Peripheral markers of oxidative stress and excitotoxicity in neurodegenerative disorders: Tools for diagnosis and therapy?
Authors: Facheris, Maurizio | Beretta, Simone | Ferrarese, Carlo
Article Type: Research Article
Abstract: Oxidative stress has been implicated as a common pathogenetic mechanism in neurodegenerative disorders. Central nervous system is particularly exposed to free radical injury, given its high metal content, which can catalyze the formation of oxygen free radicals, and the relatively low content of antioxidant defenses. Indeed, several studies show markers of oxidative damage – lipid peroxidation, protein oxidation, DNA oxidation and glycoxidation markers – in brain areas affected by neurodegenerative disorders. Oxidative stress damage is intimately linked to glutamate neurotoxicity – known as “excitotoxicity”. An excessive concentration of extracellular glutamate over-activates ionotropic glutamate receptors, resulting in intracellular calcium overload and …a cascade of events leading to neural cell death. In this study we reviewed pathogenetic mechanisms that link oxidative stress and excitotoxicity in three neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease) and described peripheral markers of these mechanisms, that may be analyzed in patients as possible diagnostic and therapeutic tools. Show more
Keywords: glutamate, reactive oxygen species, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease
DOI: 10.3233/JAD-2004-6210
Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 177-184, 2004
Can Traditional Board Games Prevent or Slow Down Cognitive Impairment? A Systematic Review and Meta-Analysis
Authors: Pozzi, Federico Emanuele | Appollonio, Ildebrando | Ferrarese, Carlo | Tremolizzo, Lucio
Article Type: Systematic Review
Abstract: Background: Traditional board games can entail significant skills encompassing several cognitive functions across different domains. Therefore, they may potentially represent effective cognitive interventions in the aging population with or without Alzheimer’s disease or other types of dementia. Objective: We aimed at verifying the hypothesis that traditional board games can prevent or slow down cognitive decline, through a systematic review on traditional board games and dementia. Methods: We searched five databases with tailored search strings. We included studies assessing the impact of board games on elderly subjects at risk of or suffering from cognitive impairment, or subjects with cognitive impairment irrespective …of age. Studies where the effect of board games was not separated by cards or other games were excluded. A meta-analysis was performed for specific cognitive and non-cognitive outcomes. Results: Board games improved mental function, as measured by Montreal Cognitive Assessment (p = 0.003) and Mini-Mental State Examination (p = 0.02). Ska and Go improved Trail Making Test –A, while Mahjong improved executive functions. There was no consistent effect across different games on Digit Span or Categorical Fluency. Chess improved quality of life measured with the WHO-QoL-OLD scale (p < 0.00001). Mahjong temporarily improved depressive symptoms. Go increased BDNF levels and left middle temporal gyrus and bilateral putamen metabolism. Conclusions: Traditional board games may slow global cognitive decline and improve the quality of life in elderly subjects. Different games have varying impacts on specific cognitive domains, possibly mediated by functional and biological factors. Show more
Keywords: Alzheimer’s disease, cognition, dementia, primary prevention, recreational games, secondary prevention, systematic review, tertiary prevention
DOI: 10.3233/JAD-230473
Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 829-845, 2023
TSPO Modulates Oligomeric Amyloid-β-Induced Monocyte Chemotaxis: Relevance for Neuroinflammation in Alzheimer’s Disease
Authors: Conti, Elisa | Grana, Denise | Angiulli, Federica | Karantzoulis, Aristotelis | Villa, Chiara | Combi, Romina | Appollonio, Ildebrando | Ferrarese, Carlo | Tremolizzo, Lucio
Article Type: Research Article
Abstract: Background: Neuroinflammation is one of the cardinal mechanisms of Alzheimer’s disease (AD). with amyloid-β (Aβ) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aβ species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. Objective: We aimed to evaluate the role of the oligomeric Aβ1-42 isoform at inducing peripheral monocyte chemotaxis, and the possible involvement of …TSPO in this process. Methods: In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n = 60), and comparable cognitively intact controls (n = 30) were used. Chemotaxis analyses were carried out through both μ -slide chambers and Boyden assays, using 125 pM oligomeric Aβ1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). Results: Oligomeric Aβ directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aβ-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. Conclusion: Oligomeric Aβ1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS. Show more
Keywords: Alzheimer’s disease, amyloid-β, chemotaxis, monocytes, neuroinflammation, PK11195, TSPO
DOI: 10.3233/JAD-230239
Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 549-559, 2023
Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-β Autophagy
Authors: La Rosa, Francesca | Saresella, Marina | Marventano, Ivana | Piancone, Federica | Ripamonti, Enrico | Al-Daghri, Nasser | Bazzini, Chiara | Zoia, Chiara Paola | Conti, Elisa | Ferrarese, Carlo | Clerici, Mario
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is associated with the accumulation of amyloid-β (Aβ) within senile plaques in the brain and neuroinflammation, possibly driven by the activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the NLRP3 inflammasome assembly. Objective: We utilized an in vitro model reproducing the Aβ-driven inflammation seen in AD to analyze whether stavudine (D4T), a prototypical NRTI, modulates Aβ-mediated inflammasome activation and the ability of macrophages to eliminate Aβ via phagocytosis and autophagy. Methods: THP-1-derived macrophages were stimulated in vitro with Aβ42 or with Aβ42 after LPS-priming in the presence/absence of D4T. NLRP3 and TREM2 expression …was analyzed by RT-PCR; phagocytosis, as well as ASC-Speck formation, was analyzed by Amnis FlowSight Imaging; NLRP3-produced cytokines were quantified by ELISA and, finally, autophagy was analyzed by measuring p-ERK1/2, p-AKT, beclin, p70-S6Kinase, and Lamp by ELISA and western blot. Results: IL-1β, IL-18, and caspase-1 were increased whereas Aβ phagocytosis and TREM2 were reduced in LPS+Aβ42 -stimulated cells. D4T reduced NLRP3 assembly as well as IL-18 and caspase-1 production, but did not affect IL-1β production and TREM2 expression. Notably, whereas D4T reduced Aβ phagocytosis, Aβ autophagy by macrophages was stimulated by D4T, as witnessed by the down-modulation of ERK1/2 and AKT phosphorylation and the upregulation of beclin, LAMP, and p70-S6K, their downstream targets. Conclusion: In this in vitro model of AD, D4T reduces NLRP3 inflammasome-associated inflammation and stimulates Aβ autophagy by macrophages. It will be interesting to verify the possibly beneficial effects of D4T in the clinical scenario. Show more
Keywords: Alzheimer’s disease, amyloid-β phagocytosis, autophagy, cytokines, D4T, NLRP3-inflammasome
DOI: 10.3233/JAD-181259
Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 401-412, 2019
Adult-Onset Epilepsy in Presymptomatic Alzheimer’s Disease: A Retrospective Study
Authors: DiFrancesco, Jacopo C. | Tremolizzo, Lucio | Polonia, Valeria | Giussani, Giorgia | Bianchi, Elisa | Franchi, Carlotta | Nobili, Alessandro | Appollonio, Ildebrando | Beghi, Ettore | Ferrarese, Carlo
Article Type: Research Article
Abstract: Background: The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer’s disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation. Objective: Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia. Methods: We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of …AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP). Results: In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3–28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD. Conclusions: Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia. Show more
Keywords: Alzheimer’s disease, disease modifying therapies, epilepsy, neurodegeneration, prevalence, seizure
DOI: 10.3233/JAD-170392
Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1267-1274, 2017
Does Gut Microbiota Influence the Course of Parkinson’s Disease? A 3-Year Prospective Exploratory Study in de novo Patients
Authors: Cilia, Roberto | Piatti, Marco | Cereda, Emanuele | Bolliri, Carlotta | Caronni, Serena | Ferri, Valentina | Cassani, Erica | Bonvegna, Salvatore | Ferrarese, Carlo | Zecchinelli, Anna L. | Barichella, Michela | Pezzoli, Gianni
Article Type: Research Article
Abstract: Background: Although abnormalities in gut microbiota are hypothesized to influence the pathogenesis and clinical phenotype of Parkinson’s disease (PD), prospective studies on de novo patients are lacking. Objective: To preliminarily investigate whether gut microbiota in early untreated PD may predict motor and non-motor features progression over a 3-year period. Methods: 16S ribosomal RNA gene amplicons were sequenced on fecal samples of 39 de novo PD patients. Multiple confounders were taken into account, including dietary habits. Motor and non-motor symptoms were assessed using validated scales at baseline and followed-up yearly for 3 years. At last follow-up, a detailed neuropsychological assessment was …additionally performed. A general linear model for repeated measurements— adjusted by dopaminergic therapy at follow-up— was used to investigate the relationship between bacterial taxa abundance at baseline (stratified by the median of distribution at baseline) and outcome variables. Results: Twenty-five patients were included (11 refused, 2 lost at follow-up, 1 died). Lower abundance of Roseburia (Firmicutes phylum) at baseline was associated with worse evolution of motor, non-motor and cognitive functions at 3-year follow-up. Similarly, lower abundance of Ruminococcaceae and Actinobacteria at baseline was associated with faster worsening of global cognitive functions. At follow-up, frontal lobe functions were the features most robustly associated with baseline microbial abnormalities. Conclusion: In the present exploratory study on de novo PD, we found an association between abnormal distribution of specific bacterial taxa and the progression of motor and non-motor features over a 3-year period. This proof-of-principle study supports the design of a larger observational study aiming to determine whether these differences survive multiple-comparison correction and define microbiota-specific subgroups suitable for therapeutic targeting. Show more
Keywords: Parkinson’s disease, de novo, gut microbiota, prospective study, prognosis
DOI: 10.3233/JPD-202297
Citation: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 159-170, 2021
Learning From Mistakes: Cognitive and Metabolic Correlates of Errors on Picture Naming in the Alzheimer’s Disease Spectrum
Authors: Isella, Valeria | Rosazza, Cristina | Ferri, Francesca | Gazzotti, Maria | Impagnatiello, Valentina | Mapelli, Cristina | Morzenti, Sabrina | Crivellaro, Cinzia | Appollonio, Ildebrando M. | Ferrarese, Carlo
Article Type: Research Article
Abstract: Background: Analysis of subtypes of picture naming errors produced by patients with Alzheimer’s disease (AD) have seldom been investigated yet may clarify the cognitive and neural underpinnings of naming in the AD spectrum. Objective: To elucidate the neurocognitive bases of picture naming in AD through a qualitative analysis of errors. Methods: Over 1000 naming errors produced by 70 patients with amnestic, visuospatial, linguistic, or frontal AD were correlated with general cognitive tests and with distribution of hypometabolism on FDG-PET. Results: Principal component analysis identified 1) a Visual processing factor clustering visuospatial tests and unrecognized stimuli, pure visual errors and visual-semantic …errors, associated with right parieto-occipital hypometabolism; 2) a Concept-Lemma factor grouping language tests and anomias, circumlocutions, superordinates, and coordinates, correlated with left basal temporal hypometabolism; 3) a Lemma-Phonology factor including the digit span and phonological errors, linked with left temporo-parietal hypometabolism. Regression of brain metabolism on individual errors showed that errors due to impairment of basic and higher-order processing of object visual attributes, or of their interaction with semantics, were related with bilateral occipital and left occipito-temporal dysfunction. Omissions and superordinates were linked to degradation of broad and basic concepts in the left basal temporal cortex. Semantic-lexical errors derived from faulty semantically- and phonologically-driven lexical retrieval in the left superior and middle temporal gyri. Generation of nonwords was underpinned by impairment of phonology within the left inferior parietal cortex. Conclusion: Analysis of individual naming errors allowed to outline a comprehensive anatomo-functional model of picture naming in classical and atypical AD. Show more
Keywords: Alzheimer’s disease, aphasia, brain metabolism, dementia, FDG-PET, language, naming, naming errors
DOI: 10.3233/JAD-220053
Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1033-1053, 2022
Voluptuary Habits and Risk of Frontotemporal Dementia: A Case Control Retrospective Study
Authors: Tremolizzo, Lucio | Bianchi, Elisa | Susani, Emanuela | Pupillo, Elisabetta | Messina, Paolo | Aliprandi, Angelo | Salmaggi, Andrea | Cosseddu, Maura | Pilotto, Andrea | Borroni, Barbara | Padovani, Alessandro | Bonomini, Cristina | Zanetti, Orazio | Appollonio, Ildebrando | Beghi, Ettore | Ferrarese, Carlo
Article Type: Short Communication
Abstract: Alcohol, coffee, and tobacco consumption was assessed on 151 FTD outpatients and 151 matched controls in a multicenter retrospective case-control design. No association was found for smoking and coffee intake. The risk of FTD was decreased by alcohol consumption (adj. OR 0.30, 95% CI 0.14–0.63); risk reduction was significant in current alcohol consumers (adj. OR 0.22, 95% CI 0.10–0.51). The risk of FTD inversely correlated with the duration of exposure (adj. OR 0.88, 95% CI 0.81–0.95, for every 5 years of exposure increase). Retrospective information and the unknown amount of consumed alcohol are limits of the present work.
Keywords: Alcohol, coffee, frontotemporal dementia, risk factor, smoking, voluptuary habits
DOI: 10.3233/JAD-170260
Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 335-340, 2017
Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease
Authors: Domenighetti, Cloé | Sugier, Pierre-Emmanuel | Sreelatha, Ashwin Ashok Kumar | Schulte, Claudia | Grover, Sandeep | Mohamed, Océane | Portugal, Berta | May, Patrick | Bobbili, Dheeraj R. | Radivojkov-Blagojevic, Milena | Lichtner, Peter | Singleton, Andrew B. | Hernandez, Dena G. | Edsall, Connor | Mellick, George D. | Zimprich, Alexander | Pirker, Walter | Rogaeva, Ekaterina | Lang, Anthony E. | Koks, Sulev | Taba, Pille | Lesage, Suzanne | Brice, Alexis | Corvol, Jean-Christophe | Chartier-Harlin, Marie-Christine | Mutez, Eugénie | Brockmann, Kathrin | Deutschländer, Angela B. | Hadjigeorgiou, Georges M. | Dardiotis, Efthimos | Stefanis, Leonidas | Simitsi, Athina Maria | Valente, Enza Maria | Petrucci, Simona | Duga, Stefano | Straniero, Letizia | Zecchinelli, Anna | Pezzoli, Gianni | Brighina, Laura | Ferrarese, Carlo | Annesi, Grazia | Quattrone, Andrea | Gagliardi, Monica | Matsuo, Hirotaka | Kawamura, Yusuke | Hattori, Nobutaka | Nishioka, Kenya | Chung, Sun Ju | Kim, Yun Joong | Kolber, Pierre | van de Warrenburg, Bart PC | Bloem, Bastiaan R. | Aasly, Jan | Toft, Mathias | Pihlstrøm, Lasse | Guedes, Leonor Correia | Ferreira, Joaquim J. | Bardien, Soraya | Carr, Jonathan | Tolosa, Eduardo | Ezquerra, Mario | Pastor, Pau | Diez-Fairen, Monica | Wirdefeldt, Karin | Pedersen, Nancy L. | Ran, Caroline | Belin, Andrea C. | Puschmann, Andreas | Hellberg, Clara | Clarke, Carl E. | Morrison, Karen E. | Tan, Manuela | Krainc, Dimitri | Burbulla, Lena F. | Farrer, Matt J. | Krüger, Rejko | Gasser, Thomas | Sharma, Manu | Elbaz, Alexis | on behalf of the Comprehensive Unbiaised Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (Courage-PD) consortium
Article Type: Research Article
Abstract: Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method …to compute odds ratios (ORIVW ) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. Show more
Keywords: Smoking, alcohol, coffee, Parkinson’s disease, Mendelian randomisation
DOI: 10.3233/JPD-212851
Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 267-282, 2022