Journal of Alzheimer's Disease - Volume 53, issue 2

Authors: Di Meco, Antonio | Praticò, Domenico

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, amyloid-beta, microRNAs, neuroinflammation, tau, therapeutic target

DOI: 10.3233/JAD-160203

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 367-372, 2016

Authors: Szalárdy, Levente | Zádori, Dénes | Klivényi, Péter | Vécsei, László

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, dementia, diagnosis, prodromal, tau

DOI: 10.3233/JAD-160037

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 373-392, 2016

Authors: Li, Wei | Huang, Edgar

Article Type: Review Article

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 ɛ 4 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. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, type 2 diabetes mellitus, vascular dementia

DOI: 10.3233/JAD-160114

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 393-402, 2016

Authors: Taipa, Ricardo | Sousa, Ana Luísa | Melo Pires, Manuel | Sousa, Nuno

Article Type: Review Article

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) and late-onset AD (>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. Show more

Keywords: Aging, Alzheimer’s disease, inflammation, microglia, phenotype

DOI: 10.3233/JAD-160121

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 403-417, 2016

Authors: Landel, Véréna | Annweiler, Cédric | Millet, Pascal | Morello, Maria | Féron, François

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, clinical trials, cognitive function, vitamin D

DOI: 10.3233/JAD-150943

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 419-444, 2016

Authors: Galimberti, Daniela | Bertram, Kelly | Formica, Alessandra | Fenoglio, Chiara | Cioffi, Sara M.G. | Arighi, Andrea | Scarpini, Elio | Colosimo, Carlo

Article Type: Short Communication

Abstract: Progranulin gene (GRN ) mutations are characterized by heterogeneous presentations. Corticobasal syndrome (CBS) is often associated with GRN mutations, whereas association with 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 cases of CBS, even in the absence of positive family history for …dementia and/or movement disorders. Show more

Keywords: Corticobasal syndrome, progranulin, progressive supranuclear palsy syndrome, tau, TDP-43

DOI: 10.3233/JAD-160073

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 445-449, 2016

Authors: Araújo, Larissa Fortunato | Mirza, Saira Saeed | Bos, Daniel | Niessen, Wiro J. | Barreto, Sandhi Maria | van der Lugt, Aad | Vernooij, Meike W. | Hofman, Albert | Tiemeier, Henning | Ikram, M. Arfan

Article Type: Research Article

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. Show more

Keywords: Brain imaging, brain tissue, coffee consumption, cognitive function, epidemiology, MRI

DOI: 10.3233/JAD-160116

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 451-461, 2016

Authors: Roh, Hyun Woong | Hong, Chang Hyung | Lee, Yunhwan | Lee, Kang Soo | Chang, Ki Jung | Kang, Dae Ryong | Lee, Jung-Dong | Choi, Seong Hye | Kim, Seong Yoon | Na, Duk L. | Seo, Sang Won | Kim, Doh Kwan | Back, Joung Hwan | Chung, Young Ki | Lim, Ki Young | Noh, Jai Sung | Son, Sang Joon

Article Type: Research Article

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. Show more

Keywords: Clinical conversion, community, dementia, hospital, mild cognitive impairment, reversion, recruitment source

DOI: 10.3233/JAD-160341

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 463-473, 2016

Authors: Sassi, Celeste | Capozzo, Rosa | Gibbs, Raphael | Crews, Cynthia | Zecca, Chiara | Arcuti, Simona | Copetti, Massimiliano | Barulli, Maria R. | Brescia, Vincenzo | Singleton, Andrew B. | Logroscino, Giancarlo

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, progranulin, splice site mutation

DOI: 10.3233/JAD-151170

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 475-485, 2016

Authors: Li, Hanzhi | Jia, Jianping | Yang, Zhiqiang

Article Type: Research Article

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. Show more

Keywords: Dementia, elderly, mild cognitive impairment, Mini-Mental State Examination

DOI: 10.3233/JAD-160119

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 487-496, 2016