Pages 1259-1272
Review
Boaz Levy, Elena Tsoy, Samuel Gable (Handling Associate Editor: Amos Korczyn)
Developing Cognitive Markers of Alzheimer’s Disease for Primary Care: Implications for Behavioral and Global Prevention
Abstract: A comprehensive approach to the prevention of Alzheimer’s disease (AD) warrants a synergy across multiple domains and procedures. Whereas the study of biological markers has mobilized major activity in the field, the development of cognitive markers is largely ignored, despite the unique advantages they may offer. Cognitive markers essentially assess the core clinical feature that biological markers intend to predict. In this respect, cognitive markers expand the foundation of preclinical diagnostics and disease staging in a manner that integrates both physiological and psychological factors. In addition, the cost-effective implementation of cognitive markers makes them remarkably conducive to community-wide screenings, and thereby a vital component of any global blueprint for prevention. Specifically, in the primary care setting, cognitive markers may provide effective gate keeping for more invasive, labor intensive, and expensive procedures. From this perspective, cognitive markers may provide the first step for identifying preclinical treatment recipients in general public. Moreover, the detection of preclinical decline via cognitive markers can increase awareness of AD risk and the motivation for making protective lifestyle changes. The behavioral approach might be expedient for prevention in light of the compelling evidence of lifestyle amelioration of AD risk. In an integrative view, incorporating cognitive markers to primary care may facilitate a synergetic development in preventive interventions that carries epidemiological significance. This paper addresses the theoretical, methodological, and pragmatic aspects of this prospect.
Pages 1273-1281
Review
Ruth F. Itzhaki
Herpes and Alzheimer’s Disease: Subversion in the Central Nervous System and How It Might Be Halted
Abstract: The last 8 or so years have seen a large increase in the number of studies supporting the concept of a major role for herpes simplex virus type 1 (HSV1) in Alzheimer's disease (AD). The main advances have been made through studies in humans and in mice, investigating the likelihood of reactivation of the latent virus in brain. Others have aimed to explain the mechanisms in cells whereby the increase in amyloid-beta (Aβ) production on HSV1 infection of cells and mouse brains occurs, and the reason that infected cells make this increase. The possibility that other herpesviruses are involved in the development of AD has been explored, and human herpesvirus type 6, Epstein-Barr virus, and cytomegalovirus, in particular, have been implicated. Epidemiological studies have further supported the role specifically of HSV1 and its reactivation in the disease. Antiviral studies have continued, comparing those acting by different mechanisms, such as restricting viral replication, or blocking viral entry into cells, to treat HSV1-infected cell cultures, and then examining the extent to which the virus-induced increases in Aβ and AD-like tau are reduced. All the studies support the usage of antiviral treatment to slow or halt the progression of AD.
Pages 1283-1290
Review
Kilmer S. McCully (Handling Associate Editor: Jack de la Torre)
Homocysteine, Infections, Polyamines, Oxidative Metabolism, and the Pathogenesis of Dementia and Atherosclerosis
Abstract: Hyperhomocysteinemia is a risk factor for development of dementia and Alzheimer’s disease (AD), and low blood levels of folate and cobalamin are associated with hyperhomocysteinemia and AD. In elderly subjects with cognitive decline, supplementation with folate, cobalamin, and pyridoxal demonstrated reduction of cerebral atrophy in gray matter regions vulnerable to the AD process. Multiple pathogenic microbes are implicated as pathogenic factors in AD and atherosclerosis, and the deposition of amyloid-β (Aβ), phosphorylation of tau protein, neuronal injury, and apoptosis in AD are secondary to microbial infection. Glucose utilization and blood flow are reduced in AD, and these changes are accompanied by downregulation of glucose transport, Na, K-ATPase, oxidative phosphorylation, and energy consumption. Thioretinaco ozonide, the complex formed from thioretinamide, cobalamin, ozone, and oxygen is proposed to constitute the active site of oxidative phosphorylation, catalyzing synthesis of adenosine triphosphate (ATP) from nicotinamide adenine dinucleotide (NAD+) and phosphate. Pathogenic microbes cause synthesis of polyamines in host cells by increasing the transfer of aminopropyl groups from adenosyl methionine to putrescine, resulting in depletion of intracellular adenosyl methionine concentrations in host cells. Depletion of adenosyl methionine causes dysregulation of methionine metabolism, hyperhomocysteinemia, reduced biosynthesis of thioretinamide and thioretinaco ozonide, decreased oxidative phosphorylation, decreased production of nitric oxide and peroxynitrite, and impaired host response to infectious microbes, contributing to the pathogenesis of dementia and atherosclerosis.
Pages 1291-1295
Short Communication
Dimitri Renard, Audrey Gabelle, Christophe Hirtz, Christophe Demattei, Eric Thouvenot, Sylvain Lehmann
Cerebrospinal Fluid Alzheimer’s Disease Biomarkers in Isolated Supratentorial Cortical Superficial Siderosis
Abstract: We evaluated cerebrospinal fluid amyloid-β 1-40 (Aβ40), amyloid-β 1-42 (Aβ42), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n=13), Alzheimer’s disease patients (AD, n=42), and controls (n=16). Compared to controls, SS patients showed statistically significant higher t-tau (p=0.019) and lower Aβ42 (p=0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aβ40 compared to AD (p=0.0063, p=0.0004, and p=0022, respectively), and higher p-tau compared to LH-CAA (p=0.012).
Pages 1297-1302
Short Communication
Philip S.J. Weston, Ross W. Paterson, John Dickson, Anna Barnes, Jamshed B. Bomanji, Irfan Kayani, Michael P. Lunn, Catherine J. Mummery, Jason D. Warren, Martin N. Rossor, Nick C. Fox, Henrik Zetterberg, Jonathan M. Schott (Handling Associate Editor: Eloi Magnin)
Diagnosing Dementia in the Clinical Setting: Can Amyloid PET Provide Additional Value Over Cerebrospinal Fluid?
Abstract: Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer’s disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist’s working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic uncertainty remains.
Pages 1303-1317
Paula Iso-Markku, Katja Waller, Eero Vuoksimaa, Kauko Heikkilä, Juha Rinne, Jaakko Kaprio, Urho M. Kujala
Midlife Physical Activity and Cognition Later in Life: A Prospective Twin Study
Abstract: Background: Physical activity has been associated with a reduced risk of cognitive decline but the nature of this association remains obscure. Objective: To study associations between midlife physical activity and cognition in old age for a prospective cohort of Finnish twins. Methods: Physical activity in the Finnish Twin Cohort was assessed using questionnaire responses collected in 1975 and 1981. After a mean follow-up of 25.1 years, the subjects’ (n = 3050; mean age 74.2; range 66-97) cognition was evaluated with a validated telephone interview. Both participation in vigorous physical activity, and the volume of physical activity, divided into quintiles, were used as predictors of cognitive impairment. Metrics collected by TELE were used to categorize participants as: cognitively impaired, suffering mild cognitive impairment, or cognitively healthy. Results: Participation in vigorous physical activity compared to non-participation for both 1975 and 1981 was associated with a lower risk of cognitive impairment in individual-based analyses (fully adjusted OR 0.50, 95% CI 0.35- 0.73). Pairwise analyses yielded similar but statistically non-significant associations. In terms of the volume of physical activity, the most active quintile of individuals (OR 0.69, 95% CI 0.46- 1.04) had a reduced risk of cognitive decline compared with the most sedentary quintile in the fully adjusted model although no clear dose-response was found. Conclusion: Vigorous midlife physical activity was associated with less cognitive impairment but without a clear dose-response association between the volume of physical activity and cognition.
Pages 1319-1331
Kerstin Ritter, Catharina Lange, Martin Weygandt, Anja Mäurer, Anna Roberts, Melanie Estrella, Per Suppa, Lothar Spies, Vikas Prasad, Ingo Steffen, Ivayla Apostolova, Daniel Bittner, Mehmet Gövercin, Winfried Brenner, Christine Mende, Oliver Peters, Joachim Seybold, Jochen B. Fiebach, Elisabeth Steinhagen-Thiessen, Harald Hampel, John-Dylan Haynesa, Ralph Buchert
Combination of Structural MRI and FDG-PET of the Brain Improves Diagnostic Accuracy in Newly Manifested Cognitive Impairment in Geriatric Inpatients
Abstract: Background: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease. Objective: To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients. Methods: Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimer’s disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), which remained uncertain after standard diagnostic workup. Additional procedures performed after enrolment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis. Results: Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p=0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p≤0.001). Integration of all modalities resulted in 76% accuracy (p≤0.001). Conclusion: These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process.
Pages 1333-1338
Ambreen Mirza, Andrew King, Claire Troakes, Christopher Exley
The Identification of Aluminum in Human Brain Tissue Using Lumogallion and Fluorescence Microscopy
Abstract: Aluminum in human brain tissue is implicated in the etiologies of neurodegenerative diseases including Alzheimer’s disease. While methods for the accurate and precise measurement of aluminum in human brain tissue are widely acknowledged, the same cannot be said for the visualization of aluminum. Herein we have used transversely-heated graphite furnace atomic absorption spectrometry to measure aluminum in the brain of a donor with Alzheimer’s disease, and we have developed and validated fluorescence microscopy and the fluor lumogallion to show the presence of aluminum in the same tissue. Aluminum is observed as characteristic orange fluorescence that is neither reproduced by other metals nor explained by autofluorescence. This new and relatively simple method to visualize aluminum in human brain tissue should enable more rigorous testing of the aluminum hypothesis of Alzheimer’s disease (and other neurological conditions) in the future.
Pages 1339-1348
Susan A. Farr, Karin E. Sandoval, Michael L. Niehoff, Ken A. Witt, Vijaya B. Kumar, John E. Morley (Handling Associate Editor: William Banks)
Peripheral Administration of GSK-3β Antisense Oligonucleotide Improves Learning and Memory in SAMP8 and Tg2576 Mouse Models of Alzheimer’s Disease
Abstract: Glycogen synthase kinase (GSK)-3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer’s disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ), and neurodegeneration. We have previously shown that an antisense oligonucleotide directed at the Tyr 216 site on GSK-3β (GAO) when injected centrally can decrease GSK-3β levels, improve learning and memory, and decreases oxidative stress. In addition, we showed that GAO can cross the blood-brain barrier. Herein the impact of peripherally administered GAO in both the non-transgenic SAMP8 and transgenic Tg2576 (APPswe) models of AD were examined respective to learning and memory. Brain tissues were then evaluated for expression changes in the phosphorylated-Tyr 216 residue, which leads to GSK-3β activation, and the phosphorylated-Ser9 residue, which reduces GSK-3β activity. SAMP8 GAO-treated mice showed improved acquisition and retention using aversive T-maze, and improved declarative memory as measured by the novel object recognition (NOR) test. Expression of the phosphorylated-Tyr 216 was decreased and the phosphorylated-Ser9 was increased in GAO-treated SAMP8 mice. Tg2576 GAO-treated mice improved acquisition and retention in both the T-maze and NOR tests, with an increased phosphorylated-Ser9 GSK-3β expression. Results demonstrate that peripheral administration of GAO improves learning and memory, corresponding with alterations in GSK-3β phosphorylation state. This study supports peripherally administered GAO as a viable means to mediate GSK-3β activity within the brain and a possible treatment for AD.
Pages 1349-1357
Yuta Yoshino, Takaaki Mori, Taku Yoshida, Kiyohiro Yamazaki,Yuki Ozaki, Tomoko Sao, Yu Funahashi, Jun-ichi Iga, and Shu-ichi Ueno
Elevated mRNA Expression and Low Methylation of SNCA in Japanese Alzheimer’s Disease Subjects
Abstract: Despite the continuing debate about the amyloid hypothesis in Alzheimer's disease (AD), the precise pathogenesis is still unclear. Mixed pathology is common and multiple different protein aggregates are seen in human postmortem brains. Aggregates consisting of the alpha-synuclein protein encoded by the Synuclein Alpha gene (SCNA) are common in both dementia with Lewy bodies and AD. We examined SNCA mRNA expression and methylation rates of the CpG island at intron 1 of SNCA in peripheral leukocytes in 50 AD and age- and sex-matched control subjects to verify whether alpha-synuclein pathology affects the AD pathogenesis. SNCA mRNA expression in AD subjects was significantly higher than that in control subjects (1.62 ± 0.73 versus 0.98 ± 0.50, p < 0.001). We found significant differences between AD and control subjects at seven CpG sites (average rate; 8.8 ± 2.7 versus 9.5 ± 2.5, respectively: p = 0.027). The methylation rates tended to be lower in AD subjects at all CpG sites. We conclude that mRNA expression and methylation of SNCA intron 1 are altered in AD, which may be caused by Lewy body pathology in AD.
Pages 1359-1364
Candice A. Myers, Jeffrey N. Keller, H. Raymond Allen, Robert M. Brouillette, Heather Foil, Allison B. Davis, Frank L. Greenway, William D. Johnson, Corby K. Martin (Handling Associate Editor: Russell Swerdlow)
Reliability and Validity of a Novel Internet-Based Battery to Assess Mood and Cognitive Function in the Elderly
Abstract: Dementia is a chronic condition in the elderly and depression is often a concurrent symptom. As populations continue to age, accessible and useful tools to screen for cognitive function and its associated symptoms in elderly populations are needed. The aim of this study was to test the reliability and validity of a new internet-based assessment battery for screening mood and cognitive function in an elderly population. Specifically, the Helping Hand Technology (HHT) assessments for depression (HHT-D) and global cognitive function (HHT-G) were evaluated in a sample of 57 elderly participants (22 male, 35 female) aged 59-85 years. The study sample was categorized into three groups: 1) dementia (n=8; Mini-Mental State Exam (MMSE) score 10-24), 2) mild cognitive impairment (n=24; MMSE score 25-28), and 3) control (n=25; MMSE score 29-30). Test-retest reliability (Pearson correlation coefficient, r) and internal consistency reliability (Cronbach’s alpha, α) of the HHT-D and HHT-G were assessed. Validity of the HHT-D and HHT-G was tested via comparison (Pearson r) to commonly used pencil-and-paper based assessments: HHT-D versus the Geriatric Depression Scale (GDS) and HHT-G versus the MMSE. Good test-retest (r=0.80; p<0.0001) and acceptable internal consistency reliability (α=0.73) of the HHT-D were established. Moderate support for the validity of the HHT-D was obtained (r=0.60 between the HHT-D and GDS; p<0.0001). Results indicated good test-retest (r=0.87; p<0.0001) and acceptable internal consistency reliability (α=0.70) of the HHT-G. Validity of the HHT-G was supported (r=0.71 between the HHT-G and MMSE; p<0.0001). In summary, the HHT-D and HHT-G were found to be reliable and valid computerized assessments to screen for depression and cognitive status, respectively, in an elderly sample.
Pages 1365-1372
Bernd Brüggenjürgen, Frank Andersohn, Jörg Burkowitz, Nadja Ezzat, Maren Gaudig, Stefan N. Willich
Cohort Study on Predictors of Need for Nursing Care in Alzheimer’s Disease: An Analysis of Healthcare Data
Abstract: Background: The individual and societal burden of Alzheimer’s disease (AD) is substantial. Identifying relevant factors deteriorating AD and inducing need for nursing care would be of high relevance for healthcare planning. Objective: The main objective of this study was the identification of predictors of first assignment of a level of long-term care in AD, used as an approximation for disease progression. Methods: In a retrospective cohort study using data from a large German statutory health and long-term care insurance (SHI) company, co-morbidities and drug exposure were evaluated with respect to their predictive value for disease progression (first day the amount of daily nursing care exceeded 1.5 hours). Time to disease progression was modeled using COX-proportional hazard regression with stepwise selection of predictor variables. Results: The risk of nursing care need increased substantially with increasing age. Number of hospitalizations and number of different drugs used were significant indicators for progression, whereas outpatient visits were associated with a reduced need for care. Gender did not indicate significant influence on progression. Malignant neoplasms of illdefined, secondary, and unspecified sites, malnutrition, renal failure, and injuries increased the risk of need for nursing care most significantly. Among prescribed drugs, significant increased risks were associated with drugs used in diabetes, preparations for treatment of wounds and ulcers, antiseptics and disinfectants, and analgesics. Conclusions: Physical comorbidities are relevant contributors to an increase in need for nursing care. Some medical predicting conditions may be linked to cognition, while others may be directly linked to demand for care. AD patients with these comorbidities should be monitored with special attention, as they may be under an increased risk of care dependency.
Pages 1373-1383
Marat A. Mukhamedyarov*, Albert A. Rizvanov*, Eduard Z. Yakupov, Andrey L. Zefirov, Andrey P. Kiyasov, Helton J. Reis, Antônio L. Teixeira, Luciene B. Vieira, Luciana M. Lima, Ilnur I. Salafutdinov, Elena O. Petukhova, Svetlana F. Khaiboullina, Karen A. Schlauch, Vincent C. Lombardi, András Palotás *These authors contributed equally to this work.
Transcriptional Analysis of Blood Lymphocytes and Skin Fibroblasts, Keratinocytes, and Endothelial Cells as a Potential Biomarker for Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a devastating and progressive form of dementia that is typically associated with a build-up of amyloid-β plaques and hyperphosphorylated and misfolded tau protein in the brain. Presently, there is no single test that confirms AD; therefore, a definitive diagnosis is only made after a comprehensive medical evaluation, which includes medical history, cognitive tests, and a neurological examination and/or brain imaging. Additionally, the protracted prodromal phase of the disease makes selection of control subjects for clinical trials challenging. In this study we have utilized a gene-expression array to screen blood and skin punch biopsy (fibroblasts, keratinocytes, and endothelial cells) for transcriptional differences that may lead to a greater understanding of AD as well as identify potential biomarkers. Our analysis identified 129 differentially expressed genes from blood of dementia cases when compared to healthy individuals, and four differentially expressed punch biopsy genes between AD subjects and controls. Additionally, we identified a set of genes in both tissue compartments that showed transcriptional variation in AD but were largely stable in controls. The translational products of these variable genes are involved in the maintenance of the Golgi structure, regulation of lipid metabolism, DNA repair, and chromatin remodeling. Our analysis potentially identifies specific genes in both tissue compartments that may ultimately lead to useful biomarkers and may provide new insight into the pathophysiology of AD.
Pages 1385-1393
André Karch*, Franc Llorens*, Matthias Schmitz, Amandeep Arora, Saima Zafar, Peter Lange, Christian Schmidt, Inga Zerr *These authors contributed equally to this work.
Stratification by Genetic and Demographic Characteristics Improves Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers in Rapidly Progressive Dementia
Abstract: Background: Cerebrospinal fluid (CSF) biomarkers are routinely used for the differential diagnosis of rapidly progressive dementia, but are also affected by patients’ characteristics. Objective: To assess if stratification by age, sex, and genetic risk factors improves the accuracy of cerebrospinal fluid (CSF) biomarkers in patients with rapidly progressive dementia. Methods: 1,538 individuals with sporadic Creutzfeldt-Jakob disease (CJD), 173 with classic Alzheimer’s disease (cAD), 37 with rapidly progressive Alzheimer’s disease (rpAD), and 589 without signs of dementia were included in this retrospective diagnostic study. The effect of age, sex, PRNP codon 129, and APOE genotype on CSF levels of tau, p-tau, Aβ1-42, and Aβ1-40 values measured at time of diagnostic work-up was assessed. Results: Tau was a better marker for the differentiation of CJD and rpAD in older (AUC:0.97; 95%CI:0.96-1.00) than in younger (AUC:0.91; 95%CI:0.87-0.94) patients as tau levels increased with age in CJD patients, but not in rpAD patients. PRNP codon 129 and APOE genotype had complex effects on biomarkers in all diseases, making stratification by genotype a powerful tool. In females (AUC:0.78; 95%CI:0.65-0.91) and patients older than 70 (AUC:0.78; 95%CI:0.62-0.93), tau was able to differentiate with moderate accuracy between cAD and rpAD patients. Conclusion: Implementation of stratum-specific reference ranges improves the diagnostic accuracy of CSF biomarkers for the differential diagnosis of rapidly progressive dementia. Diagnostic criteria developed for this setting have to take this into account.
Pages 1395-1408
Annie M. Racine , Lindsay R. Clark, Sara E. Berman, Rebecca L. Koscikb, Kimberly D. Mueller, Derek Norton, Christopher R. Nicholas, Kaj Blennow, Henrik Zetterberg, Bruno Jedynak, Murat Bilgel, Cynthia M. Carlsson, Bradley T. Christian, Sanjay Asthana, Sterling C. Johnson
Associations between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer’s Disease
Abstract: It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer’s disease (AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer’s Prevention (mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery (CAB) of seven tests and demographic characteristics; traditional paper-based neuropsychological tests as well as a composite cognitive impairment index; cognitive impairment status (determined by consensus review); and biomarkers for amyloid and tau (CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury (CSF neurofilament light protein). CSF and PET-PiB were collected in n=71 and n=91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD.
Pages 1409-1423
Baoyu Yuan, ChunmingXie, Hao Shu, Wenxiang Liao, Zan Wang, Duan Liu, Zhijun Zhang
Differential Effects of APOE Genotypes on the Anterior and Posterior Subnetworks of Default Mode Network in Amnestic Mild Cognitive Impairment
Abstract: Background: The apolipoprotein E (APOE) ε4 carriers are at increased risk of developing Alzheimer’s disease (AD) while the ε2 carriers appear to be protected against the disease. The default mode network (DMN), based in ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), consists of functionally differentiable anterior and posterior subnetworks. Objective: This study was to investigate whether there are differential effects of APOE polymorphisms on DMN subnetworks in amnestic mild cognitive impairment (aMCI). Methods: Functional connectivity (FC) analyses were performed in DMN subnetworks in 74 aMCI (9 APOE ε2ε3, 44 ε3ε3, and 21 ε3ε4) and 105 healthy controls (HC; 32 APOE ε2ε3, 39 ε3ε3, and 34 ε3ε4). Logistic regression analysis was performed to obtain a model for classifying aMCI and HC. Results: Significant interactions of APOE by aMCI on FCs were found in right cerebellum posterior lobe, left lingual gyrus, and right middle cingulate cortex in the vmPFC subnetwork, and bilateral fusiform gyrus, left inferior frontal gyrus, and left precuneus in the PCC subnetwork. The impairment of episodic memory for ε4-carriers in aMCI negatively correlated with altered FC between vmPFC and right middle cingulate cortex, while positively correlated with altered FC between PCC and left fusiform gyrus. A model composed of episodic memory and FCs dexterity correctly classified 89.4% of aMCI and HC. Conclusions: APOE ε4 and ε2 alleles differentially mediate anterior and posterior DMN subnetworks. Furthermore, it further suggests that the anterior and posterior DMN subnetworks in aMCI play an opposing role on the impairment of episodic memory.
Pages 1425-1435
Edwin C.K. Tan, J Simon Bell, Christine Y. Lu, Sengwee Toh (Handling Associate Editor: Diana Wucherer)
National Trends in Outpatient Antihypertensive Prescribing in People with Dementia in the United States
Abstract: Background/Objective: The objectives were to investigate national trends in outpatient antihypertensive prescribing in people with dementia in the United States between 2006 and 2012, and to investigate clinical and demographic factors associated with different antihypertensive prescribing patterns. Methods: This was an analysis of the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department component of the National Hospital Ambulatory Medical Care Survey (NHAMCS). Outpatient visits by people aged ≥65 years with documented dementia were analyzed. Complex samples multivariate logistic regression was conducted to estimate temporal trends and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for factors associated with prescribing of antihypertensives, multiple antihypertensives and different antihypertensive classes. Results: There was a statistically significant increase in the proportion of physician visits by older people with dementia with a documented diagnosis of hypertension from 49.3% (95%CI: 41.3%–57.4%) in 2006 to 55.7% (95%CI: 50.2%–61.2%) in 2012. There were non-significant increases in overall antihypertensive use and the use of multiple antihypertensive classes. Male sex was associated with any antihypertensive use (AOR 1.37, 95%CI 1.02–1.84) and multiple antihypertensive class use (AOR 1.52, 95%CI 1.14–2.04). Black race (AOR 2.04, 95%CI 1.12–3.71) and Midwest residence (AOR 2.03, 95%CI 1.46–2.82) were associated with multiple antihypertensive use. Conclusion: There was an increase in documented hypertension in physician visits by older people with dementia from 2006 to 2012, but minimal increases in overall antihypertensive use. Various demographic and clinical factors were associated with the prescribing of antihypertensives in people with dementia.
Pages 1437-1457
Andrea Chincarini, Francesco Sensi, Luca Rei, Irene Bossert, Silvia Morbelli, Ugo Paolo Guerra, Giovanni Frisoni, Alessandro Padovani, Flavio Nobili, and for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Patrizia Mecocci)
Standardized Uptake Value Ratio-Independent Evaluation of Brain Amyloidosis
Abstract: The assessment of in vivo 18F images targeting amyloid deposition is currently carried on by visual rating with an optional quantification based on standardized uptake value ratio (SUVr) measurements. We target the difficulties of image reading and possible shortcomings of the SUVr methods by validating a new semi quantitative approach named ELBA. ELBA involves a minimal image preprocessing and does not rely on small, specific region of interests (ROIs). It evaluates the whole brain and delivers a geometrical/intensity score to be used for ranking and dichotomic assessment. The method was applied to 504 18F-florbetapir images from the ADNI database. Five expert readers provided visual assessment in blind and open sessions. The longitudinal trend and the comparison to SUVr measurements were also evaluated. ELBA performed with area under the roc curve (AUC) = 0.997 versus the visual assessment. The score was significantly correlated to the SUVr values (r = 0.86, p < 10−4). The longitudinal analysis estimated a test/retest error of ≈ 2.3%. Cohort and longitudinal analysis suggests that the ELBA method accurately ranks the brain amyloid burden. The expert readers con- firmed its relevance in aiding the visual assessment in a significant number (85) of difficult cases. Despite the good performance, poor and uneven image quality constitutes the major limitation.
Pages 1459-1471
Eloi Magnin, Jean-François Démonet, David Wallon, Julien Dumurgier, Anne-Cécile Troussière, Alain Jager, Emmanuelle Duron, Audrey Gabelle, Vincent de la Sayette, Lisette Volpe-Gillot, Gregory Tio, Sarah Evain, Claire Boutoleau-Bretonnière, Adeline Enderle, François Mouton-Liger, Philippe Robert, Didier Hannequin, Florence Pasquier, Jacques Hugon, Claire Paquet, on behalf of ePLM collaborators
Primary Progressive Aphasia in the Network of French Alzheimer Plan Memory Centers
Abstract: Background: Few demographical data about primary progressive aphasia (PPA) are available, and most knowledge regarding PPA is based on tertiary centers’ results. Objective: Our aims were to describe demographical characteristics of the PPA population in a large sample of PPA patients from the network of French Alzheimer plan memory centers (Sample 1), and to describe the stratification of cerebrospinal fluid (CSF) biomarkers in two different samples of PPA patients (Samples 2 and 3). Methods: All registered PPA patients in the French Alzheimer’s disease (AD) databank (Sample 1: n=2,035) and a subsample (Sample 2: n=65) derived from a multicentric prospective cohort with CSF biomarker analysis were analyzed. A multicentric retrospective cohort from language expert tertiary centers (Sample 3: n=97) with CSF biomarker analysis was added. Sample 3 was added to replicate the CSF results of the Sample 2 and to evaluate repartition of AD pathology in the three variant of PPA according to the latest classification. Results: Non-Fluent/Agrammatic, Logopenic, and Unclassifiable PPA patients (NF/A-Logo-Unclass PPA) were older and more frequent than Semantic PPA patients (2.2 versus 0.8/100,000 inhabitants; p<0.00001). Male predominance occurred after the age of 80 (p<0.00001). A higher level of education was observed in the PPA population compared to a typical amnesic AD group. No demographical significant difference between PPA due to AD and not due to AD was observed. The Logopenic variant was most frequent with 85% of AD CSF biomarker profiles (35% in NF/A PPA; 20% in Semantic PPA). Conclusion: PPA occurs also in an elderly population, especially in male patients over 80. CSF biomarkers are useful to stratify PPA. The epidemiology of PPA should be further investigated to confirm gender and cognitive reserve role in PPA to better understand the factors and mechanisms leading to this language-predominant deficit during neurodegenerative diseases.
Pages 1473-1482
Hyuma Makizako , Hiroyuki Shimada , Takehiko Doi , Kota Tsutsumimoto , Ryo Hotta, Sho Nakakubo , Keitaro Makino, Takao Suzuki
Comorbid Mild Cognitive Impairment and Depressive Symptoms Predict Future Dementia in Community Older Adults: A 24-Month Follow-Up Longitudinal Study
Abstract: Background: Older adults with mild cognitive impairment (MCI) are non-demented, but demonstrate cognitive dysfunction, and have significantly higher risk of progressing to dementia. A better understanding of more sensitive risk factors, such as combination of cognitive and psychological status, for progression of MCI to dementia may be crucial for prevention of development of dementia. Objective: To examine MCI, depressive symptoms, and comorbid MCI and depressive symptoms as risk factors for development of dementia. Methods: A total of 3,663 community-dwelling older people were included in this prospective longitudinal study. MCI was determined by age- and education-adjusted objective cognitive impairment using computerized comprehensive cognitive measures including memory, attention/executive function, and processing speed. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) and defined by a GDS score of 6 or more. Results: During the 24-month follow-up period, 72 participants (2.0%) developed dementia. Baseline MCI was significantly associated with an increased risk of incident dementia (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.8–5.5) but depressive symptoms were not (2.0; 1.0–4.2) after adjusting for age, sex, education, prescribed medications, and walking speed. Participants with comorbid MCI and depressive symptoms at baseline had a higher risk of developing dementia (HR, 4.8; 2.3–10.5). Conclusion: Although MCI and depressive symptoms may be associated with increased risk for incident dementia independently, comorbid MCI and depressive symptoms have a significantly greater impact on dementia development among community-dwelling older adults.
Pages 1483-1493
Tiantian Qiu*, Xiao Luo*, Zhujing Shen, Peiyu Huang, Xiaojun Xu, Jiong Zhou, Minming Zhang, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Disrupted Brain Network in Progressive Mild Cognitive Impairment Measured by Eigenvector Centrality Mapping is Linked to Cognition and Cerebrospinal Fluid Biomarkers
Abstract: Mild cognitive impairment (MCI) is a heterogeneous condition associated with a high risk of progressing to Alzheimer’s disease (AD). Although functional brain network alterations have been observed in progressive MCI (pMCI), the underlying pathological mechanisms of network alterations remain unclear. In the present study, we evaluated neuropsychological, imaging, and cerebrospinal fluid (CSF) data at baseline across a cohort of: 21 pMCI patients, 33 stable MCI (sMCI) patients, and 29 normal controls. Fast eigenvector centrality mapping (fECM) based on resting-state functional MRI (rsfMRI) was used to investigate brain network organization differences among these groups, and we further assessed its relation to cognition and AD-related pathology. Our results demonstrated that pMCI had decreased eigenvector centrality (EC) in left temporal pole and parahippocampal gyrus, and increased EC in left middle frontal gyrus compared to sMCI. In addition, compared to normal controls, patients with pMCI showed decreased EC in right hippocampus and bilateral parahippocampal gyrus, and sMCI had decreased EC in right middle frontal gyrus and superior parietal lobule. Correlation analysis showed that EC in the left temporal pole was related to Wechsler Memory Scale-Revised Logical Memory (WMS-LM) delay score (r=0.467, p=0.044) and total tau (t-tau) level in CSF (r=-0.509, p=0.026) in pMCI. Our findings implicate EC changes of different brain network nodes in the prognosis of pMCI and sMCI. Importantly, the association between decreased EC of brain network node and pathological changes may provide a deeper understanding of the underlying pathophysiology of pMCI.
Pages 1495-1508
Salvatore Mazzeo*, Roberto Santangelo*, Maria Paola Bernasconi, Giordano Cecchetti, Agnese Fiorino, Patrizia Pinto, Gabriella Passerini, Monica Falautano, Giancarlo Comi, Giuseppe Magnani (Handling Associate Editor: Diego Albani) *These authors contributed equally to this work.
Combining Cerebrospinal Fluid Biomarkers and Neuropsychological Assessment: A Simple and Cost-Effective Algorithm to Predict the Progression from Mild Cognitive Impairment to Alzheimer’s Disease Dementia
Abstract: Background: Correctly diagnosing Alzheimer’s disease (AD) in prodromal phases would allow the adoption of experimental therapeutic strategies that could selectively interrupt the pathogenetic process before neuronal damage get irreversible. Therefore, great efforts have been aimed at finding early reliable disease markers. Objective: The aim of this study was to identify a simple, cost effective, and reliable diagnostic algorithm to predict conversion from mild cognitive impairment (MCI) to AD. Methods: 96 consecutive MCI patients admitted to the Neurology department of San Raffaele Hospital in Milan between January 2009 and January 2015 were included. All patients underwent neuropsychological assessment and lumbar puncture with CSF analysis of amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels. Each patient underwent clinical and neuropsychological follow-up, in order to identify a possible progression from MCI to AD. The mean follow up time was 36.73 months. Results: 37 out of 96 MCI converted to AD during follow up. CSF analysis and neuropsychological assessment reliably detected MCI patients who developed AD. In a subsample of 43 subjects, a Composite Cognitive Score (CCS) was calculated including episodic memory, executive function, and verbal fluency tests. Combining together CSF biomarkers and CCS increased the accuracy of the single predictors, correctly classifying 86% of patients with a specificity of 96% and a Positive Predictive Value of 93%. Discussion: Even if preliminary, our data seem to suggest that CSF analysis and neuropsychological assessment could detect MCI patients who will convert to AD with high confidence. Their relative low cost and availability could make them worldwide essential tools in future clinical trials.
Pages 1509-1519
Mark Brody, Enchi Liu, Jianing Di, Ming Lu, Richard A. Margolin, John L. Werth, Kevin Booth, Anna Shadman, H. Robert Brashear, Gerald Novak (Handling Associate Editor: David Bergeron)
A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer’s disease
Abstract: Background: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1-42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD). Objectives: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities–edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated. Methods: In this multicenter, double-blind study, 146 patients were randomized (1:1:1:1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET). Results: Florbetapir PET SUVR decreased significantly (p=0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups. Conclusion: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.
Pages 1521-1538
Emma Mead*, Dimitra Kestoras*, Yolanda Gibson, Lucy Hamilton, Ross Goodson, Sophie Jones, Sarah Eversden, Peter Davies, Michael O’Neill, Michael Hutton, Philip Szekeres, Joanna Wolak (Handling Associate Editor: Jean-Pierre Brion) *These authors contributed equally to this work.
Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation
Abstract: Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer’s disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau’s propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.
Pages 1539-1550
Kimberly Diggle Mueller, Rebecca L. Koscik, Lyn S. Turkstra, Sarah K. Riedeman, Asenath LaRue, Lindsay R. Clark, Bruce Hermann, Mark A. Sager, Sterling C. Johnson (Handling Associate Editor: Peter Garrard)
Connected Language in Late Middle-Aged Adults at Risk for Alzheimer’s Disease
Abstract: Connected language is often impaired among people with Alzheimer’s disease (AD), yet little is known about when language difficulties first emerge on the path to a clinical diagnosis. The objective of this study was to determine whether individuals with psychometric (preclinical) evidence of amnestic mild cognitive impairment (pMCI) showed deficits in connected language measures. Participants were 39 pMCI and 39 cognitively healthy (CH) adults drawn from the Wisconsin Registry for Alzheimer’s Prevention, who were matched for age, literacy, and sex. Participants completed a connected language task in which they described the Cookie Theft picture from the Boston Diagnostic Aphasia Examination. Language samples were analyzed across three language domains: content, syntactic complexity, and speech fluency. Paired t-tests were used to compare CH and pMCI groups on all variables, and Cohen’s d effect sizes were calculated for each comparison. The CH and pMCI groups differed significantly on measures of content (e.g., CH group produced more semantic units, more unique words and had larger idea density, on average, than the pMCI group). The picture description findings are consistent with previous retrospective studies showing semantic language differences in adults with autopsy-confirmed AD. Given that these comparisons are between cognitively healthy and pMCI individuals (before a clinical MCI diagnosis), these findings may represent subtle language difficulty in spontaneous speech, and may be predictive of larger language changes over time.
Pages 1551-1560
Oriol Turró-Garriga, Josep Garre-Olmo, Ramon Reñé-Ramírez, Laia Calvó-Perxas, Jordi Gascón-Bayarri, Josep-Lluís Conde-Sala
Consequences of Anosognosia on the Cost of Caregivers’ Care in Alzheimer’s Disease
Abstract: Background. Anosognosia is common in patients with Alzheimer’s disease (AD) and it is frequently related to an increase in time of care demand. Objective. The aim of the study was to examine the effect of anosognosia on the total costs of informal care in patients with AD. Methods. This was a prospective longitudinal study with community-dwelling AD patients. Anosognosia, time of informal care, and the use of support services (e.g., day care centers) were recorded at baseline and after 24 months. The cost of informal caregiving was calculated as ‘market price’. Results. At baseline, the prevalence of anosognosia was 54.3% (n=221), and 43.9% were classified as mild-AD. The average time of care was 5 h/day ±2.4 (IADL: 1.3 h/day ±1.4 and BADL: 3.6 h/day ±1.5). Thirty percent of the patients used home care services, and 25.1% attended a day care center. Patients with anosognosia received more time of care and were more likely to use support services than did their no-anosognosia peers, including institutionalization. The mean cost of support services was 490.4€/month (SD=413.1€; range=25-2,212.38€), while the overall cost of care (support services plus informal care) was 1,787€/month (SD=972.4€), ranging from 834.1€ in mild-AD without anosognosia patients, to 2,424.8€ in severe-AD with incident anosognosia patients. Conclusions. Anosognosia was associated with an increased number of hours of informal care, and a greater use of support services, regardless of the severity of the dementia, which lead to an increase of the total family-care costs.
Pages 1561-1591
Ioulietta Lazarou, Anastasios Karakostas, Thanos G. Stavropoulos, Theodoros Tsompanidis, Georgios Meditskos, Ioannis Kompatsiaris, Magda Tsolaki
A Novel and Intelligent Home Monitoring System for Care Support of Elders with Cognitive Impairment
Abstract: Background: Assistive technology, in the form of a smart home environment, is employed to support people with dementia. Objectives: To propose a system for continuous and objective remote monitoring of problematic daily living activity areas and design personalized interventions based on system feedback and clinical observations for improving cognitive function and health-related quality of life. Methods: The assistive technology of the proposed system, including wearable, sleep, object motion, presence, and utility usage sensors, was methodically deployed at four different home installations of people with cognitive impairment. Detection of sleep patterns, physical activity, and activities of daily living, based on the collected sensor data and analytics, was available at all times through comprehensive data visualization solutions. Combined with clinical observation, targeted psychosocial interventions were introduced to enhance the participants’ quality of life and improve their cognitive functions and daily functionality. Meanwhile, participants and their caregivers were able to visualize a reduced set of information tailored to their needs. Results: Overall, paired-sample t-test analysis of monitored qualities revealed improvement for all participants in neuropsychological assessment. Moreover, improvement was detected from the beginning to the end of the trial, in physical condition and in the domains of sleep. Detecting abnormalities via the system, for example in sleep quality, such as REM sleep, has proved to be critical to assess current status, drive interventions, and evaluate improvements in a reliable manner. Conclusion: It has been proved that the proposed system is suitable to support clinicians to reliably drive and evaluate clinical interventions toward quality of life improvement of people with cognitive impairment.
Pages 1593-1605
Erik Portelius, Emilie Durieu, Marion Bodin, Morgane Cam, Josef Pannee, Charlotte Leuxc, Aloïse Mabondzo, Nassima Oumata, Hervé Galons, Jung Yeol Lee, Young-Tae Chang, Kathrin Stüber, Philipp Koch, Gaëlle Fontaine, Marie-Claude Potier, Antigoni Manousopoulou, Spiros Garbis, Adrian Covaci, Debby Van Dam, Peter De Deyn, Frank Karg, Marc Flajolet, Chiori Omori, Saori Hata, Toshiharu Suzuki, Kaj Blennow, Henrik Zetterberg, Laurent Meijer
Specific Triazine Herbicides Induce Amyloid-β42 Production
Abstract: Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by secretases leads to extracellular release of amyloid-β (Aβ) peptides. Increased production of Aβ42 over Aβ40 and aggregation into oligomers and plaques constitute an Alzheimer’s disease (AD) hallmark. Identifying products of the ‘human chemical exposome’ (HCE) able to induce Aβ42 production may be a key to understanding some of the initiating causes of AD and to generate non-genetic, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds, six triazine herbicides were found that induced a β- and γ-secretases-dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells, and neurons differentiated from human-induced pluripotent stem cells (iPSCs). Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Neurons derived from iPSCs obtained from a familial AD (FAD) patient (AβPP K724N) produced more Aβ42 versus Aβ40 than neurons derived from healthy controls iPSCs (AβPP WT). Triazines enhanced Aβ42 production in both control and AD neurons. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity. In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.
Pages 1607-1618
Printha Wijesinghe, S.K. Shankar, T.C. Yasha, Catherine Gorrie, Dhammika Amaratunga, Sanjayah Hulathduwa, K. Sunil Kumara, Kamani Samarasinghe, Yoo-hun Suh, Harry W.M. Steinbusch, K. Ranil D. De Silva (Handling Associate Editor: Ignacio Casado Naranjo)
Vascular Contributions in Alzheimer’s Disease-Related Neuropathological Changes: First Autopsy Evidence from a South Asian Aging Population
Abstract: Background: Evidence from various consortia on vascular contributions has been inconsistent in determining the etiology of sporadic Alzheimer’s disease (AD). Objective: To investigate vascular risk factors and cerebrovascular pathologies associated in manifestation of AD-related neuropathological changes of an elderly population. Methods: Postmortem brain samples from 76 elderly subjects (≥50 years) were used to study genetic polymorphisms, intracranial atherosclerosis of the circle of Willis (IASCW), and microscopic infarcts in deep white matters. From this cohort, 50 brains (≥60 years) were subjected to neuropathological diagnosis using immunohistopathological techniques. Results: Besides the association with age, the apolipoproteinE ε4 allele was significantly and strongly associated with Thal amyloid-β phases ≥1 [odds ratio (OR) =6.76, 95% confidence interval (CI) 1.37-33.45] and inversely with Braak neurofibrillary tangle (NFT) stages ≥III (0.02, 0.0-0.47). Illiterates showed a significant positive association for Braak NFT stages ≥IV (14.62, 1.21-176.73) and a significant negative association for microscopic infarcts (0.15, 0.03-0.71) in deep white matters. With respect to cerebrovascular pathologies, cerebral small vessel lesions (white matter hyperintensities and cerebral amyloid angiopathy) showed a higher degree of associations among them and with AD-related neuropathological changes (p<0.05) compared to large vessel pathology (IASCW), which showed a significant association only with Braak NFT stages ≥I (p=0.050). Conclusion: These findings suggest that besides age, education, and genetic factors, other vascular risk factors were not associated with AD-related neuropathological changes and urge prompt actions be taken against cerebral small vessel diseases since evidence for effective prevention is still lacking.
Pages 1619-1627
Mario Tombini, Maura Sicari, Giovanni Pellegrino, Francesca Ursini, Pasqualina Insardà, Vincenzo Di Lazzaro (Handling Associate Editor: Christine von Arnim)
Nutritional Status of Patients with Alzheimer’s Disease and Their Caregivers
Abstract: Background. Malnutrition is one of the most important conditions that negatively affects the health of elder people, particularly in patients with dementia. Objective. To provide an assessment of nutritional status of patients affected by Alzheimer’s disease (AD) living at home and of their caregivers by means of Mini Nutritional Assessment (MNA), and to explore the influence of different factors on nutrition. Methods. 90 patients affected by AD living at home and 90 age- and sex-matched caregivers were enrolled. Patients and caregivers, coming from an urban-rural fringe of Southern Italy, were assessed using full MNA, Mini-Mental State Examination, Geriatric Depression Scale—short form, Activity of Daily Living, and Instrumental Activities of Daily Living scales. Results. Malnutrition was found with high prevalence in patients affected by AD of different severity (more than 95% of patients were malnourished or at risk of malnutrition), and associated with reduced functional status. An altered nutrition was also recognized with high rate in the group of caregivers (23.3% were malnourished and 41.1% at risk of malnutrition) and the worse nutritional condition was correlated with higher age and lower functional and cognitive status and education. A positive correlation between MNA score of AD patients and caregivers was found. Conclusion. Corrective measures should be taken in order to early identify nutritional deficiencies and risk of malnutrition observed with high rate in both groups of AD patients and their caregivers; in these subjects a nutrition education program and intervention policies are mandatory to restore nutritional status.
Pages 1629-1647
Christi L. Parham, Courtney Shaw, Lisa D. Auckland, S. Kent Dickeson, Irene Griswold-Prenner, Gregory Bix
Perlecan Domain V Inhibits Amyloid-β Induced Activation of the α2β1 Integrin-Mediated Neurotoxic Signaling Cascade
Abstract: Alzheimer’s disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (Aβ) is the major component of plaques and consists of two prominent isoforms, Aβ40 and Aβ42. As many risk factors for AD are vascular in origin and blood vessel defects in clearing Aβ from the brain are a potential key component of AD pathology, we have focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the extracellular matrix proteoglycan perlecan. Domain V (DV) is the C-terminal domain and is generated by perlecan proteolysis. DV interacts with the α2 integrin and Aβ is a ligand for both α2β1 and αvβ1. Due to the known interaction of DV with α2β1 and α2β1’s requirement for Aβ deposition and neurotoxicity, we hypothesized that DV and/or its C-terminal domain, LG3, might alter neurotoxic signaling pathways by directly blocking or otherwise interfering with α2β1 binding by Aβ. Our study suggests that α2β1 mediates Aβ-induced activation of c-Jun and caspase-3, key components of the neurotoxic pathway, in primary cortical and hippocampal neurons. We further demonstrate that DV and/or LG3 may therapeutically modulate these α2β1 mediated neurotoxic effects suggesting that they or other α2β1 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to Aβ40 and Aβ42 as further underscored by differing neuroprotective potencies of LG3 in each cell type.
Pages 1649-1657
Laura Bonanni, Raffaella Franciotti, Flavio Nobili, Milica G. Kramberger, John-Paul Taylor, Sara Garcia-Ptacek, N. Walter Falasca, Francesco Famà, Ruth Cromarty, Marco Onofrj, Dag Aarsland, on behalf of the E-DLB study group
EEG Markers of Dementia with Lewy Bodies: A Multicenter Cohort Study
Abstract: Quantitative EEG (QEEG) has demonstrated good discriminative capacity for dementia with Lewy bodies (DLB) diagnosis as compared to Alzheimer’s disease (AD) with a predictive value of 100% in a single cohort study. EEG in DLB was characterized by a dominant frequency (DF) in pre-alpha (5.5-7.5 Hz), theta, or delta bands and DF variability (DFV) >1.2 Hz, frequency prevalence (FP) pre-alpha in >40% and FP alpha in <32% of the epochs. To validate the aforementioned QEEG findings in independent cohorts of clinically diagnosed DLB versus AD patients, we analyzed EEG traces of 79 DLB and 133 AD patients (MMSE >20) collected from four European Centers. EEG traces from 19 scalp derivations were acquired as at least 10 min continuous signals and epoched in off-setting as series of 2-second-long epochs, subsequently processed by Fast Fourier Transform (frequency resolution 0.5 Hz). DLB patients showed EEG specific abnormalities in posterior derivations characterized by DF 50%, FP alpha <25%. DFV was >0.5 Hz. AD patients displayed stable alpha DF, DFV 55%. DLB and AD differed for DF (p <10-6), DFV (p <0.05), FP pre-alpha (p <10-12) and FP alpha (p <10-12). Discriminant analysis detected specific cut-offs for every EEG mathematical descriptor; DF = 8, DFV = 2.2 Hz, FP pre-alpha = 33%, FP alpha = 41% for posterior derivations. If at least one of the cut-off values was met, the percentage of DLB and AD patients correctly classified was 90% and 64%, respectively. The findings in this multicenter study support the validity of QEEG analysis as a tool for diagnosis in DLB patients.
Pages 1659-1670
Sarah Gourmaud, François Mouton-Liger, Claire Abadie, Eliane F. Meurs, Claire Paquet, Jacques Hugon
Dual Kinase Inhibition Affords Extended in vitro Neuroprotection in Amyloid-β Toxicity
Abstract: In Alzheimer’s disease (AD), the amyloid cascade hypothesis proposes that amyloid-beta (Aβ) neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they were possibly administered late in AD progression. Modulating new targets associated with Aβ toxicity, such as PKR (double-stranded RNA dependent kinase), and JNK (c-Jun N-terminal kinase) is a major goal for neuroprotection. These two pro-apoptotic kinases are activated in AD brains and involved in Aβ production, tau phosphorylation, neuroinflammation, and neuronal death. In HEK cells transfected with siRNA directed against PKR, and in PKR knockout (PKR-/-) mice neurons, we showed that PKR triggers JNK activation. Aβ-induced neuronal apoptosis, measured by cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3 levels, was reduced in PKR-/- neurons. Two selective JNK inhibitory peptides also produced a striking reduction of Aβ toxicity. Finally, the dual inhibition of PKR and JNK nearly abolished Aβ toxicity in primary cultured neurons. These results reveal that dual kinase inhibition can afford neuroprotection and this approach is worth to be tested in in vivo AD and oxidative stress models.
Pages 1671-1686
Sravani Musunuri*, Payam Emami Khoonsari*, Maria Mikus, Magnus Wetterhall, Anna Häggmark, Lars Lannfelt, Anna Erlandsson, Jonas Bergquist, Martin Ingelsson, Ganna Shevchenko, Peter Nilsson, Kim Kultima (Handling Associate Editor: Sylvain Lehmann) *These authors contributed equally to this work.
Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer’s Disease Brain
Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-β and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. Objective: This study intended to perform a proteomic profiling of postmortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. Methods: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. Results: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. Conclusions: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.
