Hereditary ataxias are rare and genetically heterogeneous disorders. Friedreich ataxia (FRDA) represent the most frequent of these forms, with a prevalence in Caucasian populations is 1:50.000. Clinical trials are particularly challenging in rare disease, therefore the selecting the most sensitive outcome measures is critical for trial designs. FRDA is characterized by juvenile onset, progressive disequilibrium and cardiomyopathy. Several outcome measures have been tested, but the majority of them require a considerable number of patients for appropriately powered studies. The aim of this project was to analyze existing outcome measures and to evaluate newly developed tools that can be used to rate FRDA disease severity and progression. A group of 207 subjects with FRDA from the Ataxia clinic of the Fondazione IRCCS Istituto Neurologico “Carlo Besta”, were included in the following studies: - Analysis of statistical properties of the Scale for the Assessment and Rating of Ataxia (SARA) and the FRDA rating scale (FARS). We assessed the properties of SARA scale in 170 subjects. We evaluated the contribution of each item to the total score. Items evaluating lower limbs, walking and stance linearly increase up to SARA score of 20-25 points (out of 40), when ambulation is lost. In non-ambulatory subjects, items assessing upper limbs rapidly increase. In longitudinal analyses subjects with lower baseline scores progressed more rapidly than subjects with higher scores. Performances of SARA and FARS scales were compared in 99 subjects. Both scales displayed good internal consistency and were mutually highly correlated and also correlated with disease duration. - Posturography. Seventy-six subjects with FRDA were assessed. Evaluations carried out at baseline and at 1- and 2-years follow-up consisted of 4 different tasks: seated, natural stance, feet together stance and tandem stance. X (medio-lateral) and Y (antero-posterior) axis sway was recorded from accelerometer placed over sternum. Posturography variables were not correlated with disease duration and ataxia severity, but were significantly related to age at ataxia onset. In longitudinal analyses significantly worse performances were identified during Feet-together-stance at 1 year follow-up. - Wet biomarkers (in collaboration with the University of Rome "Tor Vergata”, Prof. F. Malisan). Fifty-three subjects with FRDA and 27 controls were included in the first part of the study that analyzed HS-1-associated protein X-1 (HAX-1) expression as a potential biomarker in FRDA. FXN and HAX-1 expression appeared to be co-regulated, both at mRNA and protein levels. The microRNAs hsa-miR223-3p resulted up-regulated in FRDA subjects, and negative correlated with HAX-1 mRNA and protein levels. hsa-miR223-3p levels were also significantly correlated with cardiac parameters in FRDA. - Real-life activity monitoring. We tested remote monitoring with Actigraph in a cohort of 25 subjects with FRDA and 13 healthy controls. Two Actigraphs were worn by subjects (non-dominant wrist and waist) during waking hours for 7 days. Daily activity was summarized as: average active expense (Kcal), %active, MET (Metabolic Equivalent of Task) score and daily step count. Activity variables differentiated FRDA from matched controls. Step count derived from waist worn device was the variables that correlated more with clinical parameters. In conclusion, clinical scales remain essential to monitor disease progression in FRDA and knowledge of their properties is crucial for interventional trials. Biomarkers and activity measures can be used to assess specific features of the disease, and provide a more objective, real-life information. The combined use of clinical scales and functional measures may be ideal for heterogeneous diseases, such as ataxia.
Le atassie ereditarie sono malattie rare geneticamente eterogenee. L'atassia di Friedreich (AF) rappresenta la forma più frequente, con una prevalenza nelle popolazioni caucasiche di 1:50.000. A causa della bassa prevalenza la selezione delle misure di outcome più sensibili è fondamentale per gli studi clinici. Finora sono state testate diverse misure di outcome, ma la maggior parte di esse richiede un numero considerevole di pazienti per studi con potenza adeguata. Lo scopo di questo progetto è stato analizzare le misure di outcome esistenti e valutare strumenti di nuova concezione per valutare la gravità e la progressione della AF. Un gruppo di 207 soggetti con AF afferenti alla Fondazione IRCCS Istituto Neurologico “Carlo Besta” è stato incluso nei seguenti studi: - Analisi delle proprietà statistiche della Scale for the Assessment and Rating of Ataxia (SARA) e della scala FARS. Abbiamo valutato le proprietà della scala SARA in 170 soggetti. Gli item che valutano arti inferiori, deambulazione e stazione eretta aumentano linearmente fino al punteggio SARA di 20-25 punti (su 40), quando si perde la deambulazione. Nei soggetti non deambulanti, gli item che valutano gli arti superiori aumentano più rapidamente. Nell’analisi longitudinale i soggetti con punteggi basali di SARA più bassi hanno maggiore velocità di progressione rispetto ai soggetti con punteggi più alti. Le prestazioni delle scale SARA e FARS sono state confrontate in 99 soggetti. Entrambe le scale hanno mostrato una buona consistenza interna, si sono dimostrate altamente correlate reciprocamente e con la durata della malattia. - Posturografia. Sono stati valutati 76 soggetti con AF. Le valutazioni effettuate al basale e al follow-up a 1 e 2 anni prevedevano 4 situazioni: posizione seduta, e in piedi in posizione naturale, in posizione a piedi uniti e in tandem. L'oscillazione degli assi X (medio-laterale) e Y (antero-posteriore) è stata registrata da un accelerometro posizionato sopra lo sterno. Le variabili estratte non si sono mostrate correlate con la durata della malattia e la gravità dell'atassia, ma con l'età di insorgenza dell'atassia. Nelle analisi longitudinali sono state identificate prestazioni significativamente peggiori durante la posizione dei piedi uniti a 1 anno di follow-up. - Wet biomarkers (in collaborazione con l'Università di Roma "Tor Vergata", Prof. F. Malisan). 53 soggetti con AF e 27 controlli sono stati inclusi nella studio che ha analizzato la proteina HAX-1 come potenziale biomarcatore. L'espressione di FXN e HAX-1 si è dimostrata co-regolata, sia a livello di mRNA che di proteine. Il microRNA hsa-miR223-3p è risultato elevato nei soggetti con AF e correlato negativamente con i livelli di mRNA e proteina di HAX-1. I livelli di hsa-miR223-3p sono risultati significativamente correlati con i parametri cardiaci. - Monitoraggio dell’attività nella vita reale. Abbiamo testato il monitoraggio remoto con Actigraph in 25 soggetti con AF e 13 controlli. Due Actigraph sono stati indossati dai soggetti (polso non dominante e vita) durante le ore di veglia per 7 giorni. L'attività giornaliera è stata riassunta come: spesa attiva media (Kcal), %attività, MET (Metabolic Equivalent of Task) e conteggio passi giornalieri. Le variabili di attività hanno differenziato soggetti con AF dai controlli. Il conteggio passi derivato dal dispositivo indossato in vita era la variabile più correlata ai parametri clinici. In conclusione, le scale cliniche rimangono essenziali per monitorare la progressione dell’AF e la conoscenza delle loro proprietà è fondamentale per le sperimentazioni cliniche. I biomarker e le misure di attività possono essere utili per valutare caratteristiche specifiche della malattia e forniscono informazioni più obiettive e di vita reale. L'uso combinato di scale cliniche e misure funzionali è ideale per malattie eterogenee, come l'atassia.
(2023). Outcome measures in hereditary ataxias: analysis of clinical scales and evaluation of new tools to assess disease progression in Friedreich ataxia. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2023).
Outcome measures in hereditary ataxias: analysis of clinical scales and evaluation of new tools to assess disease progression in Friedreich ataxia
FICHERA, MARIO
2023
Abstract
Hereditary ataxias are rare and genetically heterogeneous disorders. Friedreich ataxia (FRDA) represent the most frequent of these forms, with a prevalence in Caucasian populations is 1:50.000. Clinical trials are particularly challenging in rare disease, therefore the selecting the most sensitive outcome measures is critical for trial designs. FRDA is characterized by juvenile onset, progressive disequilibrium and cardiomyopathy. Several outcome measures have been tested, but the majority of them require a considerable number of patients for appropriately powered studies. The aim of this project was to analyze existing outcome measures and to evaluate newly developed tools that can be used to rate FRDA disease severity and progression. A group of 207 subjects with FRDA from the Ataxia clinic of the Fondazione IRCCS Istituto Neurologico “Carlo Besta”, were included in the following studies: - Analysis of statistical properties of the Scale for the Assessment and Rating of Ataxia (SARA) and the FRDA rating scale (FARS). We assessed the properties of SARA scale in 170 subjects. We evaluated the contribution of each item to the total score. Items evaluating lower limbs, walking and stance linearly increase up to SARA score of 20-25 points (out of 40), when ambulation is lost. In non-ambulatory subjects, items assessing upper limbs rapidly increase. In longitudinal analyses subjects with lower baseline scores progressed more rapidly than subjects with higher scores. Performances of SARA and FARS scales were compared in 99 subjects. Both scales displayed good internal consistency and were mutually highly correlated and also correlated with disease duration. - Posturography. Seventy-six subjects with FRDA were assessed. Evaluations carried out at baseline and at 1- and 2-years follow-up consisted of 4 different tasks: seated, natural stance, feet together stance and tandem stance. X (medio-lateral) and Y (antero-posterior) axis sway was recorded from accelerometer placed over sternum. Posturography variables were not correlated with disease duration and ataxia severity, but were significantly related to age at ataxia onset. In longitudinal analyses significantly worse performances were identified during Feet-together-stance at 1 year follow-up. - Wet biomarkers (in collaboration with the University of Rome "Tor Vergata”, Prof. F. Malisan). Fifty-three subjects with FRDA and 27 controls were included in the first part of the study that analyzed HS-1-associated protein X-1 (HAX-1) expression as a potential biomarker in FRDA. FXN and HAX-1 expression appeared to be co-regulated, both at mRNA and protein levels. The microRNAs hsa-miR223-3p resulted up-regulated in FRDA subjects, and negative correlated with HAX-1 mRNA and protein levels. hsa-miR223-3p levels were also significantly correlated with cardiac parameters in FRDA. - Real-life activity monitoring. We tested remote monitoring with Actigraph in a cohort of 25 subjects with FRDA and 13 healthy controls. Two Actigraphs were worn by subjects (non-dominant wrist and waist) during waking hours for 7 days. Daily activity was summarized as: average active expense (Kcal), %active, MET (Metabolic Equivalent of Task) score and daily step count. Activity variables differentiated FRDA from matched controls. Step count derived from waist worn device was the variables that correlated more with clinical parameters. In conclusion, clinical scales remain essential to monitor disease progression in FRDA and knowledge of their properties is crucial for interventional trials. Biomarkers and activity measures can be used to assess specific features of the disease, and provide a more objective, real-life information. The combined use of clinical scales and functional measures may be ideal for heterogeneous diseases, such as ataxia.File | Dimensione | Formato | |
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