Pages 1-12
Review
Robert J. Molitor, Philip C. Ko, Brandon A. Ally (Handling Associate Editor: Kirk Daffner)
Eye Movements in Alzheimer’s Disease
Abstract: A growing body of literature has investigated changes in eye movements as a result of Alzheimer’s disease (AD). When compared to healthy, age-matched controls, patients display a number of remarkable alterations to oculomotor function and viewing behavior. In this article, we review AD-related changes to fundamental eye movements, such as saccades and smooth pursuit motion, in addition to changes to eye movement patterns during more complex tasks like visual search and scene exploration. We discuss the cognitive mechanisms that underlie these changes and consider the clinical significance of eye movement behavior, with a focus on eye movements in mild cognitive impairment. We conclude with directions for future research.
Pages 13-25
Review
Lina Ji, Xi Zhao, Zichun Hua
Potential Therapeutic Implications of Gelsolin in Alzheimer’s Disease
Abstract: The presence of amyloid plaques and vascular amyloid deposits is one of the pathological features of Alzheimer's disease (AD). Amyloid plaques and vascular deposits mainly consist of amyloid-β (Aβ), which is a metabolic product of amyloid-β protein precursor cleaved by β- and γ-secretase. Soluble Aβ monomers readily aggregate into oligomers preceding the formation of insoluble fibrils, and Aβ oligomers are more toxic than fibrils. Intensive therapeutic efforts have been attempted in the treatment of AD targeting Aβ, including preventing Aβ generation, inhibiting Aβ aggregation, and promoting Aβ clearance. The results show that amyloid plaque burden is reduced together with improved cognition performance in AD. Gelsolin, a multifunctional actin-binding protein, exists intracellularly as a cytoplasmic form and extracellularly as a secreted form in blood/cerebrospinal fluid. Gelsolin is suggested to be implicated in AD, based on the findings that some changes of gelsolin are correlated with disease progression rate in AD patients. Gelsolin binds Aβ, inhibits its aggregation into fibrils, and protects cells from apoptosis induced by Aβ. More importantly, administration or overexpression of gelsolin results in significant reduction of amyloid load and decrease of Aβ level in AD transgenic mice. In this article, we review the most recent progress of gelsolin as a potential therapeutic strategy for treatment of AD, and discuss the possible mechanism involved in the clearance of amyloid plaques in AD.
Pages 27-41
Review
Ahmad A. Khundakar, Alan J. Thomas (Guest Editor: Gwenn Smith)
Neuropathology of Depression in Alzheimer’s Disease: Current Knowledge and the Potential for New Treatments
Abstract: Depression is among the most common behavioral and psychological symptoms of dementia, and leads to more rapid decline and higher mortality. Treatment for depression in dementia has centered on conventional antidepressant drug treatment based around the monoamine hypothesis of depression. However, recent major studies have suggested that conventional antidepressant treatments that aim to correct underlying deficits in monoamine neurotransmitters are not effective for depression in dementia. Postmortem studies have also suggested that depression in dementia does not arise from serotonergic or noradrenergic abnormalities, or indeed from the degenerative pathology associated with Alzheimer’s disease. In contrast, considerable recent evidence has suggested that alterations in glutamatergic transmission may contribute to the pathophysiology of depression. This supports the view that treatment-resistant depressed patients, such as many dementia patients, may benefit from agents affecting glutamate transmission. This review will thus draw together the wealth of pathological data examining the basis of depression in Alzheimer’s disease and relate this to current thinking on treatment, with the aim of generating discussion on potential novel therapeutic strategies.
Pages 43-48
Short Communication
Kacee A. DiTacchio, Stephen F. Heinemann, Gustavo Dziewczapolski (Handling Associate Editor: Eileen Moore)
Metformin Treatment Alters Memory Function in a Mouse Model of Alzheimer’s Disease
Abstract: Metabolic dysfunction exacerbates Alzheimer’s disease (AD) incidence and progression. Here we report that activation of the AMPK pathway, a common target in the management of diabetes, results in gender-divergent cognitive effects in a murine model of the disease. Specifically, our results show that activation of AMPK increases memory dysfunction in males but is protective in females, suggesting that gender considerations may constitute an important factor in medical intervention of diabetes as well as AD.
Pages 49-56
Short Communication
Silvia Testi*, Stefano Tamburin*, Giampietro Zanette, Gian Maria Fabrizi (Handling Associate Editor: Ottavio Arancio) *These authors contributed equally to this work.
Co-Occurrence of the C9ORF72 Expansion and a Novel GRN Mutation in a Family with Alternative Expression of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Abstract: The C9ORF72 repeat expansion is the major cause of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. In the reported pedigree, the 47-year old proband, presenting a four-year history of frontotemporal dementia, carried the C9ORF72 expansion plus a novel GRN p.Cys246X mutation. The father and a paternal uncle, harboring the C9ORF72 expansion only, had died by pure ALS with onset at 63 and 76 years, respectively. The case report and a review of the literature emphasize that phenotypical variations of the FTLD-ALS spectrum could be due to digenic inheritance.
Pages 57-61
Short Communication
Liang Kee Goh, Wee Shiong Lim, Stephanie Teo, Aadhitthya Vijayaraghavan, Mark Chan, Laura Tay, Tze Pin Ng, Chay Hoon Tan, Tih Shih Lee, Mei Sian Chong (Handling Associate Editor: Barbara Borroni)
TOMM40 Alterations in Alzheimer’s Disease over a 2-Year Follow-Up Period
Abstract: We previously reported TOMM40 to be significantly down-regulated in whole blood of Alzheimer’s disease (AD) subjects at baseline and after one-year. In this longitudinal follow-up study of TOMM40 expression up to 2 years, we performed 6-monthly assessments for the first year and 2nd year blood sampling on 27 probable AD subjects compared with age- and gender-matched controls. TOMM40 gene expression remained significantly lower in AD patients at all time-points compared to controls, supported by confirmatory RT-PCR results. Our findings of consistently lower TOMM40 expression on longitudinal 2-year sampling support its potential role as a diagnostic blood AD biomarker.
Pages 63-67
Short Communication
Alberto Costa, Lucia Fadda, Roberta Perri, Marialuisa Brisindi, Maria Giovanna Lombardi, Carlo Caltagirone, Giovanni Augusto Carlesimo
Sensitivity of a Time-Based Prospective Memory Procedure in the Assessment of Amnestic Mild Cognitive Impairment
Abstract: This study was aimed at evaluating whether prospective memory (PM) assessment is able to assist the discrimination between amnestic mild cognitive impairment (aMCI) and healthy subjects (HCs) and between aMCI with single versus multiple domains impairment. Individuals with aMCI and HCs were administered an extensive neuropsychological tests battery and a time-based PM task. PM scores significantly improved the accuracy of the regression model in discriminating between aMCI multiple domains, but not aMCI single domain, and HCs. Moreover, the prospective score significantly contributed to the discrimination between the two aMCI subgroups. These findings indicate the usefulness of including the PM procedure in evaluations of aMCI.
Pages 69-78
Elysia Robb, Keyla Perez, Lin W. Hung, Colin L. Masters, Kevin J. Barnham, Robert A. Cherny, Ashley I. Bush, Paul A. Adlard, David I. Finkelstein (Handling Associate Editor: Rakez Kayed)
High Order W02-Reactive Stable Oligomers of Amyloid-β are Produced in vivo and in vitro via Dialysis and Filtration of Synthetic Amyloid-β Monomer
Abstract: Oligomeric forms of amyloid-β (Aβ) are thought to be responsible for the pathogenesis of Alzheimer’s disease. While many oligomers of Aβ are thought to be naturally occurring in the brain of humans and/or transgenic animals, it is well known that Aβ oligomers are also readily produced in vitro in the laboratory. In recent studies, we discovered that synthetic monomeric Aβ (4.7 kDa) could be transformed by microdialysis to higher molecular weight species (approximately 56 kDa, by western blot). Surface-enhanced laser desorption/ionization mass spectrometry and electron microscopy further identified these species’ as potential Aβ oligomers. The production of similar species could also be produced by centrifugal filtration and this formation was concentration and pore-size dependent. These higher order species of Aβ were resistant to dissolution in NaOH, HFIP, formic acid, urea, and guanidine. We postulate that we have identified a novel way of producing a high order species of oligomeric Aβ and we provide evidence to suggest that Aβ oligomers can quite easily be a product of normal laboratory practices. These data suggest that the experimental detection of higher order oligomers in tissues derived from Alzheimer’s disease brains or from animal models of disease could, in some cases, be a product the method of analysis.
Pages 79-92
Anette Hall*, Miguel Muñoz-Ruiz*, Jussi Mattila, Juha Koikkalainen, Magda Tsolaki, Patrizia Mecocci, Iwona Kloszewska, Bruno Vellas, Simon Lovestone, Pieter Jelle Visser, Jyrki Lötjonen, Hilkka Soininen for the Alzheimer Disease Neuroimaging Initiative, the AddNeuroMed consortium, DESCRIPA and Kuopio L-MCI (Handling Associate Editor: J. Wesson Ashford) *These authors contributed equally to this work.
Generalizability of the Disease State Index Prediction Model for Identifying Patients Progressing from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Background: The Disease State Index (DSI) prediction model measures the similarity of patient data to diagnosed stable and progressive mild cognitive impairment (MCI) cases to identify patients who are progressing to Alzheimer’s disease. Objectives: We evaluated how well the DSI generalizes across four different cohorts: DESCRIPA, ADNI, AddNeuroMed, and the Kuopio MCI study. Methods: The accuracy of the DSI in predicting progression was examined for each cohort separately using 10x10-fold cross-validation and for inter-cohort validation using each cohort as a test set for the model built from the other independent cohorts using bootstrapping with 10 repetitions. Altogether 875 subjects were included in the analysis. The analyzed data included a comprehensive set of age and gender corrected magnetic resonance imaging (MRI) features from hippocampal volumetry, multi-template tensor-based morphometry, and voxel-based morphometry as well as Mini-Mental State Examination (MMSE), APOE genotype, and additional cohort specific data from neuropsychological tests and cerebrospinal fluid measurements (CSF). Results: The DSI model was used to classify the patients into stable and progressive MCI cases. AddNeuroMed had the highest classification results of the cohorts, while ADNI and Kuopio MCI exhibited the lowest values. The MRI features alone achieved a good classification performance for all cohorts. For ADNI and DESCRIPA, adding MMSE, APOE genotype, CSF, and neuropsychological data improved the results. Conclusions: The results reveal that the prediction performance of the combined cohort is close to the average of the individual cohorts. It is feasible to use different cohorts as training sets for the DSI, if they are sufficiently similar.
Pages 93-101
Miika Vuorinen, Gabriela Spulber, Soheil Damangir, Eini Niskanen, Tiia Ngandu, Hilkka Soininen, Miia Kivipelto, Alina Solomon (Handling Associate Editor: Natalia García-Casares)
Midlife CAIDE Dementia Risk Score and Dementia-Related Brain Changes up to 30 Years Later on Magnetic Resonance Imaging
Abstract: Background: CAIDE Dementia Risk Score is a validated tool for estimating 20-year dementia risk in the general population based on a midlife risk profile. Objective: To investigate the associations between CAIDE score and dementia-related brain changes up to 30 years later on magnetic resonance imaging (MRI). Methods: Participants in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples surveyed in 1972, 1977, 1982, or 1987. A first re-examination was conducted in 1998, and a second re-examination in 2005-2008 (total follow-up time up to 30 years). The MRI study population included 112 individuals with MRIs from the first re-examination, and a different group of 69 individuals with MRIs from the second re-examination. MRIs from 1998 were used to determine gray matter volume, and to visually rate white matter hyperintensities (WMH) of presumed vascular origin and medial temporal lobe atrophy (MTA). MRIs from 2005-2008 were used to assess cortical thickness, gray matter and WMH volume, and to visually rate MTA. CAIDE scores were calculated for participants in both re-examinations based on midlife sociodemographic and vascular factors and additionally apolipoprotein E status. Results: Higher midlife CAIDE score was associated with more severe WMH 20 years later: RR (95% CI) was 1.69 (1.15-2.08); and with higher WMH volume (β 0.27, p=0.036) and higher MTA score (RR 1.91, 95% CI 1.16-2.34) up to 30 years later. Conclusion: CAIDE Dementia Risk Score in midlife was most consistently associated with WMH later in life. A relation with MTA was observed in individuals with longer follow-up time.
Pages 103-114
Evelyn Sieczkowski, Ivan Milenkovic, Vivek Venkataramani, Regina Giera, Thomas Ströbel, Romana Höftberger, Paweł P. Liberski, Eduard Auff, Oliver Wirths, Thomas A. Bayer, Gabor G. Kovacs
I716F AβPP Mutation Associates with the Deposition of Oligomeric Pyroglutamate Amyloid-β and α-Synucleinopathy with Lewy Bodies
Abstract: Autosomal dominant familial Alzheimer’s disease (AD) is associated with mutations in the AβPP, PSEN1, and PSEN2 genes. The clinical phenotype associated with AβPP mutations is mainly characterized by dementia or by strokes related to cerebral amyloid angiopathy (CAA). We present a comprehensive clinical, neuropathological, genetic, and biochemical study on a patient affected by familial AD associated with the I716F mutation in the AβPP gene. The clinical phenotype was characterized by early age of onset of 47 years, and rapidly progressive cerebellar ataxia, myoclonic jerks, rigidity, and dementia reminiscent of Creutzfeldt-Jakob disease (CJD), followed by a prolonged persistent vegetative state. Neuropathological evaluation of the proband revealed AD-related pathology but also α-synucleinopathy compatible with dementia with Lewy bodies neocortical stage or Parkinson’s disease corresponding to Braak stage 6. Tau-pathology in the form of neurofibrillary degeneration corresponded to stage VI according to the Braak classification. The severe Aβ pathology included CAA, numerous plaques, and deposition of N-truncated pyroglutamate-modified Aβ peptides. Remarkably, pyroglutamate Aβ oligomers were also present intracellularly in Purkinje cells corresponding to the ataxic phenotype. The detection of a CJD-like phenotype expands the spectrum of clinical presentations associated with familial AD. Our study supports the concept that the neuropathology of familial AD expands beyond the classical AD–related pathology as defined by plaques and tangles. Finally, we provide evidence for the first time that oligomeric pyroglutamate Aβ is present in a specific pattern correlating with the clinical symptoms of a patient with AβPP I716F mutation.
Pages 115-123
Hui-Fu Wang, Lan Tan, Xiao-Ke Hao, Teng Jiang, Meng-Shan Tan, Ying Liu, Dao-Qiang Zhang, Jin-Tai Yu for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Francesco Panza)
Effect of EPHA1 Genetic Variation on Cerebrospinal Fluid and Neuroimaging Biomarkers in Healthy, Mild Cognitive Impairment and Alzheimer’s Disease Cohorts
Abstract: Ephrin type-A receptor 1 (EPHA1) (11771145) was documented to be one of the most strongly associated locus with Alzheimer’s disease (AD) in a recent meta-analysis of five genome wide association studies. However, its contribution to the pathogenesis of AD remains unclear to date. Here, we addressed the role of EPHA1 in AD by investigating the influence of EPHA1 on cerebrospinal fluid and neuroimaging biomarkers in three clinical stages from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We did not detect significant association of EPHA1 with amyloid-β deposition or tau protein. However, the A-allele in the mild cognitive impairment group remarkably prevented hippocampal atrophy (partial correlation coefficient 2.812, 95% CI 0.651 to 4.973) at two-year follow-up. Additionally, AD subjects with the A-allele displayed less atrophy and greater cerebral metabolic rate for glucose (CMRgl) in the right lateral occipitotemporal gyrus (volume: partial correlation coefficient 540.10, 95% CI 247.26 to 832.95; CMRgl: partial correlation coefficient 0.056, 95% CI 0.024 to 0.087) and inferior temporal gyrus (volume: partial correlation coefficient 327.98, 95% CI 11.65 to 644.31; CMRgl: partial correlation coefficient 0.055, 95% CI 0.019 to 0.091) at baseline. This study suggests EPHA1 (rs11771145) interferes with the pathological alteration of the hippocampus and the lateral occipitotemporal and inferior temporal gyri throughout the AD process, leading to a lower risk of AD. However, the limited sample size and follow-up as well as the diversity across ethnicities precluded explanation of these findings.
Pages 125-138
Yu-Ling Chang, Ta-Fu Chen, Yao-Chia Shih, Ming-Jang Chiu, Sui-Hing Yan, Wen-Yih Isaac Tseng (Handling Associate Editor: Jason Brandt)
Regional Cingulum Disruption, Not Gray Matter Atrophy, Detects Cognitive Changes in Amnestic Mild Cognitive Impairment Subtypes
Abstract: Amnestic mild cognitive impairment (aMCI), which has a high risk of progression to Alzheimer’s disease (AD), can be classified into single domain (S-aMCI) and multiple domain (M-aMCI) subtypes. We investigated the integrity of regional gray matter and segments of the cingulum bundle with diffusion spectrum imaging tract-specific analysis, and their relationships to neuropsychological functioning, in 46 individuals with aMCI (S-aMCI n =24; M-aMCI n =22) and 36 healthy controls (HC). Results demonstrated that although both aMCI groups were impaired on all memory measures relative to HCs, the M-aMCI group demonstrated worse performance on paired association memory and on selective executive function relative to the S-aMCI group. The two aMCI groups did not show significant atrophy in regional gray matter indices as compared to the HC group, but the M-aMCI group showed significant disruption in white matter of the left anterior and inferior cingulum bundles relative to the S-aMCI and HC groups. Furthermore, disruption in the inferior cingulum bundles was significantly associated with executive function and attention/processing speed in all aMCI participants above and beyond the contribution of bilateral hippocampal volumes. Overall, these results indicate that the degeneration of cingulum fibers did not appear to arise from degeneration of the corresponding cerebral cortex. It also suggests relatively greater sensitivity of a white matter biomarker and comprehensive neuropsychological evaluation over gray matter biomarkers in early detection of AD.
Pages 139-151
Maya Semrau, Alistair Burns, Slavica Djukic-Dejanovic, Defne Eraslan, Changsu Han, Dusica Lecic-Tosevski, Antonio Lobo, Adriana Mihai, Julie Morris, Claudia Palumbo, Philippe Robert, Gerthild Stiens, Gabriela Stoppe, Umberto Volpe, Marcel Olde Rikkert, Norman Sartorius, on behalf of the International Dementia Alliance (IDEAL) study group (Handling Associate Editor: Carol Brayne)
Development of an International Schedule for the Assessment and Staging of Care for Dementia
Abstract: Background: A reliable and valid global staging scale has been lacking within dementia care. Objective: To develop an easy-to-use multi-dimensional clinical staging schedule for dementia. Methods: The schedule was developed through: i) Two series of focus groups (40 and 48 participants, respectively) in Denmark, France, Germany, Netherlands, Spain, Switzerland, and UK with a multi-disciplinary group of professionals working within dementia care, to assess the need for a dementia-staging tool and to obtain suggestions on its design and characteristics; ii) A pilot-study over three rounds to test inter-rater reliability of the newly developed schedule using written case histories, with five members of the project’s steering committee and 27 of their colleagues from Netherlands, France, and Spain as participants; and iii) A field-study to test the schedule’s inter-rater reliability in clinical practice in France, Germany, Netherlands, Spain, Italy, Turkey, South Korea, Romania, and Serbia, which included 209 dementia patients and 217 of their caregivers as participants. Results: Focus group participants indicated a clear need for a culture-fair international dementia staging scale and reached consensus on face validity and content validity. Accordingly, the schedule has been composed of seven dimensions including behavioral, cognitive, physical, functional, social, and care aspects. Overall, the schedule showed adequate face validity, content validity, and inter-rater reliability; in the nine field-sites, intraclass correlation coefficients (ICCs; absolute agreement) for individual dimensions ranged between 0.38 and 1.0, with 84.4% of ICCs over 0.7. ICCs for total sum scores ranged between 0.89 and 0.99 in the nine field-sites. Conclusion: The IDEAL schedule looks promising as tool for the clinical and social management of people with dementia globally, though further reliability and validity testing is needed.
Pages 153-162
Hadassa M. Jochemsen, Wiesje M. van der Flier, Emma L. Ashby, Charlotte E. Teunissen, Ruth E. Jones, Mike P. Wattjes, Philip Scheltens, Mirjam I. Geerlings, Patrick G. Kehoe, Majon Muller (Handling Associate Editor: Tânia Alves)
Angiotensin-Converting Enzyme in Cerebrospinal Fluid and Risk of Brain Atrophy
Abstract: Background: Higher angiotensin-converting enzyme (ACE) activity might increase the risk of Alzheimer’s disease by increasing blood pressure, and subsequent development of cerebral small vessel disease (CSVD). Yet, it may also decrease this risk, as it functions to degrade amyloid-β, thereby reducing brain atrophy. Objective: To examine the cross-sectional associations of serum and cerebrospinal fluid (CSF) ACE protein levels and activity with brain atrophy and CSVD in a memory clinic cohort. Methods: In 118 subjects from the memory clinic based Amsterdam Dementia Cohort (mean age 66±8 years), ACE protein levels (ng/ml) and activity in CSF and serum were investigated. Poisson regression analyses were used to associate ACE measurements with rated global cortical atrophy, medial temporal lobe atrophy, lacunar infarcts, white matter hyperintensities, and microbleeds on brain MRI. Results: Higher CSF ACE activity was associated with a reduced risk of global brain atrophy. The relative risk (95% CI) of having global cortical atrophy ≥2 per SD increase in CSF ACE activity was 0.67 (0.49; 0.93). ACE levels were not significantly related to measures of CSVD. Conclusions: These results show that high ACE might have protective effects on the brain. This could suggest that ACE inhibitors, which may lower CSF ACE levels, are not preferred as antihypertensive treatment in patients at risk for Alzheimer’s disease.
Pages 163-174
Xi-Chen Zhu, Yang Yu, Hui-Fu Wang, Teng Jiang, Lei Cao, Chong Wang, Jun Wang, Chen-Chen Tan, Xiang-Fei Meng, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Francesco Panza)
Physiotherapy Intervention in Alzheimer’s Disease: Systematic Review and Meta-Analysis
Abstract: Background. Many studies reported that physiotherapy interventions are available to treat Alzheimer’s disease (AD), but the efficacy remains uncertain. Objective. To evaluate the effectiveness of physiotherapy intervention on AD. Methods. The data sources were searched from literature databases, journals, and reference lists from 1 January 1990 to the end of 1 April 2014. Randomized and non-randomized controlled trials with physiotherapy intervention were included in our meta-analysis. Jadad score and Newcastle-Ottawa scale were used to assess the quality of included trials. Outcome measures were cognition function, physical function, activity of daily life (ADL) and neuropsychiatric inventory (NPI). Results. 23 trials met the inclusion standard finally. Significant changes were seen in cognitive function: Mini-Mental State Examination score (weighted mean difference (WMD): 1.84, 95% confidence interval (CI): [0.76 to 2.93], p<0.0001), and verbal fluency (standard mean difference (SMD): 0.34, 95% CI: [0.01 to 0.66], p=0.04). Other outcomes are also significant, they were timed up and go test (SMD: 0.56, 95% CI: [0.30 to 0.83], p<0.0001), berg functional balance scale (SMD: 1.11, 95% CI: [0.37 to 1.84], p=0.003), 6-min walk distance test (SMD: 141.45, 95% CI: [11.72 to 271.18], p=0.03), ADL (SMD: 0.78, 95% CI: [0.33 to 1.23], p=0.0007) and NPI (SMD: -0.69, 95% CI: [-1.31 to -0.07], p=0.03). Conclusion. The available data indicate that physiotherapy intervention may have benefits in AD. However, current data are not definitive; more carefully designed and conducted observational studies are needed to definitively establish that whether physiotherapy intervention can effectively alleviate symptoms of AD.
Pages 175-182
Jessica Lazarus, Karen A. Mather, Nicola J. Armstrong, Fei Song, Anne Poljak, Anbupalam Thalamuthu, Teresa Lee, Nicole A. Kochan, Henry Brodaty, Margaret J. Wright, David Ames, Perminder S. Sachdev, John B.J. Kwok (Handling Associate Editor: Daniela Galimberti)
DNA Methylation in the Apolipoprotein-A1 Gene is Associated with Episodic Memory Performance in Healthy Older Individuals
Abstract: Background: DNA methylation variation has been implicated in memory, cognitive performance, and dementia. Plasma apolipoprotein-A1 (ApoA1) levels may act as a biomarker of age-associated cognitive performance and decline. Objectives: To estimate the heritability of plasma ApoA1 protein levels; to examine DNA methylation variation within the APOA1 gene; and to investigate whether APOA1 methylation is associated with plasma ApoA1 levels and episodic memory performance. Method: Heritability of ApoA1 protein levels in Older Australian Twins Study (OATS) was assessed using structural equation modelling. APOA1 methylation levels were assayed in two cohorts of cognitively normal older individuals. The methylation status of 12 CpGs in 24 twin pairs from OATS was assayed using the Illumina 450K methylation array. Candidate CpGs were assayed in 453 individuals from Sydney Memory and Ageing Study (Sydney MAS) using pyrosequencing. Regression analyses assessed associations between APOA1 methylation levels, ApoA1 plasma levels, and memory performance. Results: No significant heritability was observed for ApoA1 protein levels. APOA1 candidate-gene analyses revealed CpG sites associated with memory performance in the twin study (p < 0.050). Replication of an association between methylation of a specific CpG (cg03010018) in APOA1 and memory performance was observed in Sydney MAS (β = -0.145, p = 0.010). Methylation of this CpG site was also significantly correlated with ApoA1 protein levels (β = 0.161, p = 0.019). However, no relationship between a composite memory domain score and methylation was observed (p = 0.389). Conclusion: Findings demonstrated that epigenetic control of APOA1 expression and DNA methylation levels are associated with episodic memory performance in older adults.
Pages 813-193
Per Suppa, Ulrich Anker, Lothar Spies, Irene Bopp, Brigitte Rüegger-Frey, Richard Klaghofer, Carola Gocke, Harald Hampel, Sacha Beck, Ralph Buchert (Handling Associate Editor: Babak Ardekani) Fully Automated Atlas-Based Hippocampal Volumetry for Detection of Alzheimer’s Disease in a Memory Clinic Setting Abstract: Hippocampal volume is a promising biomarker to enhance the accuracy of the diagnosis of dementia due to Alzheimer’s disease (AD). However, whereas hippocampal volume is well studied in patient samples from clinical trials, its value in clinical routine patient care is still rather unclear. The aim of the present study, therefore, was to evaluate fully automated atlas-based hippocampal volumetry for detection of AD in the setting of a secondary care expert memory clinic for outpatients. One-hundred consecutive patients with memory complaints were clinically evaluated and categorized into three diagnostic groups: AD, intermediate AD, and non-AD. A software tool based on open source software (Statistical Parametric Mapping SPM8) was employed for fully automated tissue segmentation and stereotactical normalization of high-resolution three-dimensional T1-weighted magnetic resonance images. Predefined standard masks were used for computation of grey matter volume of the left and right hippocampus which then was scaled to the patient’s total grey matter volume. The right hippocampal volume provided an area under the receiver operating characteristic curve of 84% for detection of AD patients in the whole sample. This indicates that fully automated MR-based hippocampal volumetry fulfills the requirements for a relevant core feasible biomarker for detection of AD in everyday patient care in a secondary care memory clinic for outpatients. The software used in the present study has been made freely available as an SPM8 toolbox. It is robust and fast so that it is easily integrated into routine workflow.
Pages 195-204
Su-Yeon Yu, Tae-Jin Lee, Su-Hyun Jang, Ji Won Han, Tae Hui Kim, Ki Woong Kim
Cost-Effectiveness of Nationwide Opportunistic Screening Program for Dementia in South Korea
Abstract: Although more demand for screening for dementia is envisaged, the cost-effectiveness of opportunistic population screening for dementia at a nationwide level has never been directly investigated. Since 2010, Korea has implemented “the National Dementia Early Detection Program” (NDEDP) for the aged. This study aims to investigate the cost-effectiveness of the NDEDP of Korea and to explore the requirements for enhancing its cost-effectiveness. A Markov model was developed to simulate the disease progression of dementia patients. Data sources for the model parameters included the NDEDP database for cohort characteristics and other national representative data. The model’s estimates of the expected costs and Quality Adjusted Life Years (QALYs) for each strategy were used to calculate the incremental cost-effectiveness ratio of screening compared to no screening, and sensitivity analysis was performed to assess the effect of key variables on the cost-effectiveness. Screening showed that the cost per QALY gained ranged from $24,150 to $35,661 depending on the age group. The probability of screening being cost-effective was highest in the group over 75 years old in a wide range of willingness to pay (WTP). The implementation of an opportunistic screening program for dementia can be cost-effective depending on disease severity, treatment effect, costs by disease stage, ages of the participants, and the societal WTP. Above all things, improving access to more effective therapies in slowing the course of the disease is essential since the main benefit of earlier diagnosis for dementia is starting early treatment and subsequent savings. Although it is too early to conclude the cost-effectiveness of opportunistic population screening for dementia, this current study may be a meaningful step toward generating practical evidence for implementing an effective and efficient dementia screening program.
Pages 205-214
Carl Eckerström, Erik Olsson, Niklas Klasson, Josef Berge, Arto Nordlund, Maria Bjerke, Anders Wallin (Handling Associate Editor: Ben Schmand)
Multimodal Prediction of Dementia with up to 10 Years Follow Up: The Gothenburg MCI Study
Abstract: Background: Neuropsychological tests, CSF Aβ42, T-tau, P-tau181, hippocampal volume, and white matter lesions have been shown to predict conversion to dementia in patients with mild cognitive impairment (MCI). Objective: To examine the predictive value of combinations of these markers and to examine if the absence of pathological markers provides a lasting reduction of conversion rates. Methods: Gothenburg MCI study is a clinically based study. Seventy-three MCI patients were included in the present sub-study and followed for a maximum of ten years. Thirty-four patients converted to dementia (18 to AD) and 39 remained stable. At inclusion, patients were classified into positive or negative risk groups according to results from neuropsychological testing (Rey auditory verbal learning test, Boston naming test, Trail making test B), CSF biomarkers (amyloid β42, T-tau, and P-tau181, and MRI scans (hippocampal volume, white matter lesions). Results: Trail making test B (TMT-B) was the best single predictor for the prediction of dementia (AUC 0.89, HR 25), and T-tau was the best predictor of AD (AUC 0.97, HR 41). The combination of hippocampal volume and TMT-B was the best combination for the prediction of dementia (HR 25), and the combination of hippocampal volume and T-tau was the best combination for the prediction of AD (HR 37). Conclusion: Neuropsychological tests, CSF markers, and hippocampal volume predicted conversion from MCI to AD and general dementia. The absence of pathological markers provided a long-time protection from dementia.
Pages 215-231
Kai Lun Chang, Hai Ning Pee, Wee Pin Tan, Gavin S. Dawe, Elaine Holmes, Jeremy K. Nicholson, Eric C.Y. Chan, Paul C. Ho
Metabolic Profiling of CHO-AβPP695 Cells Revealed Mitochondrial Dysfunction Prior to Amyloid-β Pathology and Potential Therapeutic Effects of Both PPARγ and PPARα Agonisms for Alzheimer’s Disease
Abstract: In this study, we performed gas chromatography time-of-flight mass spectrometry (GC-TOFMS)-based extracellular metabolic profiling on AβPP-transfected CHO cells (CHO-AβPP695) and its wildtype. Orthogonal partial least squares discriminant analysis (OPLS-DA) was then used to identify discriminant metabolites, which gave clues on the effects of AβPP transgene on cellular processes. To confirm the hypotheses generated based on the metabolic data, we performed biochemical assays to gather further evidence to support our findings. The OPLS-DA showed a robust differentiation following 24 h of incubation (Q2(cum) = 0.884) and 15 discriminant metabolites were identified. In contrast, extracellular Aβ42 was identified to increase significantly in CHO-AβPP695 only after incubation for 48 h. The observed 24-h metabolic fluxes were associated with increased mitochondrial AβPP and reduced mitochondrial viabilities, which occurred before extracellular Aβ accumulation. We also investigated the therapeutic potential of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, namely rosiglitazone (RSG) and pioglitazone (PIO), by employing the same approach to characterize the metabolic profiles of CHO-AβPP695 treated with RSG and PIO, with or without their respective receptor blockers. Treatment with PIO was found to reduce the perturbation of the discriminant metabolites in CHO-AβPP695 to a larger extent than treatment with RSG. We also attributed the PIO effects on the lowering of Aβ42, and restoration of mitochondrial activity to PPARγ and PPARα agonism, respectively. Taken together, PIO was demonstrated to be therapeutically superior to RSG. Our findings provide further insights into early disease stages in this AβPP model, and support the advancement of PIO in AD therapy.
Pages 233-242
Michael C. Woodward, Christopher C. Rowe, Gareth Jones, Victor L. Villemagne, Tammie A. Varos
Differentiating the Frontal Presentation of Alzheimer’s Disease with FDG-PET
Abstract: Background: Alzheimer’s disease (AD) can present with behavioral changes with this syndrome described as frontal variant AD (FvAD). Excess frontal pathology may explain this presentation. Neuroimaging with fluoro-deoxy-glucose positron emission tomography (FDG- PET) can be used to examine the effects of pathology in FvAD. Methods: We administered an assessment scale for frontal behavioral impairment, the Frontal Behavioral Inventory (FBI), to 53 patients with AD. Scores in the top quartile were defined as FvAD. FDG- PET was analyzed in 8 frontal regions. Results: The Z (SD) score for metabolism was significantly higher (indicating greater hypometabolism) in the FvAD group than the remaining AD group for combined left and right orbitofrontal regions (2.64 (SD 0.99) versus 2.11 (1.22), p<0.03)) and combined left and right medial frontal regions (2.38 (0.63) versus 1.82 (0.88) p<0.003) but insignificantly different in combined lateral frontal and superior frontal regions. Statistical parametric mapping revealed these frontal regions to be the only brain regions with significantly different metabolism between the FvAD and the remainder of the AD groups. Conclusions: Medial and orbital frontal hypometabolism is greater in AD patients presenting with more frontal/behavioral features, likely reflecting a greater pathological load in these brain regions in FvAD patients. These frontal regions may be more linked to behavioral features than other frontal brain regions.
Pages 243-250
Marco Bozzali, Claire Dowling, Laura Serra, Barbara Spanò, Mario Torso, Camillo Marra, Diana Castelli, Nicholas G. Dowell, Giacomo Koch, Carlo Caltagirone, Mara Cercignani (Handling Associate Editor: Daniela Galimberti)
The Impact of Cognitive Reserve on Brain Functional Connectivity in Alzheimer’s Disease
Abstract: One factor believed to impact brain resilience to the pathological damage of Alzheimer’s disease (AD) is the so-called “cognitive reserve” (CR). A critical issue that still needs to be fully understood is the mechanism by which environmental enrichment interacts with brain plasticity to determine resilience to AD pathology. Previous work using PET suggests that increased brain connectivity might be at the origin of the compensatory mechanisms implicated in this process. This study aims to further clarify this issue using resting-state functional MRI. Resting-state functional MRI was collected for 11 patients with AD, 18 with mild cognitive impairment (MCI), and 16 healthy controls, and analyzed to isolate the default mode network (DMN). A quantitative score of CR was obtained by combining information about number of years of education and type of schools attended. Consistent with previous reports, education was found to modulate functional connectivity in the posterior cingulate cortex, whose disconnection with the temporal lobes is known to be critical for the conversion from MCI to AD. This effect was highly significant in AD patients, less so in patients with MCI, and absent in healthy subjects. These findings show the potential neural mechanisms underlying the individual’s ability to cope with brain damage, although they should be treated with some caution based on small numbers.
Pages 251-260
Xia Liu, Keqiang Ye, David Weinshenker (Handling Associate Editor: Elliott Mufson)
Norepinephrine Protects against Amyloid-β Toxicity via TrkB
Abstract: The locus coeruleus (LC), the brainstem noradrenergic nucleus that is the sole source of norepinephrine (NE) in the forebrain, is one of the first structures affected in Alzheimer’s disease (AD). Experimental ablation of the LC exacerbates, while increasing NE abates, AD-like neuropathology and cognitive deficits in animal models of the disease. Some neuroprotective effects of NE appear to be mediated by tropomyosin-related kinase B (TrkB), the canonical receptor for brain-derived neurotrophic factor. Here, we report that NE dose-dependently protected primary cortical and LC neurons from amyloid-β toxicity. The neuroprotective effects of NE were fully prevented by the Trk receptor antagonist K252a but only partially attenuated by adrenergic receptor antagonists and not mimicked by adrenergic agonists. Activation of TrkB by NE in cortical and LC neurons was confirmed by immunoblot and immunocytochemistry for phospho-TrkB. These results indicate that NE can activate TrkB and protect against amyloid-β toxicity, at least in part, via adrenergic receptor-independent mechanisms, and have implications for the consequences of LC degeneration in AD and potential therapies for the disease.
Pages 261-275
Yoon Sun Chun, Yurim Park, Hyun Geun Oh, Tae-Wan Kim, Hyun Ok Yang, Myoung Kyu Park, Sungkwon Chung (Handling Associate Editor: Inhee Mook-Jung)
O-GlcNAcylation Promotes Non-Amyloidogenic Processing of Amyloid-β Protein Precursor via Inhibition of Endocytosis from the Plasma Membrane
Abstract: Amyloid-β protein precursor (AβPP) is transported to the plasma membrane, where it is sequentially cleaved by α-secretase and g-secretase. This is called non-amyloidogenic pathway since it precludes the production of amyloid-β (Aβ), the main culprit of Alzheimer’s disease (AD). Alternatively, once AβPP undergoes clathrin-dependent endocytosis, it can be sequentially cleaved by β-secretase and γ-secretase at endosomes, producing Aβ (amyloidogenic pathway). β-N-acetylglucosamine (GlcNAc) can be attached to serine/threonine residues of the target proteins. This novel type of O-linked glycosylation is called O-GlcNAcylation mediated by O-GlcNAc transferase (OGT). The removal of GlcNAc is mediated by O-GlcNAcase (OGN). Recently, it is shown that O-GlcNAcylation of AβPP increases the non-amyloidogenic pathway. To investigate the regulatory role for O-GlcNAcylation in AβPP processing, we first tested the effects of inhibitor for OGN, PUGNAc, on AβPP metabolism in HeLa cells stably transfected with Swedish mutant form of AβPP. Increasing O-GlcNAcylated AβPP level increased α-secretase product while decreased β-secretase products. We found that PUGNAc increased the trafficking rate of AβPP from the trans-Golgi network to the plasma membrane, and selectively decreased the endocytosis rate of AβPP. These events may contribute to the increased AβPP level in the plasma membrane by PUGNAc. Inhibiting clathrin-dependent endocytosis prevented the effect of PUGNAc on Aβ, suggesting that the effect of PUGNAc was mainly mediated by decreasing AβPP endocytosis. These results strongly indicate that O-GlcNAcylation promotes the plasma membrane localization of AβPP, which enhances the non-amyloidogenic processing of AβPP. Thus, O-GlcNAcylation of AβPP can be a potential therapeutic strategy for AD.
Pages 277-282
Alberto Calvi*, Sara M.G. Cioffi*, Paolo Caffarra, Chiara Fenoglio, Maria Serpente, Anna M. Pietroboni, Andrea Arighi, Laura Ghezzi, Simona Gardini, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Beatrice Arosio) *These authors contributed equally to this work.
The Novel GRN g.1159_1160delTG Mutation is associated with Behavioral Variant Frontotemporal Dementia
Abstract: Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration and are associated with a wide phenotypic heterogeneity. Here, we describe two probands with behavioral variant frontotemporal dementia with a novel mutation in this gene (1159_1160delTG). Both had a positive family history for dementia and showed atypical feature at imaging. Their progranulin plasma levels were undetectable, and the mutation was not present in cDNA, suggesting haploinsufficiency. Progranulin levels were low even in asymptomatic carriers of the variant. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.
Pages 283-295
Richard McClure, Daijiro Yanagisawa, Donald Stec, Dave Abdollahian, Dmitry Koktysh, Dritan Xhillari, Rudolph Jaeger, Gregg Stanwood, Eduard Chekmenev, Ikuo Tooyama, John C. Gore, Wellington Pham
Inhalable Curcumin: Offering the Potential for Translation to Imaging and Treatment of Alzheimer’s Disease
Abstract: Curcumin is a promising compound that can be used as a theranostic agent to aid research in Alzheimer’s disease. Beyond its ability to bind to amyloid plaques, the compound can also cross the blood-brain barrier. Presently, curcumin can be applied only to animal models, as the formulation needed for iv injection renders it unfit for human use. Here, we describe a novel technique to aerosolize a curcumin derivative, FMeC1, and facilitate its safe delivery to the brain. Aside from the translational applicability of this approach, a study in the 5XFAD mouse model suggested that inhalation exposure to an aerosolized FMeC1 modestly improved the distribution of the compound in the brain. Additionally, immunohistochemistry data confirms that following aerosol delivery, FMeC1 binds amyloid plaques expressed in the hippocampal areas and cortex.
Pages 297-307
Hiroyoshi Kawada, Karen Blessing, Tomomi Kiyota, Theodor Woolman, Lee Winchester, Peter F. Kador
Effects of Multifunctional Antioxidants on Mitochondrial Dysfunction and Amyloid-β Metal Dyshomeostasis
Abstract: Background: Redox-active metal dyshomeostasis and oxidative stress are associated with mitochondrial dysfunction and amyloid-β (Aβ) neurotoxicity that are linked to both the development of age-related macular degeneration (AMD) and Alzheimer’s disease (AD). As potential therapeutic agents, orally active multifunctional antioxidants (MFAOs) possessing two independent functional groups capable of binding redox-active metals and scavenging free radicals have been synthesized. Objective: To determine whether MFAOs affect mitochondrial function and reduce the presence of Aβ plaque formation. Methods: The MFAOs were evaluated in cultured SH-SY5Y cells and ARPE-19 cells. MFAO effects on mitochondrial function were investigated using rhodamine 123 staining after 2 hour exposure to MnCl2. MFAO effects on Aβ:Zn complex formation were evaluated with Zinquin staining and the ability of the Aβ:Zn complex to be degraded by matrix metalloproteinase-2 (MMP-2). The ability of MFAOs to reduce Aβ plaque in the brain was determined by orally feeding MFAO for one year to B6;129-Psen1tm1Mpm Tg(AβPPSwe,tauP301L) 1Lfa/Mmjax transgenic mice. Aβ levels were determined by ELISA. Results: MFAOs neither adversely affected mitochondrial signaling nor labile cytoplasmic zinc levels. MFAOs protected cells against Mn2+-induced mitochondrial dysfunction. MFAOs also removed zinc from the Aβ:Zn complex so that Aβ plaque could be degraded by MMP-2. Zinquin staining indicated that the removed zinc was present in the cytoplasm as labile zinc. Orally administered MFAOs reduced the brain levels of both Aβ40 and Aβ42 isoforms of Aβ. Conclusion: These studies demonstrate that these MFAOs have metal attenuating properties with therapeutic potential in the treatment of both AMD and AD.
Pages 309-318
Katherine A. Gifford, Dandan Liu, Stephen M. Damon, William G. Chapman, Raymond R. Romano, Lauren R. Samuels, Zengqi Lu, Angela L. Jefferson for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Frank Jessen)
Subjective Memory Complaint Only Relates to Verbal Episodic Memory Performance in Mild Cognitive Impairment
Abstract: Background: A cognitive concern from the patient, informant, or clinician is required for the diagnosis of mild cognitive impairment (MCI); however, the cognitive and neuroanatomical correlates of complaint are poorly understood. Objective: We assessed how self-complaint relates to cognitive and neuroimaging measures in older adults with MCI. Method: MCI participants were drawn from the Alzheimer’s Disease Neuroimaging Initiative and dichotomized into two groups based on the presence of self-reported memory complaint (no complaint n=191, 77±7 years; complaint n=206, 73±8 years). Cognitive outcomes included episodic memory, executive functioning, information processing speed, and language. Imaging outcomes included regional lobar volumes (frontal, parietal, temporal, cingulate) and specific medial temporal lobe structures (hippocampal volume, entorhinal cortex thickness, parahippocampal gyrus thickness). Results: Linear regressions, adjusting for age, gender, race, education, Mini-Mental State Examination score, mood, and apolipoprotein E4 status, found that cognitive complaint related to immediate (β=-1.07, p<0.001) and delayed episodic memory performances assessed on a serial list learning task (β=-1.06, p=0.001) but no other cognitive measures or neuroimaging markers. Conclusions: Self-reported memory concern was unrelated to structural neuroimaging markers of atrophy and measures of information processing speed, executive functioning, or language. In contrast, memory self-complaint related to objective verbal episodic learning performance. Future research is warranted to better understand the relation between cognitive complaint and surrogate markers of abnormal brain aging, including Alzheimer’s disease, across the cognitive aging spectrum.
Pages 319-328
Mario Riverol, James T. Becker , Oscar L. López, Cyrus A. Raji, Paul M. Thompson, Owen T. Carmichael, H. Michael Gach, William T. Longstreth Jr., Linda Fried, Russell P. Tracy, Lewis H. Kuller
Relationship between Systemic and Cerebral Vascular Disease and Brain Structure Integrity in Normal Elderly Individuals
Abstract: Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline.
Pages 329-338
Anna Zimny, Joanna Bladowska, Adam Macioszek, Paweł Szewczyk, Elzbieta Trypka, Renata Wojtynska, Leszek Noga, Jerzy Leszek, Marek Sasiadek (Handling Associate Editor: Khalid Iqbal)
Evaluation of the Posterior Cingulate Region with FDG-PET and Advanced MR Techniques in Patients with Amnestic Mild Cognitive Impairment: Comparison of the Methods
Abstract: Background: The posterior cingulate region is an area of the earliest pathological changes in amnestic mild cognitive impairment (aMCI). The utility of FDG-PET imaging in dementia is already well established. Objectives: The aim of the study was to compare FDG-PET with advanced MR measurements: MR spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI) within the posterior cingulate region in patients with aMCI. Methods: Fifty-five patients diagnosed with aMCI (66.5 y) and 20 age-matched controls (69 y) underwent MR examination including MRS, PWI, and DTI followed by FDG-PET scanning. Values of MRS metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr), PWI cerebral blood volume (rCBV), and DTI fractional anisotropy (FA) were compared to the FDG-PET rates of glucose metabolism. Results: Compared to controls, aMCI patients showed significant (p<0.05) glucose hypometabolism, and lower rCBV and FA values. FDG-PET results correlated significantly with rCBV values. Compared to FDG-PET, PWI showed similar and DTI greater accuracy in distinguishing aMCI from controls. According to FDG-PET findings, two groups of aMCI patients were established: those with lower (PET-positive) and normal (PET-negative) glucose uptake. PET-positive aMCI subjects showed normal MRS findings, lower rCBV and FA values, while PET-negative patients revealed normal MRS and PWI results but significantly lower FA values. Conclusions: Advanced MR techniques such as PWI and particularly DTI may be regarded as competitive techniques to FDG-PET. DTI was the only method to show alterations in aMCI patients with normal FDG-PET, PWI, and MRS findings. DTI seems to be a very sensitive biomarker of early degeneration in aMCI.
