Clinical Science

Motor Neuron Diseases (MND):

The motor neuron diseases (MNDs) represent a heterogeneous group of diseases of which the most known is the Amyotrophic Lateral Sclerosis (ALS). ALS, which was erroneously considered a rare disease (incidence 2-3 cases per 100.000 persons), has a low prevalence because of the fast and inescapable course. In the last few years the definition of familiar genetically related forms has considerably developed after the recognition that ALS presents in about 40% of cases also a cognitive and/or behavioral involvement. The biological bases imprinted by the identification of common inclusions of the protein TDP-43 in affected tissues, have definitively indicated a continuum between two pathologies, which were before considered remote, Frontotemporal Dementia (FTD) and ALS. ALS’s genetic boundaries are today very wide, involving FTD even in sporadic cases. The recent discovery of the gene C9orf72 has further extended ALS’s limits and changed perspectives on neurodegenerative diseases: a single gene can express different clinical phenotypes that ranging from the motor neuronal to cortical  (FTP) or extrapyramidal involvement (parkinsonisms). The new scenery, which has emerged due to the new impulse of the recent genetic discoveries, has influenced the clinical approach, leading to a more personalized definition of the patient in relation with the molecular mechanisms responsible for the different clinical features. The clinical diagnosis of the different forms now requires an exhaustive study of every possible biological marker (DNA, serum, liquor) obtained from the patient, comprehensive of the collection of muscular and cutaneous biopsies to obtain fibroblast cultures to acquire pluripotent stem cells (iPSC). The availability of broad DNA banks coupled with careful collection of clinical data has permitted to define the mutational frequency of the different genes in the Italian population as well as to identify new causative genes (Profiline 1) by taking advantage of new and fast technologies in the nucleic acid research. The study of the sporadic forms without a genetic transmission of Mendelian type appears more complex, but we’ve developed different approaches such as Genome-Wide Association studies (GWAs). The discoveries of the last few years haven’t found an adequate correspondence in the definition of new therapeutic strategies, but they have lead to the outlining of common pathogenetic mechanisms between sporadic and familiar forms of ALS, both characterized by the formation of TDP-43 aggregates. Recently, therapies with molecules directed to correct the deficit of the SOD1 enzyme, which is related to some genetic cases, have been started, and other molecules are in an advanced stage to be applied to the patients.


Cognitive and Behavioral Disorders:

The cognitive disorders represent a social problem of particular relevance in the Italian population and the Alzheimer’s disease, together with the Frontotemporal (FTD) and Cerebrovascular dementia, constitute an area of particular interest to which the “Dino Ferrari” Center dedicates a vast investment of resources meant to define the molecular bases of the different clinical forms. In particular, the pathogenetic overlapping of ALS and FTD has directed the efforts into defining the common molecular bases of the two affections. The research on the motor neuron involvement in the FTD and, vice versa, the definition of cognitive and/or behavioral disorders in ALS characterize the modern neuroscience’s development and our clinical approach to the patients. The improvement of the neuropsychological evaluation also due to the use of advanced technologies (Brain-Computer Interface or BCI) is complemented by the neuroradiological evaluation, which can be also non-conventional (PET), and by the research of serum and liquor specific biomarkers. A point of interest because of the common molecular bases with Alzheimer’s Disease is the study on Cerebral Amyloid Angiopathy, on which we concentrated in both clinic and genetics to discover the molecular mechanisms are responsible for the vessel or parenchymal expression of the amyloid protein. New discoveries represent the preliminary step for the definition of new therapeutic strategies, which are particularly inexistent in FTD.

Thanks to the Neuropsychology and Clinical Psychology Service, headed by Dr. Barbara Poletti together with Dr. Annalisa Lafronza, Dr. Federica Solca, and Dr. Laura Carelli, the “Dino Ferrari” Center has not only a great support in the clinical and rehabilitative diagnosis, but has also launched research projects in collaboration with other international Institutes. Particularly the ‘eBrain: BCI-ET in ALS’ international project was meant to create and validate a cognitive ‘assessment’ protocol based on the use of two innovative methods (Brain-Computer Interface and Eye Tracking), aiming to permit the neuropsychological evaluation of ALS patients during the whole disease’s course. The verbal and motor limitations have in fact impeded a homogeneous neuropsychological evaluation of ALS patients through traditional testing. The ‘Highcare’ study, which was conducted on the Everest base camp (2008), and the ‘Highcare Alps’ study, conducted on the Monte Rosa Massif (2010), have on the other hand investigated the cognitive and psycho-emotional changes due to the exposition to conditions of hypobaric hypoxia in healthy participants, representing an experimental model for functional cognitive changes in conditions characterized by reduced oxygen supply to the brain (sleep obstructive apnea syndrome, cerebrovascular damage). The results have confirmed a higher sensitivity of the computerized assessment (Eye-Tracking) than traditional examinations in recording the cognitive alterations, underlining the specific involvement of the frontal efficiency.


Parkinson’s Disease and Parkinsonisms:

The modern definition of the extrapyramidal disorders requires a sophisticated and updated clinical orientation to outline the different forms of Parkinson-plus, which often entail an accurate clinical diagnosis supported by instrumental investigations. Of particular interest are the definition of Progressive Supernuclear Palsy (PSP),  Multisystem Atrophy (MSA) and Corticobasal Syndrome. The interest in the extrapyramidal forms starts from a correct clinical evaluation paying attention to the cognitive and/or behavioral changes supported by the collection of liquor or serum biomarkers and with the use of non-conventional radiology to distinguish specific clinical cases (PET or SPECT). The concentration on the familiar forms, also with a larger prospective of overlapping with dementing diseases, suggests the collection of DNA and the genetic analysis for specific mutations, not least for the genes C9orf72 and GBA1, known to be involved in extrapyramidal diseases.


Huntington’s Disease:

The Huntington’s Disease is a hereditary neurologic disease that causes the progressive dysfunction and loss of neurons in different areas of the brain. The affection was reported for the first time by the physician George Huntington who described in 1872 the main clinical aspects of the disease: the appearance of behavioral disorders, the cognitive deficits and the movement alterations. In 1993 the cause for Huntington’s Disease was identified: the mutation of a gene called IT-15 localized on the short arm of chromosome 4. From that day on a lot has been understood about the molecular mechanisms that lead to the progressive loss of neuronal striatal cells, although there isn’t yet an efficient therapy for delaying the progress or preventing the onset of the disease in patients carrying the mutation. Nevertheless, today there are numerous prescriptions able to reduce significantly the motor and psychiatric symptoms, considerably improving the life standard of patients affected by MdH. The Laboratory of Neuroscience has recently dedicated its attention to define the molecular mechanisms of mitochondrial dysfunction in Huntington’s Disease. The further molecular mechanisms’ identification is the basis for development of new therapeutic strategies.


Stem Cells:

In the last ten years stem cells have represented the new frontier of medicine to repair organs and tissues that have been damaged by different diseases, particularly neurodegenerative ones. Stem cells are undifferentiated cells, which have generally the task of regenerating the organ or the tissue in which they are located. They can potentially differentiate into every tissue type if exposed to the right stimuli. Hemopoietic or stem cells from the umbilical cord are nowadays largely used for therapeutic aims in hematologic diseases and in future stem cells with different origins could represent a real hope for defeating diseases that seemed incurable. The tissue regeneration can take place through different mechanisms. The damaged cells can be substituted through the differentiation of pluripotent cells. For this aim, the cells with higher potentiality are the embryonic stem cells, whose use is limited, though because of the set of problems of ethical origin, which are correlated to them. A valid alternative is represented by induced pluripotent stem cells (iPSCs). These originate from adult fibroblasts that are reprogrammed into pluripotent cells and that present characteristics which are very similar to the embryonic cells. Also adult stem cells, although they present a lower differentiation ability than the embryonic or iPSCs, can result very useful for the cellular therapy through a mechanism of protection or stimulus to the endogenous regeneration. There is a large and growing number of clues, which in fact point out that, after a transplant of adult stem cells (e.g. mesenchymal stem cells coming from the bone marrow), it should be possible to modify the tissue conditions of the affected area through the secretion of trophic and protective factors.


Research area

Department of Neurology-Stroke Unit

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