Fronto-Temporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two neurodegenerative diseases that have been widely investigated from the late 19th century. FTD comprises a complex group of neurodegenerative disorders mainly involving frontal and temporal lobes. The clinical hallmarks are depicted by behavioural, executive and verbal deficits. In ALS degeneration affects distinctively the upper motor neuron located in motor cortex and the lower motor neuron located in the brainstem and in the anterior horn of spinal cord. ALS clinical phenotype is predominated by progressive muscular weakness and muscle mass wasting, leading to death after a few years, typically by respiratory failure. Although in the last century several studies have reported the presence of cognitive dysfunctions in ALS patients and motor impairment in FTD subjects, in the last decade growing evidence supports the hyposthesis that FTD and ALS represent the two extremes of a same continuum disorder. This hypothesis has been strengthened by recent evidences showing how FTD and ALS often present overlapping pathological, clinical and genetic features, determined by the identification of TDP-43 protein as the main component of the protein inclusions in almost all ALS cases and in around half of FTD cases and by the identification of exhanucleotidic expansion (G4C2) of the C9orf72 gene as the first cause of familial ALS, familial FTD and ALS-FTD overlap cases. Three groups of patients exemplifying the ALS-FTD continuum (subjects diagnosed with ALS, FTD and ALS-FTD overlap) were recruited in the present study, with the aim of investigating their respective cognitive function and neuroradiological hallmarks. Neuropsychological tests exploring executive and verbal functions (Frontal Assessment Battery -FAB, phonemic fluency -FAS and semantic fluency tests) were administered together with neuroradiological investigation using a 3 Tesla MRI scanner. Voxel-based Morphometry (VBM), an advanced neuroimaging technique that allows investigation of focal volume differences in brain anatomy, was applied for identifying specific patterns of atrophy for ALS, FTD and ALS-FTD patients. Furthermore a regression analysis was applied with the aim of correlating neuropsychological test scores to cerebral atrophy patterns specific for each group of patients. FTD showed the worst performance in neuropsychological assessments, followed by ALS-FTD and ALS patients. VBM analyses pointed out atrophy in bilateral fronto-temporal regions in FTD subjects, in left precentral and corticospinal districts in ALS subjects and in left fronto-temporal areas in ALS-FTD patients. Lower neuropsychological tests scores are related to atrophic areas in white matter involving mainly superior longitudinal fasciculus and corpus callosum in FTD subjects, while in ALS subjects lower scores are related with atrophic regions of cerebellar, frontal and temporal gray matter.
La Demenza Fronto-Temporale (FTD) e la Sclerosi Laterale Amiotrofica (SLA) sono due patologie neurodegenerative le cui prime descrizioni risalgono alla seconda metà del XIX secolo. La FTD rappresenta un gruppo complesso di disordini neurodegenerativi coinvolgenti preminentemente i lobi frontali e temporali, che si contraddistinguono clinicamente per la presenza di importanti disturbi a carico della sfera comportamentale, esecutiva e linguistica. Nella SLA la degenerazione interessa in maniera peculiare il I motoneurone, localizzato a livello corticale e il II motoneurone, localizzato nel tronco encefalico e nelle corna anteriori del midollo spinale. Il fenotipo clinico della SLA è dominato da una progressiva e ingravescente debolezza muscolare, accompagnata da atrofia delle masse muscolari, la quale porta generalmente a morte del paziente nel giro di qualche anno, tipicamente per insufficienza respiratoria. Sebbene da più di un secolo si abbiano notizie di disfunzioni cognitive in pazienti con diagnosi di SLA e di disturbi motori in pazienti con diagnosi di FTD, soltanto nell'ultimo decennio è emersa una chiara linea di pensiero che considera la FTD e la SLA come due estremi di unico continuum. Tale visione è stata rafforzata da recenti evidenze che hanno mostrato come la SLA e la FTD presentino spesso un ampia sovrapposizione clinica, patologica e genetica, determinata principalmente dalla scoperta della proteina TDP-43 come principale costituente delle inclusioni proteiche nella maggioranza dei casi SLA e nella metà circa delle forme FTD e dalla scoperta dell'espansione esanucleotidica (G4C2) del gene C9orf72 quale principale causa di SLA famigliare, FTD famigliare e di overlap SLA-FTD. Nel presente studio sono stati arruolati tre categorie di pazienti che esemplificano il continuum SLA-FTD (individui con diagnosi di SLA, FTD e overlap SLA-FTD) con l'intento di indagare la rispettiva funzione cognitiva e i caratteri neuroradiologici. Si è proceduto quindi alla somministrazione di test neuropsicologici esploranti la sfera esecutiva e verbale (Frontal Assessment Battery - FAB, fluenza fonemica - FAS e fluenza semantica) insieme ad una valutazione neuroradiologica tramite risonanza magnetica 3 Tesla, con applicazione della tecnica Voxel-based Morphometry (VBM), una metodica di neuroimaging avanzato che permette di studiare differenze focali di volume delle strutture encefaliche. Lo studio è stato completato mediante un'analisi di regressione al fine di correlare i punteggi dei test neuropsicologici a pattern di atrofia cerebrale specifici nelle diverse classi di pazienti. In media, i soggetti FTD hanno ottenuto la performance peggiore ai test neuropsicologici, seguiti dagli individui SLA-FTD e dai soggetti con diagnosi di SLA. L'analisi VBM ha evidenziato la presenza di atrofia in regioni fronto-temporali bilaterali nei soggetti FTD, in sede precentrale e corticospinale a sinistra nei soggetti SLA e in aree fronto-temporali prevalentemente a sinistra negli individui SLA-FTD. Punteggi bassi ai test neuropsicologici correlano con aree di atrofia della sostanza bianca coinvolgente principalmente il corpo calloso e il fascicolo longitudinale superiore nei soggetti FTD, mentre nei soggetti SLA i punteggi bassi correlano con aree atrofiche della sostanza grigia cerebellare, frontale e temporale.
Il CONTINUUM. Sclerosi Laterale Amiotrofica – Demenza Fronto-Temporale. Studio clinico, neuropsicologico e di imaging avanzato.
TIWANA, NAVPREET
2015/2016
Abstract
Fronto-Temporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two neurodegenerative diseases that have been widely investigated from the late 19th century. FTD comprises a complex group of neurodegenerative disorders mainly involving frontal and temporal lobes. The clinical hallmarks are depicted by behavioural, executive and verbal deficits. In ALS degeneration affects distinctively the upper motor neuron located in motor cortex and the lower motor neuron located in the brainstem and in the anterior horn of spinal cord. ALS clinical phenotype is predominated by progressive muscular weakness and muscle mass wasting, leading to death after a few years, typically by respiratory failure. Although in the last century several studies have reported the presence of cognitive dysfunctions in ALS patients and motor impairment in FTD subjects, in the last decade growing evidence supports the hyposthesis that FTD and ALS represent the two extremes of a same continuum disorder. This hypothesis has been strengthened by recent evidences showing how FTD and ALS often present overlapping pathological, clinical and genetic features, determined by the identification of TDP-43 protein as the main component of the protein inclusions in almost all ALS cases and in around half of FTD cases and by the identification of exhanucleotidic expansion (G4C2) of the C9orf72 gene as the first cause of familial ALS, familial FTD and ALS-FTD overlap cases. Three groups of patients exemplifying the ALS-FTD continuum (subjects diagnosed with ALS, FTD and ALS-FTD overlap) were recruited in the present study, with the aim of investigating their respective cognitive function and neuroradiological hallmarks. Neuropsychological tests exploring executive and verbal functions (Frontal Assessment Battery -FAB, phonemic fluency -FAS and semantic fluency tests) were administered together with neuroradiological investigation using a 3 Tesla MRI scanner. Voxel-based Morphometry (VBM), an advanced neuroimaging technique that allows investigation of focal volume differences in brain anatomy, was applied for identifying specific patterns of atrophy for ALS, FTD and ALS-FTD patients. Furthermore a regression analysis was applied with the aim of correlating neuropsychological test scores to cerebral atrophy patterns specific for each group of patients. FTD showed the worst performance in neuropsychological assessments, followed by ALS-FTD and ALS patients. VBM analyses pointed out atrophy in bilateral fronto-temporal regions in FTD subjects, in left precentral and corticospinal districts in ALS subjects and in left fronto-temporal areas in ALS-FTD patients. Lower neuropsychological tests scores are related to atrophic areas in white matter involving mainly superior longitudinal fasciculus and corpus callosum in FTD subjects, while in ALS subjects lower scores are related with atrophic regions of cerebellar, frontal and temporal gray matter.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/18627