Pages 1157-1176
Review
Shan-Shan Tang, Jun Li, Lan Tan, Jin-Tai Yu
Genetics of Frontotemporal Lobar Degeneration: From the Bench to the Clinic
Abstract: Frontotemporal lobar degeneration (FTLD) is a clinically heterogeneous neurodegenerative disease with a strong genetic component. In this review, we summarize most common mutations in MAPT, GRN, and C90RF72, as well as less common mutations in VCP, CHMP2B, TARDBP, FUS gene and so on. Several guidelines have been developed to help gene testing based on genotype–phenotype correlation, the underlying histopathological subtypes, and the neuroanatomic associations. Furthermore, we also summarize molecular pathways implicated by genes and novel targets for FTLD prevention and management in recent years.
Pages 1177-1187
Review
Grant P. Otto, Devdutt Sharma, Robin S.B. Williams (Handling Associate Editor: Bing Zhou)
Non-Catalytic Roles of Presenilin Throughout Evolution
Abstract: Research into Alzheimer’s disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase complex in the cleavage of amyloid-β protein precursor and resultant amyloid tangle deposition. Over the last 25 years, screening novel drugs to control this aberrant proteolytic activity has yet to identify effective treatments for the disease. In the search for other mechanisms of presenilin pathology, several studies have demonstrated that mammalian presenilin proteins also act in a non-proteolytic role as a scaffold to co-localize key signaling proteins. This role is likely to represent an ancestral presenilin function, as it has been described in genetically distant species including non-mammalian animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from the human lineage over a billion years ago. Here, we review the non-catalytic scaffold role of presenilin, from mammalian models to other biomedical models, and include recent insights using Dictyostelium, to suggest that this role may provide an early evolutionary function of presenilin proteins.
Pages 1189-1202
Review
Ângela Rego, Sofia D. Viana, Carlos A. Fontes Ribeiro, Paulo Rodrigues-Santos, Frederico C. Pereira
Monophosphoryl Lipid-A: A Promising Tool for Alzheimer’s Disease Toll
Abstract: Neuroinflammation is a two-edged sword in Alzheimer’s disease (AD). A certain degree of neuroinflammation is instrumental in the clearance of amyloid-β (Aβ) peptides by activated microglia, although a sustained neuroinflammation might accelerate Aβ deposition, thus fostering the neurodegenerative process and functional decline in AD. There is an increasing body of evidence suggesting that the innate immune system via Toll-like receptor 4 (TLR4) finely orchestrates the highly regulated inflammatory cascade that takes place in AD pathology. Herein we critically review pre-clinical (in vitro and in vivo approaches) and clinical studies showing that monophosphoryl lipid A (MPL), a partial TLR4 agonist, may have beneficial effect on AD physiopathology. The in vivo data elegantly showed that MPL enhanced Aβ plaque phagocytosis thus decreasing the number and the size of Aβ deposits and soluble Aβ in brain from APPswe/PS1 mice. Furthermore, MPL also improved their cognition. The mechanism underlying this MPL effect was proposed to be microglial activation by recruiting TLR4. Additionally, it was demonstrated that MPL increased the Aβ antibody titer and showed a safe profile in mice and primates, when used as a vaccine adjuvant. Clinical studies using MPL as an adjuvant in Aβ immunotherapy are currently ongoing. Overall, we argue that the TLR4 partial agonist MPL is a potentially safe and effective new pharmacological tool in AD.
Pages 1203-1208
Short Communication
Ferdinando Clarelli, Elisabetta Mascia, Roberto Santangelo, Salvatore Mazzeo, Giacomo Giacalone, Daniela Galimberti, Federica Fusco, Marta Zuffi, Chiara Fenoglio, Massimo Franceschi, Elio Scarpini, Gianluigi Forloni, Giuseppe Magnani, Giancarlo Comi, Diego Albani, Filippo Martinelli Boneschi (Handling Associate Editor: Benedetta Nacmias)
CHRNA7 Gene and Response to Cholinesterase Inhibitors in an Italian Cohort of Alzheimer’s Disease Patients
Abstract: Previous studies suggest that genetic variants in CHRNA7, which encodes for the major subunit of the acetylcholine receptor (α7-nAChR), are associated with the clinical response to cholinesterase inhibitors (ChEI) in Alzheimer’s disease (AD) patients. We sought to replicate association of two SNPs in the CHRNA7 gene, rs6494223 and rs8024987, with response to ChEI treatment in an Italian cohort of 169 AD patients, further extending the study to gene-level analysis. None of the tested variants was associated with clinical response. However, rs6494223 showed a consistent effect direction (OR=1.4; p=0.17), which after meta-analysis with previous study yielded a significant result (OR=1.57, p=0.02, I2=0%).
Pages 1209-1214
Short Communication
Anna Pliássova*, Paula M. Canas*, Ana Carolina Xavier, Beatriz S. da Silva, Rodrigo A. Cunha, Paula Agostinho *These authors contributed equally to this work.
Age-Related Changes in the Synaptic Density of Amyloid-β Protein Precursor and Secretases in the Human Cerebral Cortex
Abstract: Amyloid-β protein precursor (AβPP) is involved in synaptic formation and function. In the human cingulate cortex, AβPP was preferentially located in the presynaptic active zone as in rodents, indicating a preserved subsynaptic AβPP distribution across species and brain regions. Synaptic AβPP immunoreactivity was decreased with aging in cortical samples collected from autopsies of males (20-80 years), whereas the synaptic levels of α-secretase (ADAM10) and β-secretase (BACE1) did not significantly change. Decreased AβPP levels may be related to lower allostasis of synapses in the aged brain and their greater susceptibility to dysfunction characteristic of the onset of neurodegenerative disorders.
Pages 1215-1225
Stephan Müller, Christian Mychajliw, Carolin Reichert, Tobias Melcher, Thomas Leyhe (Handling Associate Editor: Panos Alexopoulos)
Autobiographical Memory Performance in Alzheimer’s Disease Depends on Retrieval Frequency
Abstract: Alzheimer’s disease (AD) is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures. As proposed by current theories of memory formation, this decrease is mediated by the age of the acquired knowledge. However, they cannot fully explain specific patterns of retrograde amnesia in AD. In the current study we examined an alternative approach and investigated whether the extent and severity of retrograde amnesia in AD is mediated by the frequency of memory retrieval or whether it depends on the mere age of knowledge. We compared recall of autobiographical incidents from three life periods in patients with amnestic mild cognitive impairment (aMCI), patients with early dementia of Alzheimer type (eDAT), and healthy control (HC) individuals using the Autobiographical Memory Interview. Retrieval frequency was operationalized by a paired comparison analysis. In contrast to HC individuals, recall of autobiographical incidents was impaired in patients with aMCI and eDAT following Ribot’s gradient, with a reduced memory loss for remote compared to more recent life events. However, there was a strong effect of retrieval frequency on memory performance with frequently retrieved incidents memorized in more detail than less frequently retrieved episodes. Remote memories were recalled more often than recent ones. These findings suggest that more frequently retrieved autobiographical memories generally become more independent of the hippocampal complex and might thus be better protected against early hippocampal damage related to AD. Hence, the extent of retrograde amnesia in AD appears mainly mediated by the frequency of memory retrieval, which could plausibly explain why cognitive activity can effectively delay the onset of memory decline in AD.
Pages 1227-1235
Enrico Premi, Vera Gualeni, Paolo Costa, Maura Cosseddu, Roberto Gasparotti, Alessandro Padovani, Barbara Borroni
Looking for Measures of Disease Severity in the Frontotemporal Dementia Continuum
Abstract: Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, 40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits.
Pages 1237-1243
Byoung Seok Ye, Yoonju Lee, Kichang Kwak, Yeong-Hun Park, Jee Hyun Ham, Jae Jung Lee, Na-Young Shin, Jong-Min Lee, Young H Sohn, Phil Hyu Lee
Posterior Ventricular Enlargement to Differentiate Dementia with Lewy Bodies from Alzheimer’s Disease
Abstract: Background: Enlargement of the lateral ventricle is observed in dementia associated with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Objective: The degree of anteroposterior ventricular enlargement and its correlation with clinical and neuropsychological features were investigated in DLB patients. Methods: Forty-eight patients with DLB, 76 with AD, and 45 subjects with normal cognition (NC) underwent structural brain MRI and detailed neuropsychological tests. Ventricular shape was compared among the groups by visual inspection. Posterior ventricle enlargement (PVE) was defined as the ratio of the distance between the temporal and occipital horns of the lateral ventricle to the distance between the temporal horn of the lateral ventricle and occipital pole of the brain. Results: After controlling for age, sex, and education, higher PVE was observed in the DLB group than in the AD group (68.5 ± 7.9% versus 62.8 ± 9.0%, respectively; p = 0.001) or the NC group (61.9 ± 9.9%, p = 0.002). However, higher PVE was not associated with poorer neuropsychological performance, nor was it associated with any clinical features in the DLB group after controlling for age, sex, and education. Conclusion: PVE occurs more often in DLB than in AD and NC. However, it is unclear how PVE is related to the clinical and neuropsychological features of DLB.
Pages 1245-1250
Samrah Ahmed, Ian Baker, Masud Husain, Sian Thompson, Christopher Kipps, Michael Hornberger, John R. Hodges, Christopher R. Butler (Handling Associate Editor: Sharon Naismith)
Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy
Abstract: Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer’s disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke’s Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p<0.001), visuospatial skills (p<0.001), and memory (p<0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p<0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p<0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA and second. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.
Pages 1251-1262
Mohamed Reda Bensaïdane, Jean-Mathieu Beauregard, Stéphane Poulin, François-Alexandre Buteau, Jean Guimond, David Bergeron, Louis Verret, Marie-Pierre Fortin, Michèle Houde, Rémi W. Bouchard, Jean-Paul Soucy, Robert Jr Laforce
Clinical Utility of Amyloid PET Imaging in the Differential Diagnosis of Atypical Dementias and Its Impact on Caregivers
Abstract: Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer’s disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers’ outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones.
Pages 1263-1275
Xinyi Li, Yuanli Song, Charles R. Sanders, Joel N. Buxbaum (Handling Associate Editor: Rakez Kayed)
Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of The Amyloid-β Protein Precursor
Abstract: In Alzheimer’s disease (AD), most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed overexpression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study, in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP with Kd = 86±9 µM. In cultured cells expressing both proteins, the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1, these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis.
Pages 1277-1298
Kim E. Innes, Terry Kit Selfe, Dharma Singh Khalsa, Sahiti Kandati (Handling Associate Editor: J. Wesson Ashford)
Effects of Meditation versus Music Listening on Perceived Stress, Mood, Sleep, and Quality of Life in Adults with Early Memory Loss: A Pilot Randomized Controlled Trial
Abstract: Background: Older adults with subjective cognitive decline (SCD) are at increased risk not only for Alzheimer’s disease, but for poor mental health, impaired sleep, and diminished quality of life (QOL), which in turn, contribute to further cognitive decline, highlighting the need for early intervention. Objective: In this randomized controlled trial, we assessed the effects of two 12-week relaxation programs, Kirtan Kriya Meditation (KK) and music listening (ML), on perceived stress, sleep, mood, and health-related QOL in older adults with SCD. Methods: Sixty community-dwelling older adults with SCD were randomized to a KK or ML program and asked to practice 12 minutes daily for 12 weeks, then at their discretion for the following 3 months. At baseline, 12 weeks, and 26 weeks, perceived stress, mood, psychological well-being, sleep quality, and health-related QOL were measured using well-validated instruments. Results: Fifty-three participants (88%) completed the 6-month study. Participants in both groups showed significant improvement at 12 weeks in psychological well-being and in multiple domains of mood and sleep quality (p’s≤0.05). Relative to ML, those assigned to KK showed greater gains in perceived stress, mood, psychological well-being, and QOL-Mental Health (p’s≤0.09). Observed gains were sustained or improved at 6 months, with both groups showing marked and significant improvement in all outcomes. Changes were unrelated to treatment expectancies. Conclusions: Findings suggest that practice of a simple meditation or ML program may improve stress, mood, well-being, sleep, and QOL in adults with SCD, with benefits sustained at 6 months and gains that were particularly pronounced in the KK group.
Pages 1299-1310
Miles Berger, Jacob W. Nadler, Allan Friedman, David L. McDonagh, Ellen R. Bennett, Mary Cooter, Wenjing Qi, Daniel T. Laskowitz, Vikram Ponnusamy, Mark F. Newman, Leslie M. Shaw, David S. Warner, Joseph P. Mathew, Michael L. James for the MAD-PIA investigators (Handling Associate Editor: Daqing Ma)
The Effect of Propofol versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer’s Disease: Results of a Randomized Trial
Abstract: Background: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer’s disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). Objective: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. Methods: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n=21) or propofol (n=18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. Results: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p=1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p=2.002x10-6 and p=1.985x10-6, respectively), mean CSF p-tau levels decreased (p=0.005), and Aβ levels did not change (p=0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n=9 polymorphisms, p>0.05 for all associations). Conclusion: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.
Pages 1311-1319
Yun Zhai, Toru Yamashita, Yumiko Nakano, Zhuoran Sun, Ryuta Morihara, Yusuke Fukui, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe
Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in an Alzheimer’s Disease Mouse Model
Abstract: A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer’s disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Nav1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier’s nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action.
Pages 1321-1333
Mareike Müller, H. Bea Kuiperij, Alexandra A.M. Versleijen, Davide Chiasserini, Lucia Farotti, Francesca Baschieri, Lucilla Parnetti, Hanne Struyfs, Naomi De Roeck, Jill Luyckx, Sebastiaan Engelborghs, Jurgen A. Claassen, Marcel M. Verbeek
Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study
Abstract: MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer’s disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.
Pages 1335-1342
Iman Beheshti, Hossain G.T. Olya, Hasan Demirel, for the Alzheimer’s Disease Neuroimaging Initiative
Risk Assessment of Alzheimer’s Disease using the Information Diffusion Model from Structural Magnetic Resonance Imaging
Abstract: Background: Recently, automatic risk assessment methods have been a target for the detection of Alzheimer’s disease (AD) risk. Objective: This study aims to develop an automatic computer-aided AD diagnosis technique for risk assessment of AD using information diffusion theory. Methods: Information diffusion is a fuzzy mathematics logic of set-value that is used for risk assessment of natural phenomena, which attaches fuzziness (uncertainty) and incompleteness. Data were obtained from voxel-based morphometry analysis of structural magnetic resonance imaging. Results and Conclusion: The information diffusion model results revealed that the risk of AD increases with a reduction of the normalized gray matter ratio (p>0.5, normalized gray matter ratio <40%). The information diffusion model results were evaluated by calculation of the correlation of two traditional risk assessments of AD, the Mini-Mental State Examination and the Clinical Dementia Rating. The correlation results revealed that the information diffusion model findings were in line with Mini-Mental State Examination and Clinical Dementia Rating results. Application of information diffusion model contributes to the computerization of risk assessment of AD, which has a practical implication for the early detection of AD.
Pages 1343-1360
Anandhi Iyappan*, Michaela Gündel*, Mohammad Shahid, Jiali Wang, Hui Li, Heinz-Theodor Mevissen, Bernd Müller, Juliane Fluck, Viktor Jirsa, Lia Domide, Erfan Younesi, Martin Hofmann-Apitius *These authors contributed equally to this work.
Toward a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration
Abstract: Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer’s disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer’s disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer’s disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.
Pages 1361-1371
Nathalie Bier, Patricia da Cunha Belchior, Guillaume Paquette, Émilie Beauchemin, Ariane Lacasse-Champagne, Chantal Messier, Marie-Line Pellerin, Marisol Petit, Eneida Mioshi, Carolina Bottari
The Instrumental Activity of Daily Living Profile in Aging: A Feasibility Study
Abstract: Background: Dysfunctions in complex activities of daily living (ADLs) are a normal part of the aging process. However, differentiating functional decline associated with healthy aging from the subtle decline experienced by individuals with mild cognitive impairment and early dementia constitutes a challenge. Finding an appropriate tool that can capture these subtle but important functional changes represents a priority. Objectives: The aims of this study were to evaluate the feasibility of using the Instrumental Activities of Daily Living Profile (IADL Profile) with elderly participants and to describe their level of difficulty encountered in each task. Methods: The tool was administered to a group of 40 elderly participants living in the community. Results: The IADL Profile was found to be feasible to use in older individuals; the tool also showed sensitivity to the difficulties experienced by this population in everyday functioning. Conclusion: The IADL Profile is a promising ecological tool to evaluate independence in aging and may help to identify individuals with MCI. This tool may also contribute to the development of tailored interventions to enhance everyday functioning in the older population.
Pages 1373-1383
Siobhan M. Hoscheidt, Erika J. Starks, Jennifer M. Oh, Henrik Zetterberg, Kaj Blennow, Rachel A. Krause, Carey E. Gleason, Luigi Puglielli, Craig S. Atwood, Cynthia M. Carlsson, Sanjay Asthana, Sterling C. Johnson, Barbara B. Bendlin
Insulin Resistance is Associated with Increased Alzheimer’s Disease Pathology and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults
Abstract: Background: Type 2 diabetes is associated with an increased risk for Alzheimer’s disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for, or have a parental family history of, AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. Objective: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOE ε4 carriage would be associated with greater CSF AD pathology and poor memory performance. Methods: Cognitively asymptomatic middle-aged adults (N=70, mean age=57.7 years) from the Wisconsin Alzheimer’s Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOE ε4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOE ε4 status. Results: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42. APOE ε4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to non-carriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. Conclusion: Overall, the findings suggest that IR and APOE ε4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.
Pages 1385-1401
Kenichi Ota, Naoya Oishi, Kengo Ito, Hidenao Fukuyama, SEAD-J Study Group, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Stefan Teipel)
Prediction of Alzheimer’s Disease in Amnestic Mild Cognitive Impairment Subtypes: Stratification Based on Imaging Biomarkers
Abstract: Background: Prediction of progression to Alzheimer’s disease (AD) in amnestic mild cognitive impairment (MCI) is challenging because of its heterogeneity. Objective: To evaluate a stratification method on different cohorts and to investigate whether stratification in amnestic MCI could improve prediction accuracy. Methods: We identified 80 and 79 patients with amnestic MCI from different cohorts, respectively. They underwent baseline magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans. We performed hierarchical clustering with three imaging biomarkers: brain volume on MRI, left hippocampus grey matter loss on MRI, and left inferior temporal gyrus glucose hypometabolism on FDG-PET. Regions-of-interest for biomarkers were defined by the Automated Anatomical Labeling atlas. We performed voxel-wise statistical parametric mapping to explore differences between clusters in patterns of grey matter loss and glucose hypometabolism. We compared time to progression using an interval-censored parametric model. We evaluated predictive performance using logistic regression. Results: Similar clusters were found in different cohorts. MCI1 had the healthiest biomarker profile of cognitive performance and imaging biomarkers. MCI2 had cognitive performance and MRI measures intermediate between those of nonconverters and converters. MCI3 showed the severest reduction in brain volume and left hippocampal atrophy. MCI4 showed remarkable glucose hypometabolism in the left inferior temporal gyrus, and also demonstrated significant decreases in most cognitive scores, including non-memory functions. MCI4 showed the highest risk for progression. The prediction of progression of MCI2 especially benefited from the stratification. Conclusion: Stratification with imaging biomarkers in amnestic MCI can be a good approach for improving predictive performance.
Pages 1403-1413
Min Jeong Wang, SangHak Yi, Jee-young Han, So Young Park, Jae-Won Jang, In Kook Chun, Vo Van Giau, Eva Bagyinszky, Kun Taek Lim, Sung Min Kang, Seong Su A. An, Young Ho Park, Young Chul Youn, SangYun Kim
Analysis of Cerebrospinal Fluid and [11C]PIB PET Biomarkers for Alzheimer’s Disease with Updated Protocols
Abstract: Background: Recently, a Korean research group suggested a consensus protocol, based on the Alzheimer’s Disease Neuroimaging Initiative study protocol but with modifications for minimizing the confounding factors, for the evaluation of cerebrospinal fluid (CSF) biomarkers. Objective: Here, we analyzed fluid and imaging biomarkers of Alzheimer’s disease (AD) in Korean population. We used the updated protocol to propose a more accurate CSF biomarker value for the diagnosis of AD. Methods: Twenty-seven patients with AD and 30 cognitively normal controls (NC) were enrolled. CSF was collected from 55 subjects (patients with AD =26, NC = 29) following the Korea consensus protocol. CSF biomarkers were measured using the INNO-BIA AlzBio3 immunoassay, and Pittsburgh compound B (PIB) positron emission tomography (PET) scans were also performed. Results: The cutoff values of CSF amyloid beta 1-42 (Aβ42), total tau (t-Tau), and phosphorylated tau (p-Tau) proteins were 357.1 pg/ml, 83.35 pg/ml, and 38.00 pg/ml, respectively. The cutoff values of CSF t-Tau/Aβ42 and p-Tau/Aβ42 ratio- were 0.210 (sensitivity 100%, specificity 86.21%) and 0.1350 (sensitivity 88.46%, specificity of 92.86%). The concordance rate with PIB-PET was higher using the CSF t-Tau/Aβ42 ratio (κ=0.849, CI 0.71–0.99) than CSF Aβ42 alone (κ=0.703, CI 0.51–0.89). Conclusions: Here, we improved controversial factors associated with the previous CSF study protocol and suggested a new cutoff value for the diagnosis of AD. Our results showed good diagnostic performance for differentiation of AD. Thus, we expect our findings could be a cornerstone in the establishment and clinical application of biomarkers for AD diagnosis.
Pages 1415-1430
May A. Beydoun, Jose-Atilio Canas, Greg A. Dore, Hind A. Beydoun, Ola S. Rostant, Marie T. Fanelli-Kuczmarski, Michele K. Evans, Alan B. Zonderman
Serum Uric Acid and Its Association with Longitudinal Cognitive Change Among Urban Adults
Abstract: Uric acid, a waste metabolite among humans, was linked to various cognitive outcomes. We describe sex and age-group specific associations of baseline serum uric acid (SUAbase) and significant change in SUA (∆SUA: 1 versus 0=decrease versus no change; 2 versus 0=increase versus no change) with longitudinal annual rate of cognitive change among a large sample of urban adults. Data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2004-2009 (visit 1) and 2009-2013 (visit 2) were used. Of 3,720 adults selected at baseline (age range: 30-64 y), complete data were available for N=1,487-1,602 with a mean repeat of 1.5-1.7 visits/participant. Cognitive test domains spanned attention, processing speed, learning/memory, executive function, visuo-spatial/visuo-construction ability, language/verbal, and global cognitive function. SUA was measured at both visits. Multiple mixed-effect regression analyses were conducted. In the total population, a higher SUAbase was associated with a faster annual rate of decline on a measure of visual memory/visuo-construction ability (the Benton Visual Retention Test) by γ=0.07 with a standard error of 0.02, p
Pages 1431-1442
Tali Shindler-Itskovitch, Ramit Ravona-Springer, Arthur Leibovitz, Khitam Muhsen
A Systematic Review and Meta-Analysis of the Association between Helicobacter pylori Infection and Dementia
Abstract: Background: A positive association between Helicobacter pylori infection and dementia has been reported, yet findings are inconsistent. Objective: To examine the association between H. pylori infection and dementia. Methods: A literature search was performed using the databases OVID-Medline, Institute of Scientific Information Web of Science, and EMBASE. The meta-analysis was conducted using the random effects model. The primary analysis included studies in which the exposure variable was presence of H. pylori infection (yes versus no) and the outcome was incident dementia (yes versus no), which was pre-selected as the end-result of gradual cognitive decline overtime. Publication bias was explored using funnel plot and the Egger regression intercept. Results: A total of 260 records were identified; 13 addressed cognition and/or dementia in relation to H. pylori infection, of which only seven were included in the meta-analysis. The primary analysis showed a significant positive association between H. pylori infection and dementia; pooled odds ratio 1.71 (95% CI 1.17-2.49) (pv=0.01). No significant evidence of publication bias was found. Conclusions: H. pylori may play a role in the etiology of dementia. Identification of the biological mechanisms of such association is needed, as well as assessment of the impact of H. pylori therapy on the risk and progression of dementia.
Pages 1443-1451
Stefan Teipel, Michel J. Grothe; for the Alzheimer’s Disease Neuroimaging Initiative
Association Between Smoking and Cholinergic Basal Forebrain Volume in Healthy Aging and Prodromal and Dementia Stages of Alzheimer’s Disease
Abstract: Background: Smoking has been found associated with decreased cerebral volumes in healthy adults and in various neuropsychiatric disorders. Objective: We aimed to determine whether chronic nicotine exposure through smoking is associated with reduced volume of cortically projecting cholinergic basal forebrain nuclei in healthy aging, mild cognitive impairment (MCI), and dementia stages of Alzheimer’s disease (AD). Methods: We retrieved cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database including 179 cognitively normal elderly subjects, 270 subjects with early stage MCI, 136 subjects in later, more advanced, stage of MCI, and 86 subjects in dementia stages of AD. We determined the association between past or current smoking versus lifetime non-smoker status on the volumes of the basal forebrain determined from volumetric MRI scans. Hippocampus volume was used as a control region. Significant effects were controlled for mediating or moderating effects of respiratory and cardiovascular morbidity. Results: In cognitively healthy individuals and early MCI, past or current smoking was significantly associated with smaller basal forebrain volume. This effect was independent from age, sex, or cardiovascular or respiratory morbidity. Hippocampus volume was not associated with smoking. In late MCI and AD dementia, smoking was not associated with basal forebrain or hippocampus volumes. Conclusions: Our findings suggest that chronic nicotine exposure through smoking may lead to atrophy of cholinergic input areas of the basal forebrain. This effect may account for an increased risk of AD dementia onset with smoking by exhausting the cholinergic system reserve capacity.
Pages 1453-1459
Masaaki Waragai, Anthony Adame, Ivy Trinh, Kazunari Sekiyama, Yoshiki Takamatsu, Kaori Une, Eliezer Masliah, Makoto Hashimoto
Possible Involvement of Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer’s Disease
Abstract: Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.
Pages 1461-1470
Pengcheng Han, Jiong Shi
A Theoretical Analysis of the Synergy of Amyloid and Tau in Alzheimer’s Disease
Abstract: Amyloid plaques and Tau protein neurofibrillary tangles are considered the two most important pathogenic factors in Alzheimer’s disease. The prevailing amyloid cascade hypothesis suggests that amyloid-β (Aβ) elevation induces downstream Tau hyperphosphorylation and aggregation, synaptic dysfunction, and neuronal loss that ultimately results in cognitive impairment. Alternatively, the dual-pathway hypothesis suggests that Aβ and abnormal Tau are two independent factors that exert synergistic effects on synaptic dysfunction and neuronal loss. We hypothesize that the intrinsic interaction of Aβ and Tau would predict better cognitive impairment. Herein, we propose an Aβ-Tau interactive model based on a review of the medical literature, mathematic modeling, and analysis of our clinicopathological data.
Pages 1471-1478
Ana M. Fernandez, Ruben Hervas, Manuel Dominguez-Fraile, Victoria Garrido, Patricia Gomez-Gutierrez, Miguel Vega, Javier Vitorica, Juan J. Perez, Ignacio Torres Aleman
Blockade of the Interaction of Calcineurin with FOXO in Astrocytes Protects Against Amyloid-β-Induced Neuronal Death
Abstract: Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer’s disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aβ-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aβ-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Aβ levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted.
Pages 1479-1485
José Augusto Ferrari Cestari, Gisele Maria Campos Fabri, Jorge Kalil, Ricardo Nitrini, Wilson Jacob-Filho, José Tadeu Tesseroli de Siqueira, Silvia Regina DT Siqueira
Oral Infections and Cytokine Levels in Patients with Alzheimer’s Disease and Mild Cognitive Impairment Compared with Controls
Abstract: Background: Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer’s disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines. Objective: The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α, and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls. Methods: Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6. Results: Patients with AD had high serum IL-6 levels (p=0.029), and patients with periodontitis had high serum TNF-α levels (p=0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p=0.023). Conclusion: The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation.
Pages 1487-1501
Marta Ramos-Goicoa, Santiago Galdo-Álvarez, Fernando Díaz, Montserrat Zurrón (Handling Associate Editor: George Stothart)
Effect of Normal Aging and of Mild Cognitive Impairment on Event-Related Potentials to a Stroop Color-Word Task
Abstract: Event-related potentials (ERPs) were recorded from 84 adults (51 to 87 years old) with the aim of exploring the effects of aging (middle-aged and older groups) and cognitive status (healthy or with amnestic mild cognitive impairment, aMCI) on the neural functioning associated with stimulus and response processing in a Stroop color-word task. An interference (or Stroop) effect was observed in the Reaction Time (RT), and the RT and number of errors results were consistent with the age-related decline in performance. Cognitive status did not affect the behavioral performance of the task, but age and cognitive status affected several ERP parameters. Aging was associated with a) slowing of the neural processing of the stimuli (P150, N2, and P3b latencies were longer), b) greater activation of the motor cortex for response preparation (LRP-R amplitude was larger), and c) use of more neural resources for cognitive control of stimuli (N2 amplitude was larger to the congruent and incongruent stimuli than to the colored X-strings, in the older group). Independent of age, aMCI dedicated more neural resources to processing the irrelevant dimension of the stimulus (they showed a greater difference than the control participants between the amplitude to the colored X-strings and to the congruent/incongruent stimuli) and showed a deficit in the selection and preparation of the motor response (with smaller LRP-S and LRP-R amplitudes). Furthermore, the middle-aged aMCI participants evaluated and classified both congruent and incongruent stimuli more slowly (they showed longer P3b latencies) relative to middle-aged controls.
Pages 1503-1513
Heather E. Barry, Janine A. Cooper, Cristín Ryan, A. Peter Passmore, A. Louise Robinson, Gerard J. Molloy, Carmel M. Darcy, Hilary Buchanan, Carmel M. Hughes
Potentially Inappropriate Prescribing Among People with Dementia in Primary Care: A Retrospective Cross-Sectional Study Using the Enhanced Prescribing Database
Abstract: Background: Little is known about prescribing appropriateness for community-dwelling people with dementia (PWD). Objective: To estimate potentially inappropriate prescribing (PIP) prevalence among PWD in primary care in Northern Ireland, and to investigate associations between PIP, polypharmacy, age, and gender. Methods: A retrospective cross-sectional study was conducted, using data from the Enhanced Prescribing Database. Patients were eligible if a medicine indicated for dementia management was dispensed to them during 1 January 2013–31 December 2013. Polypharmacy was indicated by use of ≥4 repeat medications from different drug groups. A subset of the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria, comprising 36 indicators, was applied to the dataset. Overall prevalence of PIP and the prevalence per each STOPP criterion was calculated as a proportion of all eligible persons in the dataset. Logistic regression was used to investigate associations between PIP, polypharmacy, age, and gender. Results: The study population comprised 6826 patients. Polypharmacy was observed in 81.5% (n=5,564) of patients. PIP prevalence during the study period was 64.4% (95% CI 63.2–65.5; n=4,393). The most common instance of PIP was the use of anticholinergic/antimuscarinic medications (25.2%; 95% CI 24.2–26.2; n=1,718). In multivariable analyses, both polypharmacy and gender (being female) were associated with PIP, with odds ratios of 7.6 (95% CI 6.6–8.7) and 1.3 (95% CI 1.2–1.4), respectively. No association was observed between PIP and age, after adjustments for gender and polypharmacy. Conclusion: This study identified a high prevalence of PIP in community-dwelling PWD. Future interventions may need to focus on certain therapeutic categories and polypharmacy.
