%0 Journal Article %J J Alzheimers Dis %D 2018 %T Altered Expression of Circulating Cdc42 in Frontotemporal Lobar Degeneration. %A Saraceno, Claudia %A Catania, Marcella %A Paterlini, Anna %A Fostinelli, Silvia %A Ciani, Miriam %A Zanardini, Roberta %A Binetti, Giuliano %A Di Fede, Giuseppe %A Caroppo, Paola %A Benussi, Luisa %A Ghidoni, Roberta %A Bolognin, Silvia %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Case-Control Studies %K cdc42 GTP-Binding Protein %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Male %K Middle Aged %X

The term frontotemporal lobar degeneration (FTLD) defines a group of heterogeneous conditions histologically characterized by neuronal degeneration, inclusions of various proteins, and synaptic loss. However, the molecular mechanisms contributing to these alterations are still unknown. As the Rho-GTPase family member Cell division cycle 42 (Cdc42) plays a key role in the regulation of actin cytoskeleton dynamics and spine formation, we investigated whether Cdc42 protein levels were altered in the disease. Cdc42 was increased in the frontal cortex of FTLD patients compared to age-matched controls, but also in Alzheimer's disease (AD) patients included in the data-set. On the other hand, the pool of circulating Cdc42 in the plasma was altered in FTLD but not in AD patients. Interestingly, the stratification of the FTLD patients according to the different clinical variants showed a specific decrease of Cdc42 expression in the behavioral subgroup. This data support a role of Cdc42 in FTLD and specifically in the behavioral variant.

%B J Alzheimers Dis %V 61 %P 1477-1483 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376863?dopt=Abstract %R 10.3233/JAD-170722 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort. %A Fostinelli, Silvia %A Ciani, Miriam %A Zanardini, Roberta %A Zanetti, Orazio %A Binetti, Giuliano %A Ghidoni, Roberta %A Benussi, Luisa %K Age of Onset %K Aged %K C9orf72 Protein %K Cohort Studies %K Female %K Frontotemporal Lobar Degeneration %K Genetic Counseling %K Genetic Testing %K Humans %K Italy %K Male %K Middle Aged %K Mutation %K Pedigree %K Progranulins %K tau Proteins %X

A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.

%B J Alzheimers Dis %V 61 %P 753-760 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226869?dopt=Abstract %R 10.3233/JAD-170661 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers. %A Ghidoni, Roberta %A Squitti, Rosanna %A Siotto, Mariacristina %A Benussi, Luisa %X

The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.

%B J Alzheimers Dis %V 62 %P 1507-1518 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29504534?dopt=Abstract %R 10.3233/JAD-170953 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. %A Ramos de Matos, Mafalda %A Ferreira, Catarina %A Herukka, Sanna-Kaisa %A Soininen, Hilkka %A Janeiro, André %A Santana, Isabel %A Baldeiras, Ines %A Almeida, Maria Rosário %A Lleo, Alberto %A Dols-Icardo, Oriol %A Alcolea, Daniel %A Benussi, Luisa %A Binetti, Giuliano %A Paterlini, Anna %A Ghidoni, Roberta %A Nacmias, Benedetta %A Meulenbroek, Olga %A van Waalwijk van Doorn, Linda J C %A Kuiperi, H Bea J %A Hausner, Lucrezia %A Waldemar, Gunhild %A Simonsen, Anja Hviid %A Tsolaki, Magda %A Gkatzima, Olymbia %A Resende de Oliveira, Catarina %A Verbeek, Marcel M %A Clarimón, Jordi %A Hiltunen, Mikko %A de Mendonça, Alexandre %A Martins, Madalena %X

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

%B J Alzheimers Dis %V 66 %P 639-652 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320580?dopt=Abstract %R 10.3233/JAD-180512 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum Copper is not Altered in Frontotemporal Lobar Degeneration. %A Squitti, Rosanna %A Fostinelli, Silvia %A Siotto, Mariacristina %A Ferrari, Clarissa %A Binetti, Giuliano %A Benussi, Luisa %A Rongioletti, Mauro %A Ghidoni, Roberta %X

Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

%B J Alzheimers Dis %V 63 %P 1427-1432 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843237?dopt=Abstract %R 10.3233/JAD-171074 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration. %A Zanardini, Roberta %A Benussi, Luisa %A Fostinelli, Silvia %A Saraceno, Claudia %A Ciani, Miriam %A Borroni, Barbara %A Padovani, Alessandro %A Binetti, Giuliano %A Ghidoni, Roberta %K Aged %K Biomarkers %K C-Peptide %K Female %K Frontotemporal Lobar Degeneration %K Ghrelin %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Mutation %K Nicotinamide Phosphoribosyltransferase %K Progranulins %K Resistin %X

Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.

%B J Alzheimers Dis %V 61 %P 1053-1060 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226876?dopt=Abstract %R 10.3233/JAD-170747 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia. %A Ferrari, Raffaele %A Grassi, Mario %A Graziano, Francesca %A Palluzzi, Fernando %A Archetti, Silvana %A Bonomi, Elisa %A Bruni, Amalia C %A Maletta, Raffaele G %A Bernardi, Livia %A Cupidi, Chiara %A Colao, Rosanna %A Rainero, Innocenzo %A Rubino, Elisa %A Pinessi, Lorenzo %A Galimberti, Daniela %A Scarpini, Elio %A Serpente, Maria %A Nacmias, Benedetta %A Piaceri, Irene %A Bagnoli, Silvia %A Rossi, Giacomina %A Giaccone, Giorgio %A Tagliavini, Fabrizio %A Benussi, Luisa %A Binetti, Giuliano %A Ghidoni, Roberta %A Singleton, Andrew %A Hardy, John %A Momeni, Parastoo %A Padovani, Alessandro %A Borroni, Barbara %X

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

%B J Alzheimers Dis %V 56 %P 1271-1278 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28128768?dopt=Abstract %R 10.3233/JAD-160949 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer's Disease. %A Benussi, Luisa %A Ghidoni, Roberta %A Dal Piaz, Fabrizio %A Binetti, Giuliano %A Di Iorio, Giuseppe %A Abrescia, Paolo %X

Cholesterol (C) brain accumulation seems to play a role in the Alzheimer's disease (AD) pathogenesis. 24(S)-hydroxycholesterol (24OH-C) is the predominant metabolite of brain C and its synthesis is believed to represent a way to remove excess C from neurons. Previous studies showed that 24OH-C level is altered in patients with neurodegenerative diseases, including AD. Only one study demonstrated that 24OH-C esterification is altered in neurodegenerative diseases, i.e., amyotrophic lateral sclerosis. Herein we analyzed the level of 24OH-C esters (% 24OH-CE) in i) cerebrospinal fluid (CSF) and homologous serum of AD (n = 13) and controls (n = 8); ii) plasma from AD (n = 30), controls (n = 30), mild cognitive impairment (MCI) converting to AD (n = 34), and stable MCI (n = 40). The % 24OH-CE in CSF positively correlated with that in homologous serum and was lower in both CSF and blood from AD patients as compared to controls; moreover, the plasma value of % 24OH-CE was lower in MCI conv-AD than in non-converters. Kaplan Meier Survival curves revealed a significant anticipation of the disease onset in AD and MCI conv-AD subjects with the lowest % 24OH-CE values. In conclusion, the reduction of % 24OH-CE in AD and MCI conv-AD, as well as the anticipation of the disease in patients with the lowest % 24OH-CE, support a role of the cholesterol/lecithin-cholesterol acyltransferase axis in AD onset/progression. Thus, targeting brain cholesterol metabolism could be a valuable strategy to prevent AD associated cognitive decline.

%B J Alzheimers Dis %V 56 %P 825-833 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983556?dopt=Abstract %R 10.3233/JAD-160930 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study. %A Kuiperij, H Bea %A Versleijen, Alexandra A M %A Beenes, Marijke %A Verwey, Nicolaas A %A Benussi, Luisa %A Paterlini, Anna %A Binetti, Giuliano %A Teunissen, Charlotte E %A Raaphorst, Joost %A Schelhaas, Helenius J %A Küsters, Benno %A Pijnenburg, Yolande A L %A Ghidoni, Roberta %A Verbeek, Marcel M %X

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies.

OBJECTIVE: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes.

METHODS: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers.

RESULTS: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients.

CONCLUSION: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.

%B J Alzheimers Dis %V 55 %P 585-595 %G eng %N 2 %R 10.3233/JAD-160386 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Counseling and Testing for Alzheimer's Disease and Frontotemporal Lobar Degeneration: An Italian Consensus Protocol. %A Bocchetta, Martina %A Mega, Anna %A Bernardi, Livia %A Di Maria, Emilio %A Benussi, Luisa %A Binetti, Giuliano %A Borroni, Barbara %A Colao, Rosanna %A Di Fede, Giuseppe %A Fostinelli, Silvia %A Galimberti, Daniela %A Gennarelli, Massimo %A Ghidoni, Roberta %A Piaceri, Irene %A Pievani, Michela %A Porteri, Corinna %A Redaelli, Veronica %A Rossi, Giacomina %A Suardi, Silvia %A Babiloni, Claudio %A Scarpini, Elio %A Tagliavini, Fabrizio %A Padovani, Alessandro %A Nacmias, Benedetta %A Sorbi, Sandro %A Frisoni, Giovanni B %A Bruni, Amalia C %K Alzheimer Disease %K Amyloid beta-Peptides %K Consensus %K Female %K Follow-Up Studies %K Frontotemporal Lobar Degeneration %K Genetic Counseling %K Genetic Testing %K Humans %K Italy %K Male %K Peptide Fragments %K Psychiatric Status Rating Scales %X

BACKGROUND: Genetic testing of familial Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is attracting interest thanks to innovative primary prevention clinical trials and increased request for information by at-risk individuals. However, ethical, social, and psychological implications are paramount and genetic testing must be supported by structured genetic counseling. In Italy, practice parameters and guidelines for genetic counseling in dementia are not available.

OBJECTIVE: To develop a nationally harmonized protocol for genetic counseling and testing of familial AD and FTLD.

METHODS: Activities were carried out in the context of the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) project, a national network of centers of excellence with expertise in managing patients with familial AD and FTLD. A survey of the literature on genetic counseling protocols and guidelines was conducted. Local protocols for genetic counseling were surveyed. Differences and commonalities among protocols were identified and discussed among project partners. Consensus was reached following implicit aggregation methods.

RESULTS: Consensus was reached on a protocol for patients with clinically diagnosed familial AD or FTLD and a distinct protocol for their at-risk relatives. Genetic counseling should be provided by a multidisciplinary team including a geneticist, a neurologist/geriatrician, and a psychologist/psychiatrist, according to the following schedule: (i) initial consultation with tailored information on the genetics of the dementias; (ii) clinical, psychological, and cognitive assessment; if deemed appropriate (iii) genetic testing following a structured decision tree for gene mutation search; (iv) genetic testing result disclosure; (v) psychological support follow-up.

CONCLUSION: This genetic counseling protocol provides Italian centers with a line of shared practice for dealing with the requests for genetic testing for familial AD and FTLD from patients and at-risk relatives, who may also be eligible participants for novel prevention clinical trials.

%B J Alzheimers Dis %V 51 %P 277-91 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26901402?dopt=Abstract %R 10.3233/JAD-150849 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population. %A Oldoni, Emanuela %A Fumagalli, Giorgio G %A Serpente, Maria %A Fenoglio, Chiara %A Scarioni, Marta %A Arighi, Andrea %A Bruno, Giuseppe %A Talarico, Giuseppina %A Confaloni, Annamaria %A Piscopo, Paola %A Nacmias, Benedetta %A Sorbi, Sandro %A Rainero, Innocenzo %A Rubino, Elisa %A Pinessi, Lorenzo %A Binetti, Giuliano %A Ghidoni, Roberta %A Benussi, Luisa %A Grande, Giulia %A Arosio, Beatrice %A Bursey, Devan %A Kauwe, John S %A Cioffi, Sara Mg %A Arcaro, Marina %A Mari, Daniela %A Mariani, Claudio %A Scarpini, Elio %A Galimberti, Daniela %K Aged %K Atrophy %K Frontal Lobe %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Humans %K Italy %K Language %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Neuropsychological Tests %K Prion Proteins %K Prions %K Temporal Lobe %X

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%).

%B J Alzheimers Dis %V 50 %P 353-7 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757195?dopt=Abstract %R 10.3233/JAD-150863