Showing papers by "Giuliano Binetti published in 2021"

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

Abstract: Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

Copper Imbalance in Alzheimer’s Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants

Abstract: Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

Plasma Extracellular Vesicle Size and Concentration Are Altered in Alzheimer's Disease, Dementia With Lewy Bodies, and Frontotemporal Dementia.

Abstract: Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) are the three major neurodegenerative dementias. In this study, we provide evidence that an alteration in extracellular vesicles (EVs) release is common across the three most common neurodegenerative dementias, AD, DLB, and FTD. Specifically, we analyzed plasma EVs in three groups of patients affected by AD, DLB, and FTD, and we found a significant reduction in EVs concentration and larger EVs size in all patient groups. We then investigated whether the loss of neurotrophic factors is also a common pathogenic mechanism among FTD, DLB, and AD, and if levels of neurotrophic factors might affect EVs release. Plasma levels of progranulin and cystatin C (CysC) were partially altered; however, taking together all variables significantly associated with the diagnostic groups only EVs size and concentration were able to distinguish patients from controls. The diagnostic performance of these two EVs parameters together (ratio) was high, with a sensitivity of 83.3% and a specificity of 86.7%, able to distinguish patients from controls but not to differentiate the different forms of dementias. Among the candidate neurotrophic factors, only CysC levels were associated with EVs concentration. Our study suggests that an alteration in the intercellular communication mediated by EVs might be a common molecular pathway underlying neurodegenerative dementias. The identification of shared disease mechanisms is of pivotal importance to develop treatments to delay disease progression. To this aim, further studies investigating plasma EVs size and concentration as early biomarkers of dementia are required.

Language training for oral and written naming impairment in primary progressive aphasia: a review.

Abstract: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by a gradual, insidious and progressive loss of language abilities, with naming difficulties being an early and persistent impairment common to all three variants. In the absence of effective pharmacological treatments and given the progressive nature of the disorder, in the past few decades, many studies have investigated the effectiveness of language training to minimize the functional impact of word-finding difficulties in daily life. We review language treatments most commonly used in clinical practice among patients with different variants of PPA, with a focus on the enhancement of spoken and written naming abilities. Generalization of gains to the ability to name untrained stimuli or to other language abilities and the maintenance of these results over time are also discussed. Forty-eight studies were included in this literature review, identifying four main types of language treatment: a) lexical retrieval treatment, b) phonological and/or orthographic treatment, c) semantic treatment, and d) a multimodality approach treatment. Overall, language training is able to induce immediate improvements of naming abilities in all variants of PPA. Moreover, despite the large variability among results, generalization and long-term effects can be recorded after the training. The reviewed studies also suggest that one factor that determines the choice of a particular approach is the compromised components of the lexical/semantic processing system. The majority of studies have demonstrated improvements of naming abilities following language treatments. Given the progressive nature of PPA, it is essential to apply language treatment in the early stages of the disease.

N-Terminally Truncated and Pyroglutamate-Modified Aβ Forms Are Measurable in Human Cerebrospinal Fluid and Are Potential Markers of Disease Progression in Alzheimer's Disease.

Abstract: Alzheimer's disease (AD) is a pathology characterized by the accumulation in the brain of intracellular and extracellular amyloid-β (Aβ) aggregates, especially of Aβ1-40 and Aβ1-42 peptides. It is known that N-terminally truncated or modified Aβ forms also exist in AD brains and cerebrospinal fluid (CSF), and they play a key role in the pathogenesis of the disease. Herein, we developed an antibody-free method based on Solid-Phase Extraction and Electrospray Ionization Liquid Chromatography Mass Spectrometry for the identification and quantitation in human CSF of Aβ isoforms. In human CSF, we could detect and quantify a panel of 19 Aβ isoforms, including N-terminally truncated and pyroglutamate-modified forms, never quantified before in CSF. Among these, we identified novel N-terminally truncated Aβ species: four bound to copper and two phosphorylated forms, which were found to be the most common proteoforms in human CSF along with Aβ1-40, Aβ3-40, and AβpE11-42. We tested the newly developed and validated method in a pilot study on CSF from elderly individuals with subjective memory complaints (SMCs, n = 9), mild cognitive impairment (MCI, n = 18), and AD (n = 15); along with Aβ1-42, five N-terminally truncated forms (Aβ11-40, Aβ3-42, AβpE11-42, AβpE3-40, and Aβ4-40 Cu2+) are altered in AD/MCI. Thus, we demonstrated that N-terminally truncated and pyroglutamate-modified Aβ can be quantified in human CSF, and five of them, along with Aβ1-42, are potential markers of AD progression. The described method could represent a useful tool for patients' stratification and monitoring. Moreover, the newly identified Aβ CSF species might represent new potential therapeutic targets.

A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study.

Abstract: BACKGROUND A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. METHODS A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. RESULTS When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). CONCLUSION In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.

Cognitive Tele-Enhancement in Healthy Older Adults and Subjects With Subjective Memory Complaints: A Review.

Abstract: Background: In recent years, emphasis has been placed on cognitive enhancement to stimulate cognitive abilities and prevent functional decline. Considering that traditional face-to-face interventions can be very expensive and are not accessible to all individuals, the need to transfer care from the clinic to the patient's home is evident. In this regard, cognitive tele-enhancement interventions have received increased attention. Aim: The aim of this review was to provide an overview of protocols that apply remotely controlled cognitive training with individualized feedback on performance by the therapist in healthy older adults or participants with subjective memory complaints. Methods: Out of 35 articles assessed for eligibility, eight studies were identified. Of the selected studies, five included cognitively healthy older adults, while three included participants with subjective memory complaints. Results: Most of the reviewed studies showed beneficial effects of cognitive tele-enhancement interventions, reporting improvements in memory, sustained attention, working memory, executive functions, and language abilities. Moreover, reductions in anxiety and depression symptomatology levels, as well as in subjective memory difficulties, were described in some of the studies. Conclusions: Cognitive tele-enhancement treatment could be a good alternative to face-to-face intervention. This literature review highlights the importance of applying preventive cognitive interventions to subjects with initial subjective memory complaints. Remote modalities seem to facilitate the application of such interventions.