Neurodegenerative disorders (NDDs), such as Parkinson¿s disease (PD), Alzheimer¿s disease (AD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are characterized by aggregation and intracellular accumulation of misfolded proteins, which are believed to play a key role in synaptic dysfunction and neuronal death. Protein structural complexes in biofluids have been proposed to mirror pathological conditions suggesting their use as biomarkers for NDDs characterized by protein aggregation. In this framework, we plan to: i) collect a large cohort of NDD and prodromal patients and healthy subjects using standardized clinical and genetics procedures; ii) apply a novel method based on genomics, proteomics and bioinformatic analysis to map protein complexes in biofluids; iii) identify novel circulating biomarkers and correlate them to genetic profiling and disease endophenotypes, and; iv) validate the biological properties in human brain tissue and dopaminergic cultures.
Inclusion criteria for PD patients.
Inclusion criteria forAD patients. Patients will be selected at the Center for Cognitive Disorders and Dementias (CDCD) SCDU Neurology, AOU Maggiore della Carità, Novara. Patients with AD will be included after diagnosis of probable Alzheimer's disease according to the McKhann criteria (2011) and supported by positive biomarkers for amyloidopathy (PET with amyloid tracer or amyloid cerebrospinal fluid dosage).
Inclusion criteria for FTD/ALS patients. For UPO, patients will be selected at the tertiary center Amyotrophic Lateral Sclerosis - SCDU Neurology, AOU Maggiore della Carità, Novara. Patients with amyotrophic lateral sclerosis will be included following a diagnosis according to the El Escorial criteria - revised (2015): in this regard, only patients with a definite or probable diagnosis supported by laboratory will be included. For patients with FTD, they will be selected at both centers mentioned above with a diagnosis according to the Rascovsky criteria (2011). In this group, the diagnosis will be supported by negative biomarkers for amyloidopathy (PET with amyloid tracer or amyloid cerebrospinal fluid dosage). For patients with concomitant ALS and FTD, the El Escorial criteria (2015) associated with the Strong criteria (2017) will be used.
PD PATIENTS
pre-existing psychiatric pathologies;
neurodegenerative neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, neuromuscular diseases, epilepsy;
diagnosis of dementia;
The study will be performed on a total population of 510 subjects (140 PD, 150 AD/ALS/FTD, 120 controls, 100 relatives of patients carrying mutations), of these, 90 patients with a clinical diagnosis of neurodegenerative disease (40 PD cases, 30 AD cases, 20 ALS/FTD cases) will be recruited in this study. The study also includes the recruitment and analysis of 20 control individuals selected among those who will undergo CSF sampling in a diagnostic regimen for non-inflammatory and non-neurodegenerative diseases. The validation cohort, partially already available at the Clinical Centers involved in the study, is composed of 400 subjects of which: 100 PD patients (UO1), 100 AD/FTD/ALS patients (UO2), 100 healthy family members of NDD patients carrying pathogenic mutations and who have not yet developed the disease (UO1) and 100 control individuals (UO1).
Case-control
Prospective
Genetic: whole genome sequencing
GeneticGenetic: whole genome sequencing PD Partecipants will be assessed for disease progression: Stadio di Hoehn and Yahr, MDS-UPDRS part III, MOCA test, no motor symptoms, therapy and LID occurrence, Sleep disorders. Partecipants will be subjected to peripheral blood sampling for the purification of DNA, plasma, serum, PBMC and generation of hiPSC. DNA of each partecipants we will analysed by whole genome sequencing by next generation sequencing to identify any variant in candidate PD genes
whole exome sequencing
GeneticGenetic: whole genome sequencing AD Partecipants will be assessed for disease progression: * assessment of cognitive disorders (MMSE, MOCA test, clock test); * assessment of language disorders; * current drug therapy (and possible start date of treatment); * date of onset of cognitive disorders; * acquisition and assessment of imaging data where present (MRI, CT, PET). DNA of each partecipants we will analysed by whole genome sequencing by next generation sequencing to identify any variant in candidate AD genes
whole exome sequencing
GeneticGenetic: whole genome sequencing ALS/FTD Partecipants will be assessed for disease progression: * clinical classification according to El Escorial - revised; * assessment of cognitive disorders (and classification according to Strong criteria, 2017); * assessment of language disorders; * ongoing pharmacological therapy (and possible start date of treatment); * date of onset of motor and cognitive disorders; * acquisition and assessment of imaging data where present (MRI, CT, PET). DNA of each partecipants we will analysed by whole genome sequencing by next generation sequencing to identify any variant in candidate ALS/FTD genes
motor symptoms of PD patients will be evaluated with Hoehn and Yahr (HY) score
The Hoehn and Yahr Scale will be used to measure how Parkinson's symptoms progress and the level of disability. Itincludes stages 1 through 5: Stage 1. Unilateral involvement only, usually with minimal or no functional impairment; Stage 2 = Bilateral disease, without impairment of balance; Stage 3 = Mild to moderate bilateral disease; some postural instability; physically independent. Stage 4 = Severe disability; still able to walk or stand unassisted. Stage 5 = Wheelchair bound or bedridden unless aided.
motor and non motor symptoms of PD patients will be evaluated with MDS-UPDRS
The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of DailyLiving; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver
clinical evaluation of cognitive impairment of PD, AD, ALS/FTD patients
PD patients will be evaluated with the Montreal Cognitive Assessment (MoCA) test. This is a test used by healthcare providers to evaluate people with memory loss or other symptoms of cognitive decline. The MoCA contains 30 questions and checks different types of cognitive or thinking abilities. These include:orientation, short-term memory/delayed recall, executive function/visuospatial ability, clock-drawing test.- assessment of language disorders. ALS/FTD - assessment of cognitive disorders (and classification according to Strong criteria, 2017); - assessment of language disorders. AD patients: - assessment of cognitive disorders (MMSE, MOCA test, clock test); \- assessment of language disorders.
clinical evaluation of ALS/FTD patients
Clinical classification according to El Escorial - revised
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Neuromed IRCCS
Lead sponsor
Università del Piemonte Orientale AOU Maggiore della Carità - Novara
Collaborator
