Journal of Alzheimer's Disease - Volume 47, issue 4

Authors: Panza, Francesco | Seripa, Davide | Solfrizzi, Vincenzo | Tortelli, Rosanna | Greco, Antonio | Pilotto, Alberto | Logroscino, Giancarlo

Article Type: Review Article

Abstract: Late-life cognitive disorders may be prevented by influencing age-related conditions such as frailty, characterized by decreased resistance to stressors and increased risk for adverse health outcomes. In the present review article, we examined clinical and epidemiological studies investigating the possible role of different frailty models in modulating the risk of Alzheimer’s disease (AD), dementia, vascular dementia (VaD), mild cognitive impairment (MCI), and late-life cognitive impairment/decline that have been published over the past 3 years. Both deficit accumulation and physical frailty models were associated with late-life cognitive impairment/decline, incident dementia, AD, MCI, VaD, non-AD dementias, and AD pathology, proposing cognitive frailty …as a new clinical construct with coexisting physical frailty and cognitive impairment in nondemented older subjects. Two subtypes of this new clinical condition have been recently proposed: “potentially reversible” cognitive frailty and “reversible” cognitive frailty. The physical factors should be physical prefrailty and frailty, while the cognitive impairment of potentially reversible cognitive frailty should be MCI (Clinical Dementia rating Scale = 0.5), while the cognitive impairment of reversible cognitive frailty should be pre-MCI Subjective Cognitive Decline (SCD), as recently proposed by the SCD Initiative Working Group. The mechanisms underlying the cognitive-frailty link are multifactorial and vascular, inflammatory, nutritional, and metabolic influences may be of major relevance. Considering both physical frailty and cognition as a single complex phenotype may be crucial in the prevention of dementia and its subtypes with secondary preventive trials on cognitive frail older subjects. Show more

Keywords: Alzheimer’s disease, cognitive disorders, cognitive frailty, dementia, frailty index, mild cognitive impairment, physical frailty, subjective cognitive decline, vascular dementia

DOI: 10.3233/JAD-150358

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 793-813, 2015

Authors: Banik, Avijit | Brown, Richard E. | Bamburg, James | Lahiri, Debomoy K. | Khurana, Dheeraj | Friedland, Robert P. | Chen, Wei | Ding, Ying | Mudher, Amritpal | Padjen, Ante L. | Mukaetova-Ladinska, Elizabeta | Ihara, Masafumi | Srivastava, Sudhir | Padma Srivastava, M.V. | Masters, Colin L. | Kalaria, Raj N. | Anand, Akshay

Article Type: Review Article

Abstract: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer’s disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990–2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that …have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress. Show more

Keywords: Alzheimer’s disease, animal model, dementia, memory disorder, pre-clinical, treatment

DOI: 10.3233/JAD-150136

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 815-843, 2015

Authors: Novais, Filipa | Starkstein, Sergio

Article Type: Review Article

Abstract: Depression is among the most frequent psychiatric comorbid conditions in dementia. There is no strong consensus as to what criteria should be used to diagnose depression in AD. This is at least partially explained by the overlap between symptoms of depression and symptoms of AD. Recent studies using latent class analysis provided clarification to this diagnostic dilemma. All nine DSM-IV symptoms of major depression were found to characterize a class with a high chance (96% ) of having a clinical diagnosis of major depression, and symptoms of anxiety were also frequent. Other psychiatric symptoms may also be included under the …construct of depression in AD, since both apathy and anxiety are among the most frequent comorbid conditions for major depression in AD. Subtypes of depression should also be validated in this condition. For instance, increased awareness of cognitive and functional deficits is significantly associated with dysthymia but not with major depression, suggesting that different depressive syndromes in AD may have different etiology. Show more

Keywords: Alzheimer’s disease, anxiety, apathy, delusions, dementia, depression

DOI: 10.3233/JAD-148004

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 845-855, 2015

Authors: Pistollato, Francesca | Cavanaugh, Sarah E. | Chandrasekera, P. Charukeshi

Article Type: Research Article

Abstract: Animal models of Alzheimer’s disease (AD) have been extensively utilized for decades in an effort to elucidate the pathophysiological mechanisms of this disease and to test novel therapeutic approaches. However, research success has not effectively translated into therapeutic success for human patients. This translational failure is partially due to the overuse of animal models that cannot accurately recapitulate human AD etiopathogenesis or drug responses and the inadequate use of human-relevant research methods. Here, we propose how to mitigate this translational barrier by employing human-based methods to elucidate disease processes occurring at multiple levels of complexity, accounting for gene and protein …expression and the impact of disease at the cellular, tissue/organ, individual, and population levels. In particular, novel human-based cellular and computational models, together with epidemiological and clinical studies, represent the ideal tools to facilitate human-relevant data acquisition, in the effort to better elucidate AD pathogenesis in a human-based setting and design more effective treatments and preventive strategies. Our analysis indicates that a paradigm shift toward human-based, rather than animal-based research is required in the face of the ever-increasing prevalence of AD in the 21st century. Show more

Keywords: Alzheimer’s disease, animal models, biomarkers, computational methods, human-based methods, risk factors, stem cells, translational gap

DOI: 10.3233/JAD-150281

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 857-868, 2015

Authors: Mandal, Pravat K. | Saharan, Sumiti | Khan, Sarah A. | James, Mithun

Article Type: Editorial

Keywords: Alzheimer, screening apps, mobile application

DOI: 10.3233/JAD-150255

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 869-872, 2015

Authors: Alonso, Ruth | Pisa, Diana | Rábano, Alberto | Rodal, Izaskun | Carrasco, Luis

Article Type: Short Communication

Abstract: The identification of biomarkers for Alzheimer’s disease is important for patient management and to assess the effectiveness of clinical intervention. Cerebrospinal fluid (CSF) biomarkers constitute a powerful tool for diagnosis and monitoring disease progression. We have analyzed the presence of fungal proteins and DNA in CSF from AD patients. Our findings reveal that fungal proteins can be detected in CSF with different anti-fungal antibodies using a slot-blot assay. Additionally, amplification of fungal DNA by PCR followed by sequencing distinguished several fungal species. The possibility that these fungal macromolecules could represent AD biomarkers is discussed.

Keywords: Cerebrospinal fluid biomarker, fungal DNA, fungal infection, neurodegenerative disease, protein biomarker

DOI: 10.3233/JAD-150382

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 873-876, 2015

Authors: Catania, Marcella | Di Fede, Giuseppe | Tonoli, Elisa | Benussi, Luisa | Pasquali, Claudio | Giaccone, Giorgio | Maderna, Emanuela | Ghidoni, Roberta | Tagliavini, Fabrizio

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) accumulation in brain that is paralleled by Aβ1-42 reduction in cerebrospinal fluid (CSF). We analyzed the pattern of Aβ peptides, including the N- and C-terminal truncated fragments, in brain and CSF from two familial and one sporadic AD cases. We found that (i) each patient is characterized by a distinct Aβ profile in CSF and brain deposits and (ii) the CSF Aβ pattern mirrors the Aβ profile of cerebral amyloid. These results suggest the existence of different molecular AD subtypes which can be recognized by CSF analysis, enabling patient stratification.

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, SELDI-TOF MS

DOI: 10.3233/JAD-150179

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 877-881, 2015

Authors: Li, Ge | Xiong, Kangping | Korff, Ane | Pan, Catherine | Quinn, Joseph F. | Galasko, Douglas R. | Liu, Chunfeng | Montine, Thomas J. | Peskind, Elaine R. | Zhang, Jing

Article Type: Research Article

Abstract: Clinically diagnosed Alzheimer’s disease (AD) is pathologically heterogeneous. In this multicenter cohort of 215 clinically diagnosed AD patients and 249 controls, E-selectin and vascular cell adhesion molecule 1 (VACM-1) were measured along with amyloid-β peptide 1–42 (Aβ 42 ) and tau. We discovered that E-selectin, a biomarker of endothelial function/vascular injury, was inversely correlated with cerebrospinal fluid (CSF) tau/Aβ 42 ratio and significantly elevated in clinical AD patients without the typical AD CSF biomarker signature (i.e., low tau/Aβ 42 ratio) compared to those with the signature. These findings suggest that E-selectin may be an …objective biomarker related to vascular mechanisms contributing to dementia. Show more

Keywords: Alzheimer’s disease, Aβ42, cerebrospinal fluid, biomarkers, cerebrovascular disease, E-selectin, tau, vascular cell adhesion molecule 1

DOI: 10.3233/JAD-150420

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 883-887, 2015

Authors: Solfrizzi, Vincenzo | Panza, Francesco | Imbimbo, Bruno P. | D’Introno, Alessia | Galluzzo, Lucia | Gandin, Claudia | Misciagna, Giovanni | Guerra, Vito | Osella, Alberto | Baldereschi, Marzia | Di Carlo, Antonio | Inzitari, Domenico | Seripa, Davide | Pilotto, Alberto | Sabbá, Carlo | Logroscino, Giancarlo | Scafato, Emanuele | and for the Italian Longitudinal Study on Aging Working Group

Article Type: Research Article

Abstract: Coffee, tea, or caffeine consumption may be protective against cognitive impairment and dementia. We estimated the association between change or constant habits in coffee consumption and the incidence of mild cognitive impairment (MCI). We evaluated 1,445 individuals recruited from 5,632 subjects, aged 65–84 year old, from the Italian Longitudinal Study on Aging, a population-based sample from eight Italian municipalities with a 3.5-year median follow-up. Cognitively normal older individuals who habitually consumed moderate amount of coffee (from 1 to 2 cups of coffee/day) had a lower rate of the incidence of MCI than those who never or rarely consumed coffee [1 …cup/day: hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.211 to 1.02 or 1-2 cups/day: HR: 0.31 95% CI: 0.13 to 0.75]. For cognitively normal older subjects who changed their coffee consumption habits, those increasing coffee consumption (>1 cup of coffee/day) had higher rate of the incidence of MCI compared to those with constant habits (up to±1 cup of coffee/day) (HR: 1.80, 95% CI: 1.11 to 2.92) or those with reduced consumption (<1 cup of coffee/day) (HR: 2.17, 95% CI: 1.16 to 4.08). Finally, there was no significant association between subjects with higher levels of coffee consumption (>2 cups of coffee/day) and the incidence of MCI in comparison with those who never or rarely consumed coffee (HR: 0.26, 95% CI: 0.03 to 2.11). In conclusion, cognitively normal older individuals who increased their coffee consumption had a higher rate of developing MCI, while a constant in time moderate coffee consumption was associated to a reduced rate of the incidence of MCI Show more

Keywords: Alzheimer’s disease, caffeine use, coffee consumption, dementia, mild cognitive impairment

DOI: 10.3233/JAD-150333

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 889-899, 2015

Authors: Cloutier, Simon | Chertkow, Howard | Kergoat, Marie-Jeanne | Gauthier, Serge | Belleville, Sylvie

Article Type: Research Article

Abstract: Only a limited number of studies have investigated the decline of discrete cognitive domains as individuals progress from mild cognitive impairment (MCI) to dementia. Thus, the goal of this longitudinal study was to evaluate the cognitive changes underway during the years preceding a diagnosis of probable Alzheimer’s disease (AD), and to compare these changes to those found in MCI participants who do not progress to dementia. Participants were compared as a function of whether they later converted to AD (n  = 47) or not (n  = 74). Cognitive change was assessed prior to the conversion year, using that year as a starting …point. A combination of polynomial regression analyses and mixed ANOVAs assessed 1) the trajectory of cognitive decline for each domain and 2) the differences between non-progressors and those who had converted to AD. The different cognitive domains demonstrated very different patterns of decline in the group of MCI progressors. A quadratic function, i.e., many years of stable performance followed by a rapid decline just prior to diagnosis, was observed for delayed recall, working memory, and spatial memory. In contrast, a gradual linear decline was observed for immediate recall, executive function, and visuo-spatial abilities. Finally, language in progressors was impaired on all time periods relative to non-progressors, but there was no further change between the first assessments and conversion to AD. Individuals with MCI who progress to AD show abnormal cognition at least two years prior to their dementia diagnosis. The pattern of symptom change observed appears to depend upon the cognitive domain and thus, clinical studies should not assume similar rate of decline across domains. In contrast and, apart from verbal memory, the non-progressors present a performance similar to that of healthy older adults. Show more

Keywords: Alzheimer’s disease, cognitive trajectory, mild cognitive impairment, natural history, retrospective study

DOI: 10.3233/JAD-142910

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 901-913, 2015