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau
Pages 189-196
Christian Schmidt, Nicole Gerlach, Matthias Schmitz, Tobias Thom, Katharina Kramer, Tim Friede, Inga Zerr
Baseline CSF/Serum-Ratio of Apolipoprotein E and Rate of Differential Decline in Alzheimer’s Disease
Abstract: Background/Objective: Apolipoprotein E (ApoE) has an active part in the pathogenesis of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a biomarker potentially predictive of cognitive, functional, or motor decline, we analyzed the CSF to serum ratios of ApoE levels (CSF/serum ApoE) in AD patients in this regard. Methods: Subjects with newly diagnosed AD were followed within a longitudinal observational study (rpAD study). Annual neuropsychological testing and physical examination were performed. Multiple regression analyses were used to determine possible associations of the ApoE CSF/serum concentration ratios and velocity of decline on a variety of cognitive, functional and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusted for relevant co-variables. Results: CSF/serum ratios of ApoE levels were associated with progression on the UPDRSIII (change of UPDRSIII slope [pt/yr] per unit of ApoE CSF/serum = -0.06, p<0.01) and instrumental ADL scale (change of iADL slope [pt/yr] per unit of ApoE CSF/serum =0.01, p=0.01) (“the lower the ratio, the faster the deterioration” and vice versa). Secondarily, higher age at onset was associated with faster UPDRSIII progression, antidepressant use with faster iADL decline, and better baseline function with more rapid decline on either MMSE, iADL, or GDS scale. Conclusion: Here, CSF/serum ApoE at time of AD diagnosis was shown to be inversely associated with medium-term functional and motor progression. Whether this ratio qualifies for the use as a predictive biomarker must be validated in larger cohort studies over the long term.
Pages 197-204
Katharina Brüggen, Martin Dyrba, Frederik Barkhof, Lucrezia Hausner, Massimo Filippi, Peter J. Nestor, Karlheinz Hauenstein, Stefan Klöppel, Michel J. Grothe, Elisabeth Kasper, Stefan J. Teipel, the EDSD study group (Handling Associate Editor: Claudio Babiloni)
Basal Forebrain and Hippocampus as Predictors of Conversion to Alzheimer’s Disease in Patients with Mild Cognitive Impairment: A Multicenter DTI and Volumetry Study
Abstract: Background. Hippocampal grey matter (GM) atrophy predicts conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Pilot data suggests that mean diffusivity (MD) in the hippocampus, as measured with diffusion tensor imaging (DTI), may be a more accurate predictor of conversion than hippocampus volume. In addition, previous studies suggest that volume of the cholinergic basal forebrain may reach a diagnostic accuracy superior to hippocampal volume in MCI. Objective. The present study investigated whether increased MD and decreased volume of the hippocampus, the basal forebrain, and other AD-typical regions predicted time to conversion from MCI to AD dementia. Methods. 79 MCI patients with DTI and T1-weighted magnetic resonance imaging were retrospectively included from the European DTI Study in Dementia dataset. Of these participants, 35 converted to AD dementia after 6-46 months (mean: 21 months). We used Cox regression to estimate the relative conversion risk predicted by MD values and GM volumes, controlling for age, gender, education, and center. Results. Decreased GM volume in all investigated regions predicted an increased risk for conversion. Additionally, increased MD in the right basal forebrain predicted increased conversion risk. Reduced volume of the right hippocampus was the only significant predictor in a stepwise model combining all predictor variables. Conclusion. Volume reduction of the hippocampus, the basal forebrain, and other AD-related regions was predictive of increased risk for conversion from MCI to AD. In this study, volume was superior to MD in predicting conversion.
Pages 205-218
Angela J. Hanson, Jennifer L Bayer, Laura D. Baker, Brenna Cholerton, Brian VanFossen, Emily Trittschuh, Robert A Rissman, Michael C. Donohue, Setareh H. Moghadam, Stephen Plymate, Suzanne Craft
Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ε4 Carriers and Adults with Mild Cognitive Impairment
Abstract: Background: High intake of saturated fat (SF) and glycemic index (GI) foods is a risk factor for sporadic Alzheimer's disease. Meal challenges may elucidate mechanisms that contribute to this risk, enabling development of targeted interventions. Objective: To assess cognitive and metabolic changes after a meal high in SF and GI calories (HIGH) versus a meal low in these macronutrients (LOW) in older adults with and without cognitive impairment, and with and without the apolipoprotein E4 risk factor. Methods: 46 adults with either cognitive impairment (CI) or normal cognition (NC) ingested a LOW (25% total fat, 7% SF, GI < 55) and a HIGH meal (50% total fat, 25% SF, GI > 70) in a blinded random fashion. Participants then underwent cognitive testing and blood sampling for metabolic and Alzheimer's disease biomarkers. Data were analyzed using repeated measures ANOVA and Spearman correlations. Results: E4- adults with NC demonstrated lower delayed memory scores after the HIGH compared to the LOW meal, whereas normal E4+ and CI E4- groups had higher scores after the HIGH meal (ANOVA p=0.03). These findings were associated with meal-induced changes in glucose (p=0.05), insulin (p=0.004), triglycerides (p<0.01), and plasma Aβ42 (p=0.05). Conclusions: These preliminary data suggest that cognitive performance of adults without CI may worsen following high SF and sugar meals, whereas adults with CI or those at risk for CI due to E4 status may benefit acutely from such meals. Furthermore, plasma Aβ was affected by meal type, suggesting a relationship between metabolic response and amyloid regulation.
Pages 219-227
John J. Alam
Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged RatsAbstract: Background: P38 mitogen activated protein kinase (MAPK) α modulates microglia-mediated inflammatory responses and a number of neuronal physiological processes. Objective: To evaluate pre-clinically the pharmacological effects in the brain of p38 MAPKα inhibition with a brain-penetrant specific chemical antagonist. Methods: VX-745, a blood-brain barrier penetrant, highly selective p38 MAPKα inhibitor, and clinical stage investigational drug, was utilized. Initially, a pilot study in 26-month-old Tg2576 mice was conducted. Subsequently, a definitive dose-response study was conducted in aged (20-22 months) rats with identified cognitive deficits; n=15 per group: vehicle, 0.5, 1.5, and 4.5 mg/kg VX-745 by oral gavage twice daily for 3 weeks. Assessments in aged rats included IL-1β, PSD-95, TNFα protein levels in hippocampus; and Morris water maze (MWM) test for cognitive performance. Results: Drug effect could not be assessed in Tg2576 mice, as little inflammation was evident. In cognitively-impaired aged rats, VX-745 led to significantly improved performance in the MWM and significant reduction in hippocampal IL-1βprotein levels, though the effects were dissociated as the MWM effect was evident at a lower dose level than that required to lower IL-1β. Drug concentration-effect relationships and predicted human doses were determined. Conclusions: Selective inhibition of p38 MAPKα with VX-745 in aged rats reduces hippocampal IL-1β levels and improves performance in the MWM. As the two effects occur at different dose levels, the behavioral effect appears to be via a mechanism that is independent of reducing cytokine production. The predicted human doses should minimize risks of systemic toxicity.
Pages 229-239
Seyed-Mohammad Fereshtehnejad, Peter Johannsen, Gunhild Waldemar, Maria Eriksdotter
Dementia Diagnosis, Treatment, and Care in Specialist Clinics in Two Scandinavian Countries: A Data Comparison between the Swedish Dementia Registry (SveDem) and the Danish Dementia Registry
Abstract: Background: Two dementia quality registries have been developed in Denmark and Sweden with the aim to assess quality of dementia care based on adherence to national guidelines. Objective: To compare patient characteristics, diagnostics, treatment, and quality indicators of dementia care among patients referred to specialist units in Sweden and Denmark. Methods: Data from the Swedish Dementia Registry (SveDem) and the Danish Dementia Registry were merged. Newly diagnosed dementia cases referred to memory clinics during 2007-2012 were included (19,629 Swedish and 6,576 Danish patients). Results: The median duration between initial assessment and confirmed diagnosis was 56 and 57 days in Sweden and Denmark, respectively. Brain imaging using MRI was twice as common in Sweden. A diagnosis of dementia was established at an average MMSE of 21. An etiological diagnosis was concluded in 89.6% of the Swedish and 87.3% of the Danish cases. Alzheimer’s disease (AD) was the most common disorder (47.7% in Denmark and 36.6% in Sweden); however, more cases were diagnosed as mixed AD in Sweden (24.7% versus 10.6%). More than 80% of patients with AD, dementia with Lewy bodies, and Parkinson’s disease with dementia were treated with anti-dementia drugs. Conclusion: The targets of several quality indicators in both registries were met, such that structural brain imaging and MMSE were performed in >90% and an etiological diagnosis was concluded in >80% of the patients. However, there were also results of concern. The diagnosis of dementia was established at a mean MMSE of 21, which is already late in the course of most dementia disorders. A higher chance of vascular findings following the higher rate of MRI in Sweden may have resulted in more mixed AD diagnosis, which could be one explanation for diagnostic differences but also highlights the need to harmonize diagnostic criteria.
Pages 241-249
Jari Heiskanen, Sirpa Hartikainen, Risto P. Roine, Anna-Maija Tolppanen
30-Day Mortality after Cardiovascular Events in Persons with or without Alzheimer’s Disease
Abstract: Background and Objectives: Persons with Alzheimer’s disease (AD) have been suggested to receive suboptimal treatment. We studied the 30-day mortality after ischemic stroke, hemorrhagic stroke, or myocardial infarction in individuals with or without AD. Methods: An exposure matched cohort of all Finnish community-dwellers diagnosed with clinically verified AD in 2005-2012 (n=73,005) and 1-4 matched comparison persons/AD-affected person (n=215,449). Data on 30-day mortality after ischemic stroke (n=16,419; deaths: n=2,748), hemorrhagic stroke (n=3,570; deaths: n=1,224), and myocardial infarction (n=15,304; deaths: n=3,804) were obtained from the National Hospital Discharge register. The main analyses were restricted to first-ever events. Results: Persons with AD had slightly higher 30-day mortality after ischemic stroke (adjusted HR 1.36, 95% Confidence interval (CI) 1.24,1.49), hemorrhagic stroke (adjusted HR 1.11, 95% CI 0.98,1.25), or myocardial infarction (adjusted HR, 1.40, 9% CI 1.30,1.51). The associations were not affected by age, gender, or co-morbidities and remained similar when patients with previous ischemic strokes or infarctions were included. The absolute risk increase in 30-day mortality after ischemic or hemorrhagic stroke and myocardial infarction were 4.9% (95% CI 3.3,6.5), 3.3% (95% CI -1.6,8.2), and 7.5% (95% CI 5.0,10.0), respectively. Conclusions: Although the 30-day mortality was somewhat higher in the AD cohort, the absolute differences were small indicating that acute treatment was not notably inferior in AD patients. The slightly higher mortality was not explained by co-morbidities but may reflect the higher mortality of AD persons in general, or treatment practice of patients with severe cognitive impairment.
Pages 251-260
Lubomira Anderkova, Ilona Eliasova, Radek Marecek, Eva Janousova, Irena Rektorova (Handling Associate Editor: Claudio Babiloni)
Distinct Pattern of Gray Matter Atrophy in Mild Alzheimer’s Disease Impacts on Cognitive Outcomes of Noninvasive Brain Stimulation
Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising tool to study and modulate brain plasticity. Objective: Our aim was to investigate the effects of rTMS on cognitive functions in patients with mild cognitive impairment and Alzheimer’s disease (MCI/AD) and assess the effect of gray matter (GM) atrophy on stimulation outcomes. Methods: Twenty MCI/AD patients participated in the proof-of-concept controlled study. Each patient received three sessions of 10 Hz rTMS of the right inferior frontal gyrus (IFG), the right superior temporal gyrus (STG), and the vertex (VTX, a control stimulation site) in a randomized order. Cognitive functions were tested prior to and immediately after each session. The GM volumetric data of patients were: 1)compared to healthy controls (HC) using source-based morphometry; 2) correlated with rTMS-induced cognitive improvement. Results: The effect of the stimulated site on the difference in cognitive scores was statistically significant for the Word part of the Stroop test (ST-W, p = 0.012, linear mixed models). As compared to the VTX stimulation, patients significantly improved after both IFG and STG stimulation in this cognitive measure. MCI/AD patients had significant GM atrophy in characteristic brain regions as compared to HC (p = 0.029, Bonferroni corrected). The amount of atrophy correlated with the change in ST-W scores after rTMS of the STG. Conclusion: rTMS enhanced cognitive functions in MCI/AD patients. We demonstrated for the first time that distinct pattern of GM atrophy in MCI/AD diminishes the cognitive effects induced by rTMS of the temporal neocortex.
Pages 261-277
David Kelly, Robert F. Coen, Kwadwo Owusu Akuffo , Stephen Beatty , Jessica Dennison, Rachel Moran , Jim Stack , Alan N. Howard , Riona Mulcahy, John M. Nolan
Cognitive Function and Its Relationship with Macular Pigment Optical Density and Serum Concentrations of its Constituent Carotenoids
Abstract: Background: Macular pigment (MP) levels correlate with brain concentrations of lutein (L) and zeaxanthin (Z), and have also been shown to correlate with cognitive performance in the young and elderly. Objective: To investigate the relationship between MP, serum concentrations of L and Z, and cognitive function in subjects free of retinal disease with low MP (MP at 0.25 degrees eccentricity of less than 0.5 optical density units) (Group 1, n=105) and in subjects with AMD (Group 2, n=121). Methods: MP was measured using customized heterochromatic flicker photometry and dual-wavelength autofluorescence; cognitive function was assessed using a battery of validated cognition tests; serum L and Z concentrations were determined by HPLC. Results: Significant correlations were evident between MP and various measures of cognitive function in both groups (r = -0.273 to 0.261, p ≤ 0.05, for all). Both serum L and Z concentrations correlated significantly (r = 0.187, p ≤ 0.05 and r = 0.197, p ≤ 0.05, respectively) with semantic (animal) fluency cognitive scores in Group 2 (the AMD study group), while serum L concentrations also correlated significantly with Verbal Recognition Memory learning slope scores in the AMD study group (r = 0.200, p = 0.031). Most of the correlations with MP, but not serum L or Z, remained significant after controlling for age, gender, diet, and education level. Conclusion: MP offers potential as a non-invasive clinical biomarker of cognitive health, and appears more successful in this role than serum concentrations of L or Z.
Pages 279-286
Kosuke Matsuzono, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Shoichiro Kono, Kentaro Deguchi, Ryuta Morihara, Koji Abe
Comprehensive Clinical Evaluations of Frontotemporal Dementia Contrasting to Alzheimer’s Disease (oFTD Study)
Abstract: Background/Objective: To examine comprehensive clinical evaluations of frontotemporal dementia (FTD) patients compared with Alzheimer’s disease (AD) patients. Methods: We used eight batteries and the touch panel test to retrospectively analyze 41 FTD patients compared with 121 AD patients. Furthermore, 34 FTD and all 121 AD patients were evaluated with a frontotemporal dementia-Alzheimer’s disease index (FA index), which we developed for novel diagnosis with magnetic resonance imaging. Results: Frontal assessment battery, geriatric depression scale, and Abe’s behavioral and psychological symptom of dementia score were significantly worse in FTD patients than in AD patients (**p<0.01 in FAB, **p<0.01 in the geriatric depression scale, and ***p<0.001 in Abe’s behavioral and psychological symptom of dementia score), although there was no significant difference in the other five scores. The finding mistakes game score of the touch panel test was worse in FTD than in AD (*p<0.05). The receiver operating characteristic curve of the FA index showed 91.4% sensitivity and 89.3% specificity with the FA index ≤0.6015 to discriminate FTD from AD. Conclusion: Combining clinical scores, a computerized touch panel test, and the FA index will help to provide a more accurate diagnosis of FTD in contrast to AD.
