%0 Journal Article %J J Alzheimers Dis %D 2018 %T Frontotemporal Dementia and Chorea Associated with a Compound Heterozygous TREM2 Mutation. %A Redaelli, Veronica %A Salsano, Ettore %A Colleoni, Lara %A Corbetta, Paola %A Tringali, Giovanni %A Del Sole, Angelo %A Giaccone, Giorgio %A Rossi, Giacomina %X

Frontotemporal dementia (FTD) is clinically characterized by behavioral changes, language impairment, and executive dysfunction. FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS. However, FTD can also be associated with different clinical or pathological phenotypes caused by mutations in other genes, whose heredity can be dominant or recessive. In this work we report on a familial case of FTD characterized by behavioral changes and aphasia, very early onset and very long duration, choreic movements, and white matter lesions at magnetic resonance imaging. We performed a wide-range genetic analysis, using a next generation sequencing approach, to evaluate a number of genes involved in neurodegeneration. We found a previously unreported compound heterozygous mutation in TREM2, that is commonly associated with the recessively inherited Nasu-Hakola disease. We discuss the differential diagnosis to be taken into account in cases of FTD presenting with atypical features.

%B J Alzheimers Dis %V 63 %P 195-201 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29578490?dopt=Abstract %R 10.3233/JAD-180018 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Translational Research in Alzheimer's and Prion Diseases. %A Di Fede, Giuseppe %A Giaccone, Giorgio %A Salmona, Mario %A Tagliavini, Fabrizio %X

Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to clinical practice in neurological diseases. This information can be used to improve clinical trial designs and outcomes that will accelerate drug development, and to discover novel biomarkers which can be efficiently employed to early recognize neurological disorders and provide information regarding the effects of drugs on the underlying disease biology. Alzheimer's disease (AD) and prion disease are two classes of neurodegenerative disorders characterized by incomplete knowledge of the molecular mechanisms underlying their occurrence and the lack of valid biomarkers and effective treatments. For these reasons, the design of therapies that prevent or delay the onset, slow the progression, or improve the symptoms associated to these disorders is urgently needed. During the last few decades, translational research provided a framework for advancing development of new diagnostic devices and promising disease-modifying therapies for patients with prion encephalopathies and AD. In this review, we provide present evidence of how supportive can be the translational approach to the study of dementias and show some results of our preclinical studies which have been translated to the clinical application following the 'bed-to-bench-and-back' research model.

%B J Alzheimers Dis %V 62 %P 1247-1259 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29172000?dopt=Abstract %R 10.3233/JAD-170770 %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 2015 %T The Existence of Primary Age-Related Tauopathy Suggests that not all the Cases with Early Braak Stages of Neurofibrillary Pathology are Alzheimer's Disease. %A Giaccone, Giorgio %X

The distinction between Alzheimer's disease (AD) and Primary Age-Related Tauopathy (PART) is a hotly debated issue. As most lines of evidence support the tenet that tau pathology occurs downstream of amyloid-β deposition, it seems reasonable to consider PART as a separate disease process not necessarily related to Aβ and hence AD. Following this view, the early stages of neurofibrillary pathology may not always be the forerunner of diffuse neurofibrillary changes and AD. The ongoing debate further enhances the need for greater caution against any future predictions using tau cerebrospinal fluid and imaging biomarkers.

%B J Alzheimers Dis %8 2015 Sep 16 %G eng %R 10.3233/JAD-150435 %0 Journal Article %J Ann Neurol %D 2013 %T Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies. %A Piazza, Fabrizio %A Greenberg, Steven M %A Savoiardo, Mario %A Gardinetti, Margherita %A Chiapparini, Luisa %A Raicher, Irina %A Nitrini, Ricardo %A Sakaguchi, Hideya %A Brioschi, Monica %A Billo, Giuseppe %A Colombo, Antonio %A Lanzani, Francesca %A Piscosquito, Giuseppe %A Carriero, Maria Rita %A Giaccone, Giorgio %A Tagliavini, Fabrizio %A Ferrarese, Carlo %A DiFrancesco, Jacopo C %K Adult %K Aged %K Amyloid beta-Peptides %K Apolipoproteins E %K Autoantibodies %K Brain %K Case-Control Studies %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Inflammation %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Retrospective Studies %K Steroids %K tau Proteins %X

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri.

METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated.

RESULTS: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel.

INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

%B Ann Neurol %V 73 %P 449-58 %8 2013 Apr %G eng %N 4 %R 10.1002/ana.23857