Pages 367-372
Review
Antonio Di Meco, Domenico Praticò (Handling Associate Editor: Ottavio Arancio)
MicroRNAs as Therapeutic Targets for Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. With increasing longevity and the absence of a cure, AD has become not only a major health problem but also a heavy social and economic burden worldwide. Given this public health challenge, and that the current approved therapy for AD is limited to symptomatic treatment (i.e., cholinesterase inhibitors and NMDA receptor antagonists), exploration of new molecular pathways as novel therapeutic targets remains an attractive option for disease modifying drug development. microRNAs (miRNAs) are short non-coding RNA that control gene expression at the post-translational level by inhibiting translation of specific mRNAs or degrading them. Dysregulation of several miRNAs has been described in AD brains. Interestingly, their molecular targets are pathways that are well-established functional players in the onset and development of AD pathogenesis. Today several molecular tools have been developed to modulate miRNA levels in vitro and in vivo. These scientific advancements are affording us for the first time with the real possibility of targeting in vivo these dysregulated miRNAs as a novel therapeutic approach against AD.
Pages 373-392
Review
Levente Szalardy, Denes Zadori, Peter Klivenyi, Laszlo Vecsei
The Role of Cerebrospinal Fluid Biomarkers in the Evolution of Diagnostic Criteria in Alzheimer’s Disease: Shortcomings in Prodromal Diagnosis
Abstract: The available evidence indicates a high performance of core cerebrospinal fluid (CSF) biomarkers in differentiating between Alzheimer’s disease (AD) and other dementias, and suggests that their characteristic alterations can be detected even at the prodromal stage of AD. On this basis, the ability of core CSF biomarkers to identify prodromal AD patients from pre-dementia of all causes can be postulated, a concept that is reflected in recent revisions of AD research criteria and a consensus statement. Following an overview on the role of biomarkers in the evolution of diagnostic criteria of AD in recent decades, this paper provides a critical review of the widely applied CSF biomarker study designs and evaluating approaches that address the ability of core CSF biomarkers to diagnose prodromal AD, with special focus on their potential limitations in terms of clinical interpretation and utility. The findings together raise the question of whether we are indeed able to establish a CSF biomarker-based diagnosis of AD at the prodromal stage.
Pages 393-402
Review
Wei Li, Edgar Huang
An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia
Abstract: With the rapidly expanding evidence on brain structural and functional changes in type 2 diabetes mellitus (T2DM) patients, there is an increasing need to update our understanding on how T2DM associates with dementia as well as the underlying pathophysiological mechanisms. A literature search of T2DM and dementia or cognition impairments was carried out in electronic databases Medline, EMBASE, and Google Scholar. In this review, the chosen evidence was limited to human subject studies only, and data on either type 1 diabetes mellitus (T1DM) or non-classified diabetes were excluded. T2DM is a risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), although AD pathological marker studies have not provided sufficient evidence. T2DM interacts additively or synergistically with many factors including old age, hypertension, total cholesterol, and APOE ε4 carrier status for impaired cognition functions seen in patients with T2DM. In addition, comorbid T2DM can worsen the clinical presentations of patients with either AD or VaD. In summary, T2DM increases the risk for AD through different mechanisms for VaD although some mechanisms may overlap. Tau-related neurofibrillary tangles instead of amyloid-β plaques are more likely to be the pathological biomarkers for T2DM-related dementia. Degeneration of neurons in the brain, impaired regional blood supply/metabolism, and genetic predisposition are all involved in T2DM-associated dementia or cognitive impairments.
Pages 403-417
Review
Ricardo Taipa, Ana Luísa Sousa, Manuel Melo Pires, Nuno Sousa
Does the Interplay Between Aging and Neuroinflammation Modulate Alzheimer’s Disease Clinical Phenotypes? A Clinico-Pathological Perspective
Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and is the most common cause of dementia worldwide. Cumulative data suggests that neuroinflammation plays a prominent and early role in AD, and there is compelling data from different research groups of age-associated dysregulation of the neuroimmune system. From the clinical point of view, despite clinical resemblance and neuropathological findings, there are important differences between the group of patients with sporadic early-onset (65 years old). Thus, it seems important to understand the age-dependent relationship between neuroinflammation and the underlying biology of AD in order to identify potential explanations for clinical heterogeneity, interpret biomarkers, and promote the best treatment to different clinical AD phenotypes. The study of the delicate balance between pro-inflammatory or anti-inflammatory sides of immune players in the different ages of onset of AD would be important to understand treatment efficacy in clinical trials and eventually, not only direct treatment to early disease stages, but also the possibility of establishing different treatment approaches depending on the age of the patient. In this review, we would like to summarize what is currently known about the interplay between “normal” age associated inflammatory changes and AD pathological mechanisms, and also the potential differences between early-onset and late-onset AD taking into account the age-related neuroimmune background at disease onset.
Pages 419-444
Review
Véréna Landel, Cédric Annweiler, Pascal Millet, Maria Morello, François Féron (Handling Associate Editor: Didier Wion)
Vitamin D, Cognition, and Alzheimer’s Disease: The Therapeutic Benefit is in the D-Tails
Abstract: Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer’s disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider.
Pages 445-449
Short Communication
Daniela Galimberti, Kelly Bertram, Alessandra Formica, Chiara Fenoglio, Sara M.G. Cioffi, Andrea Arighi, Elio Scarpini, Carlo Colosimo (Handling Associate Editor: Piotr Lewczuk)
Plasma Screening for Progranulin Mutations in Patients with Progressive Supranuclear Palsy and Corticobasal Syndromes
Abstract: Progranulin gene (GRN) mutations are characterized by heterogeneous presentations. Corticobasal syndrome (CBS) is often associated with GRN mutations, whereas progressive supranuclear palsy syndrome (PSPS) is rare. Plasma progranulin levels were evaluated in 34 patients, including 19 with PSPS, 12 with CBS, and 3 with mixed signs, with the purpose to screen for the presence of causal mutations, associated with low levels. We found undetectable levels in a patient with CBS. Sequencing confirmed the presence of the Thr272fs deletion. Progranulin mutation screening is suggested in case of CBS, even in the absence of positive family history for dementia and/or movement disorders.
Pages 451-461
Larissa Fortunato Araújo, Saira Saeed Mirza, Daniel Bos, Wiro J. Niessen, Sandhi Maria Barreto, Aad van der Lugt, Meike W. Vernooij, Albert Hofman, Henning Tiemeier, M. Arfan Ikram (Handling Associate Editor: M. Cristina Polidori)
Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study
Abstract: Background: Coffee is one of the most widely consumed beverages worldwide and has been of considerable interest in research on cognition and dementia. Objective: To investigate the effect of coffee on preclinical brain MRI markers of dementia and cognitive performance. Methods: In 2,914 participants from the population-based Rotterdam Study (mean age: 59.3 ±7.2 years, 55% females), we assessed coffee consumption, performed brain MRI, and assessed cognition at baseline. To study cognitive change, cognitive assessment was repeated after 5 years of follow-up. Coffee consumption was analyzed continuously (per cup increase) and in categories (0–1, >1–3, >3 cups/day). Using logistic and linear regression, associations of coffee consumption with lacunar infarcts and brain tissue volumes on MRI, and cognitive performance (cross-sectional and longitudinal) were investigated, adjusting for relevant confounders. Results: We found that higher coffee consumption was associated with a lower prevalence of lacunar infarcts [odds ratio per cup increase: 0.88 (95%CI:0.79;0.98)], and smaller hippocampal volume [difference: -0.01 (95% CI:-0.02;0.00)]. Also, we found that the highest category of coffee consumption was associated with better performance on the Letter Digit Substitution Task [difference: 1.13(95%CI:0.39;1.88)], Word Fluency test [0.74(95%CI:0.04,1.45)], Stroop interference task [1.82(95%CI:0.23;3.41)], and worse performance on the 15-Word Learning test delayed recall [-0.38(95%CI:-0.74;-0.02)]. These associations were not found when cognition was analyzed longitudinally. Conclusion: We found complex associations between coffee consumption, brain structure, and cognition. Higher coffee consumption was cross-sectionally associated with a lower occurrence of lacunar infarcts and better executive function, but also with smaller hippocampal volume and worse memory function.
Pages 463-473
Hyun Woong Roh, Chang Hyung Hong, Yunhwan Lee, Kang Soo Lee, Ki Jung Chang, Dae Ryong Kang, Jung-Dong Lee, Seong Hye Choi, Seong Yoon Kim, Duk L. Na, Sang Won Seo, Doh Kwan Kim, Joung Hwan Back, Young Ki Chung, Ki Young Lim, Jai Sung Noh, Sang Joon Son
Clinical Conversion or Reversion of Mild Cognitive Impairment in Community versus Hospital Based Studies: GDEMCIS (Gwangju Dementia and Mild Cognitive Impairment Study) and CREDOS (Clinical Research Center for Dementia of South Korea)
Abstract: Background: In keeping with increasing interest in dementia, few recent studies suggest that clinical course of mild cognitive impairment vary across different studies with hospital-based subjects showing higher rates of conversion than community-based subjects. Objective: The main objective of the present study was to assess whether the clinical conversion or reversion rates differ according to recruitment source. Methods: The baseline study subjects comprised of patients who were diagnosed with mild cognitive impairment in community-based GDEMCIS or hospital-based CREDOS. The two studies had nearly the same protocol and were performed over a similar period. We used propensity score matching for baseline comparability. After that, Cox proportional hazards regression analyses were conducted to estimate the hazard ratios and 95% confidence intervals of clinical conversion or reversion. Results: Based on 89 GDEMCIS subjects, 1:4 propensity score matching was conducted and 356 CREDOS subjects were selected. After adjusting for covariates including baseline demographics, comorbidity, depression, disability, and neuropsychological result, Cox proportional hazard regression analysis for time to clinical conversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 2.13 (95% CI, 1.08-4.21), as compared to recruitment from community-based GDEMCIS. Similarly, Cox proportional hazard regression analysis for time to reversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 0.34 (95% CI, 0.20-0.59), as compared to recruitment from community-based GDEMCIS. Conclusion: The present study demonstrated that even after the matching process and adjustments for baseline covariates, recruitment source greatly affected the course of mild cognitive impairment.
Pages 475-485
Celeste Sassi*, Rosa Capozzo*, Raphael Gibbs, Cynthia Crews, Chiara Zecca, Simona Arcuti, Massimiliano Copetti, Maria R. Barulli, Vincenzo Brescia, Andrew B. Singleton, Giancarlo Logroscino *These authors contributed equally to this work.
A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy
Abstract: Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.
Pages 487-496
Hanzhi Li, Jianping Jia, Zhiqiang Yang (Handling Associate Editor: Noémie Moreau)
Mini-Mental State Examination in Elderly Chinese: A Population-Based Normative Study
Abstract: Background: Chinese nationwide norms of the Mini-Mental State Examination (MMSE) have not been established despite its wide use. Objective: To obtain norms for the MMSE based on age, gender, education, and rural or urban residences and to determine the optimal cut-off points of the MMSE in elderly Chinese. Methods: A cross-sectional study was conducted in Chinese community residents aged 65 years or over selected by cluster random sampling. The MMSE was administered to 9,629 subjects (7,110 cognitively normal, 2,024 with mild cognitive impairment, and 495 with dementia). The demographic influences on MMSE scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off points. Results: Years of education (standardized β = 0.399), rural residence (standardized β = −0.261), age (standardized β = −0.198), and being female (standardized β = −0.101) had significant effects on MMSE scores (p<0.001). Accordingly, we presented the demographic-stratified normative data for the MMSE. The optimal cut-off points for dementia screening were 16/17 for illiterate (sensitivity 87.6% and specificity 80.8%), 19/20 for individuals with 1-6 years of education (sensitivity 93.6% and specificity 92.7%), and 23/24 for individuals with 7 or more years of education (sensitivity 94.3% and specificity 94.3%). Conclusion: We provide the age-, gender-, education-, and residence-specific reference norms for the MMSE derived from an investigation of a large-scale, multicenter, nationwide representative Chinese elderly population. It could be of great improvement for the use of the MMSE in dementia screening in Chinese elderly population.
Pages 497-503
Saloua Akoudad, M. Edip Gurol, Panagiotis Fotiadis, Peter J. Koudstaal, Albert Hofman, M. Arfan Ikram, Steven M. Greenberg, Meike W. Vernooij
Cerebral Microbleeds and Cerebrovascular Reactivity in the General Population: The EDAN Study
Abstract: Background: In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. Recent data suggest that the latter group might have CAA. Objective: We investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds. Methods: From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all ≥ 55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude and time to peak responses) were assessed in response to visual stimulation using fMRI. Student’s t-test and linear regression were used to compare fMRI parameters in participants with and without microbleeds. Results: Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, p=0.179 and p=0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds. Conclusions: In the general population, lobar microbleeds may not relate to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA.
Pages 505-515
Antonio Di Carlo, Marzia Baldereschi, Maria Lamassa, Francesca Bovis, Marco Inzitari, Vincenzo Solfrizzi, Francesco Panza, Lucia Galluzzo, Emanuele Scafato, Domenico Inzitari, for the Italian Longitudinal Study on Aging Working Group (Handling Associate Editor: Alba Malara)
Daily Function as Predictor of Dementia in Cognitive Impairment, No Dementia (CIND) and Mild Cognitive Impairment (MCI): An 8-Year Follow-Up in the ILSA Study
Abstract: Background: Preclinical cognitive changes may predict an increased risk of dementia, allowing selection of subgroups as possible targets for preventive or therapeutic interventions. Objective: To evaluate the predictive effect of daily functioning and motor performance (MP) on the progression to dementia in normal cognition, cognitive impairment, no dementia (CIND), and mild cognitive impairment (MCI). Methods: The Italian Longitudinal Study on Aging is a large population-based survey on age-related diseases of the cardiovascular and nervous systems. After the baseline assessment, to detect prevalent cases of cognitive impairment and dementia, participants were re-examined at 4-year and 8-year follow-ups. Functional independence was evaluated using the Index of Activities of Daily Living (ADL) and the Instrumental Activities of Daily Living (IADL) Scale. A six-test battery was used to assess MP. Results: Overall, 2,386 individuals were included, for a total of 16,545 person-years. Eight-year incidence of dementia (per 1,000 person-years) was 12.69 in total sample, 9.86 in subjects with normal cognition at baseline, 22.99 in CIND, and 21.43 in MCI. Progression to dementia was significantly higher with increasing baseline ADL and IADL impairment, and with a worse MP. In Cox regression analyses controlled for demographics and major age-related conditions, increased IADL impairment was the stronger predictor of progression to dementia (p<0.001), with HR ranging from 2.16 (95% CI, 0.82-5.70) to 9.57 (95% CI, 3.40-26.91) in subjects with MCI at baseline. Conclusions: Inclusion of IADL in the MCI construct significantly improves the prediction of dementia. Individuation of different transition rates is required to plan cost-effective interventions.
Pages 517-533
Galit Yogev-Seligmann, Noga Oren, Elissa L. Ash, Talma Hendler, Nir Giladi, Yulia Lerner
Altered Topology in Information Processing of a Narrated Story in Older Adults with Mild Cognitive Impairment
Abstract: The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI.
Pages 535-546
Alberto Russu, Mahesh N. Samtani, Steven Xu, Omoniyi J. Adedokun, Ming Lu, Kaori Ito, Brian Corrigan, Sangeeta Raje, Enchi Liu, H. Robert Brashear, Scot Styren, Chuanpu Hu (Handling Associate Editor: Duygu Tosun-Turgut)
Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer’s Disease Trials of Bapineuzumab
Abstract: Background: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer’s disease (AD) patients. Objective: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. Methods: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1 hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. Results: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. Conclusions: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.
Pages 547-556
Kejal Kantarci, Val J. Lowe, Timothy G. Lesnick, Nirubol Tosakulwong, Kent R. Bailey, Julie A. Fields, Lynne T. Shuster, Samantha M. Zuk, Matthew L. Senjem, Michelle M. Mielke, Carey Gleason, Clifford R. Jack, Jr., Walter A. Rocca, Virginia M. Miller (Handling Associate Editor: Mary Tierney)
Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition
Abstract: Background: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer’s disease (AD). Objective: To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women. Methods: Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50 μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. Results: Women (age=52-65) randomized to transdermal 17β-estradiol (n=21) had lower PiB SUVR compared to placebo (n=30) after adjusting for age [odds ratio (95%CI)=0.31(0.11-0.83)]. In the APOE ε4 carriers, transdermal 17β-estradiol treated women (n=10) had lower PiB SUVR compared to either placebo (n=5) [odds ratio (95%CI)=0.04(0.004-0.44)], or the oral CEE treated group (n=3) [odds ratio (95%CI)=0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOE ε4 non-carriers. Conclusion: In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOE ε4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.
Pages 557-571
Ágnes Kasza*, Ákos Hunya*, Zsuzsa Frank, Ferenc Fülöp, Zsolt Török, Gábor Balogh, Miklós Sántha, Árpád Bálind, Sándor Bernáth, Katie L.I.M. Blundell, Chrisostomos Prodromou, Ibolya Horváth, Hans-Joachim Zeiler, Philip L. Hooper, László Vigh, Botond Penke (Handling Associate Editor: Jose Abisambra) *These authors contributed equally to this work.
Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer’s disease (AD) is thought to be caused by amyloid-β peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD.
Pages 573-581
Alexandra M.V. Wennberg, Deborah Gustafson, Clinton E. Hagen, Rosebud O. Roberts, David Knopman, Clifford Jack Jr., Ronald C. Petersen, Michelle M. Mielke (Handling Associate Editor: Gene Bowman)
Serum Adiponectin Levels, Neuroimaging, and Cognition in the Mayo Clinic Study of Aging
Abstract: Background: Adiponectin, a protein involved in inflammatory pathways, may impact the development and progression of Alzheimer’s disease (AD). Adiponectin levels have been associated with mild cognitive impairment (MCI) and AD; however, its association with Alzheimer-associated neuroimaging and cognitive outcomes is unknown. Objective: Determine the cross-sectional association between plasma adiponectin and neuroimaging and cognitive outcomes in an older population-based sample. Methods: Multivariable adjusted regression models were used to investigate the association between plasma adiponectin and hippocampal volume (HVa), PiB-PET, FDG PET, cortical thickness, MCI diagnosis, and neuropsychological test performance. Analyses included 535 non-demented participants aged 70 and older enrolled in the Mayo Clinic Study of Aging. Results: Women had higher adiponectin than men (12,631 ng/mL versus 8,908 ng/mL, p < 0.001). Among women, higher adiponectin was associated with smaller HVa (B = -0.595; 95% CI -1.19, -0.005), poorer performance in language (B = -0.676; 95% CI -1.23, -0.121), and global cognition (B = -0.459; 95% CI -0.915, -0.002), and greater odds of a MCI diagnosis (OR = 6.23; 95% CI 1.20, 32.43). In analyses stratified by sex and elevated amyloid (PiB-PET SUVR > 1.4), among women with elevated amyloid, higher adiponectin was associated with smaller HVa (B = -0.723; 95% CI -1.43, -0.014), poorer performance in memory (B = -1.02; 95% CI -1.73, -0.312), language (B = -0.896; 95% CI -1.58, -0.212), global cognition (B = -0.650; 95% CI -1.18, -0.116), and greater odds of MCI (OR = 19.34; 95% CI 2.72, 137.34). Conclusion: Higher plasma adiponectin was associated with neuroimaging and cognitive outcomes among women. Longitudinal analyses are necessary to determine whether higher adiponectin predicts neurodegeneration and cognitive decline.
Pages 583-620
Alexandre V. Ivachtchenko, Yan Lavrovsky, Ilya Okun
AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders
Abstract: Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki=153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2 - 2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41–3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer’s disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.
Pages 621-630
Walid Tajeddinn, Seyed-Mohammad Fereshtehnejad, Mohammed Seed Ahmed, Takashi Yoshitake, Jan Kehr, Tasmin Shahnaz, Micha Milovanovic, Homira Behbahani, Kina Höglund, Bengt Winblad, Angel Cedazo-Minguez, Vesna Jelic, Petter Järemo, Dag Aarsland
Association of Platelet Serotonin Levels in Alzheimer’s Disease with Clinical and Cerebrospinal Fluid Markers
Abstract: Introduction: Serotonin (5-HT) is involved in the pathology of Alzheimer’s disease (AD). Objective: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid-β 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms. Methods: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Results: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients both after normalization against total protein (p = 0.008) or platelet count (p = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p = 0.026) and tau/Aβ42 ratio (p = 0.001), compared to those with high 5-HT levels. Conclusion: AD patients have reduced platelets 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden.
Pages 631-638
Joel Lovas, Seyed-Mohammad Fereshtehnejad, Pavla Cermakova, Catarina Lundberg, Björn Johansson, Kurt Johansson, Bengt Winblad, Maria Eriksdotter , Dorota Religa
Assessment and Reporting of Driving Fitness in Patients with Dementia in Clinical Practice: Data from SveDem, the Swedish Dementia Registry
Abstract: Background: Driving constitutes a very important aspect of daily life and is dependent on cognitive functions such as attention, visuo-spatial skills, and memory, which are often compromised in dementia. Therefore, the driving fitness of patients with dementia needs to be addressed by physicians and those that are deemed unfit should not be allowed to continue driving. Objective: We aimed to investigate to what extent physicians assess driving fitness in dementia patients and determinant factors for revoking of their licenses. Methods: This study includes 15,113 patients with newly diagnosed dementia and driver’s license registered in the Swedish Dementia Registry (SveDem). The main outcomes were reporting to the licensing authority and making an agreement about driving eligibility with the patients. Results: Physicians had not taken any action in 16% of dementia patients, whereas 9% were reported to the authority to have their licenses revoked. Males (OR = 3.04), those with an MMSE score between 20-24 (OR = 1.35) and 10-19 (OR = 1.50), patients with frontotemporal (OR = 3.09) and vascular dementia (OR = 1.26) were more likely to be reported to the authority. Conclusion: For the majority of patients with dementia, driving fitness was assessed. Nevertheless, physicians did not address the issue in a sizeable proportion of dementia patients. Type of dementia, cognitive status, age, sex, and burden of comorbidities are independent factors associated with the assessment of driving fitness in patients with dementia. Increased knowledge on how these factors relate to road safety may pave the way for more specific guidelines addressing the issue of driving in patients with dementia.
Pages 639-650
Eva del Valle, Ana Navarro, Eva Martinez-Pinilla, Silvia Torices, Jorge Tolivia (Handling Associate Editor: Yu Zhang)
Apo J and Apo D: Complementary or Antagonistic Roles in Alzheimer’s Disease?
Abstract: Apolipoprotein D (Apo D) and Apolipoprotein J (Apo J) are among the only nine apolipoproteins synthesized in the nervous system. Apart from development, these apolipoproteins are implicated in the normal aging process as well as in different neuropathologies as Alzheimer’s disease (AD), where a neuroprotective role has been postulated. Different authors have proposed that Apo D and Apo J could be biomarkers for AD but as far as we know, there are no studies about the relationship between them as well as their expression pattern along the progression of the disease. In this paper, using double immunohistochemistry techniques, we have demonstrated that Apo D is mainly located in glial cells while Apo J expression preferentially occurs in neurons; both proteins are also present in AD diffuse and mature senile plaques but without signal overlap. In addition, we have observed that Apo J and Apo D immunostaining shows a positive correlation with the progression of the disease and the Braak’s stages. These results suggest complementary and cell-dependent neuroprotective roles for each apolipoprotein during AD progress.
Pages 651-660
Bernard Hanseeuw, Laurence Dricot, Rrenaud Lhommel, Lisa Quenon, Adrian Ivanoiu
Patients with Amyloid-Negative Mild Cognitive Impairment have Cortical Hypometabolism but the Hippocampus is Preserved
Abstract: Background: Patients with mild cognitive impairment (MCI) are at risk for Alzheimer’s dementia but the presence of amyloid (Aβ) strongly increases this risk. In clinical settings, when Aβ status is not available, different neurodegenerative markers are used to characterize MCI. The accuracy of these markers to discriminate between Aβ- and Aβ+ MCI is not yet determined. Objective: To compare different markers of neurodegeneration in Aβ- and Aβ+ MCI, with an Aβ- elderly control (EC) group. Methods: Patients with MCI (n=39) and EC (n=28) underwent MRI, 18F-FDG PET, and Aβ PET (18F-flutemetamol). We compared FDG and MRI biomarker values in cortical and hippocampal regions of interest, and using voxel-wise surface maps. We computed ROC curves discriminating between the three groups for each biomarker. Results: All biomarker values were reduced in Aβ+ MCI compared to EC (p<0.001). Aβ- MCI had low cortical metabolism (p=0.002), but hippocampal volume, cortical thickness, and hippocampal metabolism were not significantly different between Aβ- MCI and EC (p>0.40). Cortical metabolism best discriminated between MCI and EC (AUC=0.92/0.86, Aβ+/Aβ-) while hippocampal volume best discriminated between Aβ- MCI and Aβ+ MCI (AUC=0.79). Conclusions: Cortical hypometabolism was observed in both Aβ- MCI and Aβ+ MCI whereas hippocampal atrophy was mostly found in Aβ+ MCI. For MCI patients without available Aβ information, hippocampal atrophy is thus more informative about Aβ status than cortical hypometabolism.
Pages 661-676
Takao Yamasaki, Shizuka Horie, Yasumasa Ohyagi, Eri Tanaka, Norimichi Nakamura, Yoshinobu Goto, Shigenobu Kanba, Jun-ichi Kira, Shozo Tobimatsu (Handling Associate Editor: Pravat Mandal)
A Potential VEP Biomarker for Mild Cognitive Impairment: Evidence from Selective Visual Deficit of Higher-Level Dorsal Pathway
Abstract: Visual dysfunctions are common in Alzheimer’s disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n=15) and in healthy older (n=15) and younger controls (n=15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI.
Pages 677-691
Cristina Merino-Zamorano, Sofía Fernández-de Retana, Alex Montañola, Aina Batlle, Julien Saint-Pol, Caroline Mysiorek, Fabien Gosselet, Joan Montaner, Mar Hernández-Guillamon
Modulation of Amyloid-β1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier
Abstract: Amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) is likely caused by the impairment of its brain clearance that partly occurs through the blood-brain barrier (BBB). In this context, an in vitro BBB model is a valuable tool for studying the molecular mechanisms that regulate this process. This study assessed brain Aβ elimination across the BBB and its modulation by the natural chaperones Apolipoprotein A1 (ApoA1) and Apolipoprotein J/Clusterin (ApoJ). The model was based on primary cerebral endothelial cells that were cultured on Matrigel-coated Transwells and treated with fluorescently labeled-Aβ1-40 to track its efflux across the BBB, which corresponds to trafficking from the basolateral (brain) to apical (blood) compartments. We observed that the transport of basolateral Aβ1-40 was enhanced when it was complexed to rApoJ, whereas the complex formed with rApoA1 did not influence Aβ1-40 efflux. However, the presence of rApoA1 in the apical compartment was able to mobilize Aβ1-40 from the basolateral side. We also observed that both rApoA1 and rApoJ moderately crossed the monolayer (from blood to brain) through a mechanism involving the LDL receptor-related protein family. In contrast to the increased rApoJ efflux when complexed to Aβ1-40, rApoA1 trafficking was restricted when it was bound to the Aβ peptide. In summary, the present study highlights the role of ApoJ and ApoA1 in the in vitro modulation of Aβ elimination across the BBB.
Pages 693-704
Jing Yu, Rui Li, Yang Jiang, Lucas S. Broster, Juan Li (Handling Associate Editor: Zhanjun Zhang)
Altered Brain Activities Associated with Neural Repetition Effects in Mild Cognitive Impairment Patients
Abstract: Older adults with mild cognitive impairment (MCI) manifest impaired explicit memory. However, studies on implicit memory such as repetition effects in persons with MCI have been limited. In the present study, 17 MCI patients and 16 healthy normal controls (NC) completed a modified delayed-match-to-sample task while undergoing functional magnetic resonance imaging. We aim to examine the neural basis of repetition; specifically, to elucidate whether and how repetition-related brain responses are altered in participants with MCI. When repeatedly rejecting distracters, both NC and MCI showed similar behavioral repetition effects; however, in both whole-brain and region-of-interest analyses of functional data, persons with MCI showed reduced repetition-driven suppression in the middle occipital and middle frontal gyrus. Further, individual difference analysis found that activation in the left middle occipital gyrus was positively correlated with rejecting reaction time and negatively correlated with accuracy rate, suggesting it could predict repetition behavioral performance. These findings provide new evidence to support the view that neural mechanisms of repetition effect are altered in MCI, who manifest compensatory repetition-related brain activities along with their neuropathology.
Pages 705-712
Juan Carlos Cejudo Bolívar, Domènec Gil Saladié
Redefining Amnestic Mild Cognitive Impairment as an Early Form of Alzheimer’s Disease Based on Assessment of Memory Systems
Abstract: Background: It has been suggested that mild cognitive impairment (MCI) can be used to identify patients at risk of developing clinical stages of Alzheimer’s disease (AD). Objective: The aim of this study was to describe the characteristics of amnesic syndrome of dementia of the Alzheimer’s type (DAT) as a continuous degenerative process from normality to amnesic syndrome and provide a classification of the degrees of amnesia. Methods: Of 3,800 new incidental cases at the Memory Clinic, 747 were classified as non-demented patients. A 96-month follow-up study was conducted. We described and compared longitudinal outcomes from normality to amnesic syndrome based on immediate memory, verbal learning, free recall, and recognition using the memory scale from the Basic Neuropsychological Battery, version D (BNB-D) and created a new classification of memory impairment. Results: Based on differences observed in this longitudinal study, we classified patients in four memory stages: M1, Normal episodic memory; M2, mild impairment in learning and/or free recall; M3, clear impairment in learning and/or free recall; and M4, complete amnesic syndrome. With this new amnesia classification, we studied the chronological progression of all patients diagnosed without dementia from baseline to DAT conversion using the Kaplan-Meier estimator of survival probability (Log Rank/Mantel Cox comparison. χ2 = 171.84, p = 0.001). Conclusion: This new classification of memory impairment can help increase the prediction certainty of conversion from amnestic MCI to AD and improve research on AD biomarkers and their relationship with memory as the principal manifestation of AD.
Pages 713-729
Megan A. Hird, Peter Egeto, Corinne E. Fischer, Gary Naglie, Tom A. Schweizer (Handling Associate Editor: Nancy Pachana)
A Systematic Review and Meta-Analysis of On-Road, Simulator, and Cognitive Driving Assessment in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: Many individuals with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are at an increased risk of driving impairment. There is a need for tools with sufficient validity to help clinicians assess driving ability. Objective: Provide a systematic review and meta-analysis of the primary driving assessment methods (on-road, cognitive, driving simulation assessments) in patients with MCI and AD. Methods: We investigated (1) the predictive utility of cognitive tests and domains, and (2) the areas and degree of driving impairment in patients with MCI and AD. Effect sizes of were derived and analyzed in a random effects model. Results: Thirty-two articles (including 1,293 AD patients, 92 MCI patients, 2,040 healthy older controls) met inclusion criteria. Driving outcomes included: on-road test scores, pass/fail classifications, errors; caregiver reports; real world crash involvement; and driving simulator collisions/risky behavior. Executive function (ES [95% CI]; 0.61[0.41, 0.81]), attention (0.55 [0.33, 0.77]), visuospatial function (0.50 [0.34, 0.65]), and global cognition (0.61 [0.39, 0.83]) emerged as significant predictors of driving performance. Trail Making Test Part B (TMT-B, 0.61 [0.28, 0.94]), TMT-A (0.65 [0.08, 1.21]), and Maze test (0.88 [0.60, 1.15]) emerged as the best single predictors of driving performance. Patients with very mild AD (CDR=0.5) and mild AD (CDR=1) were more likely to fail an on-road test than healthy control drivers (CDR=0), with failure rates of 13.6%, 33.3% and 1.6%, respectively. Conclusion: The driving ability of patients with MCI and AD appears to be related to degree of cognitive impairment. Across studies, there are inconsistent cognitive predictors and reported driving outcomes in MCI and AD patients. Future large-scale studies should investigate the driving performance and associated neural networks of subgroups of AD (very mild, mild, moderate) and MCI (amnestic, non-amnestic, single-domain, multiple-domain).
Pages 731-741
Seung Wan Suh, Ji Won Han, Jae Young Park, Jong Woo Hong, Kayoung Kim, Taehyun Kim, Kyoung Hwan Lee, Guehee Han, Hyeon Jeong, Jiyeong Seo, Tae Hui Kim, Dong Young Lee, Dong Woo Lee, Seung-Ho Ryu, Shin-Gyeom Kim, Jong Chul Youn, JinHyeong Jhoo, Jeong Lan Kim, Seok Bum Lee, Jung Jae Lee, Kyung Phil Kwak, Bong-Jo Kim, Seok Woo Moon, Joon Hyuk Park, Ki Woong Kim
Impacts of Illiteracy on the Risk of Dementia: A Global Health Perspective
Abstract: Despite its significance as a contributing factor for late-life dementia risk, illiteracy is frequently underappreciated in the management of dementia. In this study, we estimated the proportion of dementia cases attributable to illiteracy using the population attributable fraction (PAF), and calculated to what extent the monetary cost of dementia could be saved in the future by reducing illiteracy from the South Korean, Latin American, South Asian/Middle Eastern, and African populations. We collected necessary data from the 2011 United Nations Human Development Report and prevalence studies conducted in these regions. Additional variables not included in the above sources were estimated using a logit model under a “trend scenario”-based assumption. Around 16% of the total number of dementia cases in South Korea in 2015 can be attributed to illiteracy, with this figure predicted to decline to around 2% by 2050. This translates to a saving in dementia care costs of approximately 52 billion USD, providing we are successful in theoretically eradicating illiteracy as of 2015, in the population aged 65 years or under. Likewise, reducing illiteracy to 50% in Latin America, South Asia/The Middle East, and Africa by 2050 could generate further cost savings of between 71 and 244 billion, 13 and 94 billion, and 17 and 78 billion USD, respectively. Even public policies aimed solely at reducing illiteracy in the childhood, adolescent, or middle-aged population could potentially have a role in the primary prevention of dementia. Moving forward, governments will need to address this issue in a purposeful and systematic manner.
