Journal of Alzheimer's Disease - Volume 61, issue 1

Authors: Medoro, Alessandro | Bartollino, Silvia | Mignogna, Donatella | Passarella, Daniela | Porcile, Carola | Pagano, Aldo | Florio, Tullio | Nizzari, Mario | Guerra, Germano | Di Marco, Roberto | Intrieri, Mariano | Raimo, Gennaro | Russo, Claudio

Article Type: Review Article

Abstract: The processing of the amyloid-β protein precursor (AβPP) by β- and γ -secretases is a pivotal event in the genesis of Alzheimer’s disease (AD). Besides familial mutations on the A βPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2 ) genes: the catalytic components of the proteolytic enzyme γ -secretase (GS). The “amyloid hypothesis”, modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration. This …theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin’s “gain of function” versus “loss of function”; and 2) the presence of several and various GS substrates, which interact with AβPP and may influence Aβ formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AβPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AβPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AβPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer. Show more

Keywords: Alzheimer’s disease, AβPP, β-secretase, cancer, cell migration, γ-secretase, LDL receptor, Notch

DOI: 10.3233/JAD-170628

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 1-15, 2018

Authors: Iverson, Grant L. | Keene, C. Dirk | Perry, George | Castellani, Rudolph J.

Article Type: Review Article

Abstract: There is tremendous recent interest in chronic traumatic encephalopathy (CTE) in former collision sport athletes, civilians, and military veterans. This critical review places important recent research results into a historical context. In 2015, preliminary consensus criteria were developed for defining the neuropathology of CTE, which substantially narrowed the pathology previously reported to be characteristic. There are no agreed upon clinical criteria for diagnosis, although sets of criteria have been proposed for research purposes. A prevailing theory is that CTE is an inexorably progressive neurodegenerative disease within the molecular classification of the tauopathies. However, historical and recent evidence suggests that CTE, …as it is presented in the literature, might not be pathologically or clinically progressive in a substantial percentage of people. At present, it is not known whether the emergence, course, or severity of clinical symptoms can be predicted by specific combinations of neuropathologies, thresholds for accumulation of pathology, or regional distributions of pathologies. More research is needed to determine the extent to which the neuropathology ascribed to long-term effects of neurotrauma is static, progressive, or both. Disambiguating the pathology from the broad array of clinical features that have been reported in recent studies might facilitate and accelerate research— and improve understanding of CTE. Show more

Keywords: Concussion, neurodegenerative, neuropathology, tau

DOI: 10.3233/JAD-170654

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 17-28, 2018

Authors: Favaretto, Silvia | Walter, Uwe | Baracchini, Claudio | Cagnin, Annachiara

Article Type: Review Article

Abstract: Transcranial sonography (TCS) of the brain parenchyma detects alterations in the substantia nigra (SN), raphe nuclei and basal ganglia; this technique has been established as a tool for the early diagnosis of Parkinson’s disease and differential diagnosis from atypical parkinsonian syndromes. Here, we aimed to review the main applications of TCS in neurodegenerative diseases presenting with dementia syndrome, focusing on Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration, idiopathic normal pressure hydrocephalus, and atypical and secondary parkinsonisms. The finding of bilaterally marked hyperechogenicity of the SN appears as a characteristic feature of DLB, while it is found …only in a minority of AD patients. SN hyperechogenicity is also detected in most patients with corticobasal degeneration and in about one third of patients with progressive supranuclear palsy, in which is constantly associated with hyperechogenic alterations of the basal ganglia. In conclusion, TCS is a valid supportive tool in the diagnostic workup of patients with dementia due to different neurodegenerative conditions. A promising new application is the differentiation of DLB from AD even at the early stages of these diseases. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, neurodegenerative diseases, sonography, substantia nigra

DOI: 10.3233/JAD-170382

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 29-40, 2018

Authors: Piaceri, Irene | Bessi, Valentina | Matà, Sabrina | Polito, Cristina | Tedde, Andrea | Berti, Valentina | Bagnoli, Silvia | Braccia, Arianna | Del Mastio, Monica | Pignone, Alberto Moggi | Pupi, Alberto | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

Abstract: A new risk gene associated with amyotrophic lateral sclerosis (ALS) has recently been identified: the Tank-binding kinase 1 (TBK1 ) gene. Up to now, 90 TBK1 variants have been described in ALS patients with or without frontotemporal dementia (FTD), thus making TBK1 the third or fourth most frequent genetic cause of ALS and FTD. A point mutation analysis in a cohort of 69 Italian ALS patients was performed in order to analyze the frequency of TBK1 mutations and the correlation with clinical phenotypes. The analysis identified the novel variant p.Tyr424Asp in a patient with a rapid progression …of the disease. Our data supports the implication of TBK1 in ALS pathogenesis in Italy. Show more

Keywords: Amyotrophic lateral sclerosis, genetics, Italy, missense mutation

DOI: 10.3233/JAD-170694

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 41-46, 2018

Authors: Arighi, Andrea | Carandini, Tiziana | Mercurio, Matteo | Carpani, Giovanni | Pietroboni, Anna Margherita | Fumagalli, Giorgio | Ghezzi, Laura | Basilico, Paola | Calvi, Alberto | Scarioni, Marta | De Riz, Milena | Fenoglio, Chiara | Scola, Elisa | Triulzi, Fabio | Galimberti, Daniela | Scarpini, Elio

Article Type: Short Communication

Abstract: The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results.

Keywords: Atrophy, dementia, magnetic resonance imaging, memory, neuropsychology

DOI: 10.3233/JAD-170712

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 47-52, 2018

Authors: Chatterjee, Paulami | Roy, Debjani | Rathi, Nitin

Article Type: Research Article

Abstract: Background: Epigenetics has emerged as an important field in drug discovery. Alzheimer’s disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD. Objective: In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome. Methods: Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with …the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied. Results: The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs. Conclusions: The findings of our work might provide insight into future AD epigenetic-therapeutics. Show more

Keywords: Alzheimer’s disease, combined interactome, epigenetic drug repositioning, epigenetic drug targets, epigenetic drug-target network, epigenetic protein-protein interaction network, epigenetics, pathway enrichment analysis

DOI: 10.3233/JAD-161104

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 53-65, 2018

Authors: Cleary, Ekaterina Galkina | Cifuentes, Manuel | Grinstein, Georges | Brugge, Doug | Shea, Thomas B.

Article Type: Research Article

Abstract: Increasing evidence points to an association of airborne pollutant exposure with respiratory, cardiovascular, and neurological pathology. We examined whether or not ground-level ozone or fine particulate matter ≤ 2.5 μm in diameter (PM2.5 ) was associated with accelerated cognitive decline. Using repeated measures mixed regression modeling, we analyzed cognitive performance of a geographically diverse sampling of individuals from the National Alzheimer’s Coordinating Center between 2004–2008. Ambient air concentrations of ozone and PM2.5 were established using a space-time Hierarchical Bayesian Model that statistically merged air monitor data and modeled air quality estimates. We then compared the ambient regional concentrations of …ozone and PM2.5 with the rate of cognitive decline in residents within those regions. Increased levels of ozone correlated with an increased rate of cognitive decline, following adjustment for key individual and community-level risk factors. Furthermore, individuals harboring one or more APOE4 alleles exhibited a faster rate of cognitive decline. The deleterious association of ozone was confined to individuals with normal cognition who eventually became cognitively impaired as opposed to those who entered the study with baseline impairment. In contrast to ozone, we did not observe any correlation between ambient PM2.5 and cognitive decline at regulatory limits set by the Environmental Protection Agency. Our findings suggest that prolonged exposure to ground-level ozone may accelerate cognitive decline during the initial stages of dementia development. Show more

Keywords: Air pollution, Alzheimer’s disease, APOE4, ozone, particulate matter

DOI: 10.3233/JAD-170658

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 67-78, 2018

Authors: Gleason, Carey E. | Norton, Derek | Anderson, Eric D. | Wahoske, Michelle | Washington, Danielle T. | Umucu, Emre | Koscik, Rebecca L. | Dowling, N. Maritza | Johnson, Sterling C. | Carlsson, Cynthia M. | Asthana, Sanjay | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture. Objective: To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181 ) and amyloid-β 42 (Aβ42 ) peptide. Methods: Dispersion in cognitive performance, IICV, was estimated with a published algorithm, …and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181 /Aβ42 , wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n  = 105) or diagnosed with MCI (n  = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181 /Aβ42 . Results: When included in models alone or in combination with CSF p-tau181 /Aβ42 , one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83–4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03–5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models. Conclusions: These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers Show more

Keywords: Alzheimer’s disease, amyloid beta-protein, biological markers, cerebrospinal fluid, cognition, cognitive dysfunction, incidence studies, mild cognitive impairment, tau protein

DOI: 10.3233/JAD-170498

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 79-89, 2018

Authors: Nation, Daniel A. | Tan, Alick | Dutt, Shubir | McIntosh, Elissa C. | Yew, Belinda | Ho, Jean K. | Blanken, Anna E. | Jang, Jung Yun | Rodgers, Kathleen E. | Gaubert, Aimée

Article Type: Research Article

Abstract: Background: Bone marrow-derived progenitor cells survey the vasculature and home to sites of tissue injury where they can promote repair and regeneration. It has been hypothesized that these cells may play a protective role neurodegenerative and vascular cognitive impairment. Objective: To evaluate progenitor cell levels in older adults with and without mild cognitive impairment (MCI), and to relate circulating levels to memory, brain volume, white matter lesion volume, and cerebral perfusion. Method: Thirty-two older adults, free of stroke and cardiovascular disease, were recruited from the community and evaluated for diagnosis of MCI versus cognitively normal (CN). …Participants underwent brain MRI and blood samples were taken to quantify progenitor reserve using flow cytometry (CD34+, CD34+CD133+, and CD34+CD133+CD309+ cells). Results: Participants with MCI (n  = 10) exhibited depletion of all CPC markers relative to those who were CN (n  = 22), after controlling for age, sex, and education. Post-hoc age, sex, and education matched comparisons (n  = 10 MCI, n  = 10 CN) also revealed the same pattern of results. Depletion of CD34+ cells correlated with memory performance, left posterior cortical thickness, and bilateral hippocampal perfusion. Participants exhibited low levels of vascular risk and white matter lesion burden that did not correlate with progenitor levels. Conclusions: Circulating progenitor cells are associated with cognitive impairment, memory, cortical atrophy, and hippocampal perfusion. We hypothesize that progenitor depletion contributes to, or is triggered by, cognitive decline and cortical atrophy. Further study of progenitor cell depletion in older adults may benefit efforts to prevent or delay dementia. Show more

Keywords: Atrophy, cognitive dysfunction, memory, perfusion, stem cells

DOI: 10.3233/JAD-170587

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 91-101, 2018

Authors: Matias-Guiu, Jordi A. | Cabrera-Martín, María Nieves | Curiel, Rosie E. | Valles-Salgado, María | Rognoni, Teresa | Moreno-Ramos, Teresa | Carreras, José Luis | Loewenstein, David A. | Matías-Guiu, Jorge

Article Type: Research Article

Abstract: Background: The Free and Cued Selective Reminding Test (FCSRT) is the most accurate test for the diagnosis of prodromal Alzheimer’s disease (AD). Recently, a novel cognitive test, the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), has been developed in order to provide an early diagnosis. Objective: To compare the diagnostic accuracy of the FCSRT and the LASSI-L for the diagnosis of AD in its preclinical and prodromal stages using 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a reference. Methods: Fifty patients consulting for subjective memory complaints without functional impairment and at risk for AD were …enrolled and evaluated using FCSRT, LASSI-L, and FDG-PET. Participants were evaluated using a comprehensive neurological and neuropsychological protocol and were assessed with the FCSRT and LASSI-L. FDG-PET was acquired concomitantly and used for classification of patients as AD or non-AD according to brain metabolism using both visual and semi-quantitative methods. Results: LASSI-L scores allowed a better classification of patients as AD/non-AD in comparison to FCSRT. Logistic regression analysis showed delayed recall and failure to recovery from proactive semantic interference from LASSI-L as independent statistically significant predictors, obtaining an area under the curve of 0.894. This area under the curve provided a better discrimination than the best FCSRT score (total delayed recall, area under the curve 0.708, p  = 0.029). Conclusions: The LASSI-L, a cognitive stress test, was superior to FCSRT in the prediction of AD features on FDG-PET. This emphasizes the possibility to advance toward an earlier diagnosis of AD from a clinical perspective. Show more

Keywords: Alzheimer’s disease, early detection, memory, mild cognitive impairment, neuropsychological assessment, positron emission tomography

DOI: 10.3233/JAD-170604

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 103-111, 2018