126 research outputs found
CLINICAL AND BIOCHEMICAL SIGNATURES OF GBA-RELATED PARKINSON DISEASE
No full textBackground: Parkinson’s disease (PD) is a common neurodegenerative disorder mainly characterized by dopaminergic neuronal loss in the substantia nigra and α-synuclein protein aggregation. Genetic factors are well known to contribute to PD susceptibility. Mutations in the glucocerebrosidase (GBA) gene are the commonest genetic risk factor for PD and also impact on disease development and progression. A better clinical and genetic classification of patients, as well as the identification of clinical and biochemical markers are therefore of utmost importance for multifold reasons:
- to improve the characterization of patient's clinical phenotype of different forms of PD;
- to identify reliable biomarkers for genetic subtypes of PD in order to obtain and early diagnosis and monitor disease progression;
- to include patients with specific mutations in ad hoc clinical trials aiming to tailor medical treatment.
Objective: The present project aims at exploring the bases of PD phenotype through the correlation of specific genetic and biochemical findings with the clinical picture, in subjects with GBA-related PD (GBA-PD) and subjects affected by idiopathic PD (non-mutated PD – NM-PD). We divided the investigation in three studies: i) definition of a clinical and biochemical profile which could distinguish GBA-PD from non-mutated PD (NM-PD) (study I); ii) longitudinal evaluation of the disease course of GBA-PD compared to NM-PD along 2-year follow-up, with a focus on clinical and biochemical parameters (study II); iii) definition of a biochemical prodomal profile in the asymptomatic GBA carriers that could differentiate subjects more at risk to develop PD.
Methods: a comprehensive clinical assessment of motor and non-motor symptoms alongside the analysis of α-synuclein levels, glucocerebrosidase (GCase) enzymatic activity and main GCase-related lysosomal proteins in peripheral blood mononuclear cells (PBMCs) were performed in all the three studies.
Results: At baseline, GBA-PD showed a worse clinical outcome both on motor and non-motor features compared to NM-PD, as well a distinctive biochemical profile in PBMCs showing significantly higher α –synuclein levels, lower GCase activity, higher LIMP-2 and lower Saposin C levels.
Over time, both the GBA-PD and the NM-PD groups separately displayed a significant deterioration in dysautonomic functions, motor performance, cognitive functions and mood disorder compared to baseline, while GBA-PD had a more severe motor progression with a higher disease severity compared to NM-PD. At 2-year follow-up, the level of α-synuclein in PBMCs was able to differentiate GBA-PD from NM-PD and HC.
Finally, a unique biochemical profile was observed also in the asymptomatic GBA mutation carriers, in which the combination of higher level of α-synuclein with lower Gcase activity was able to define a malignant prodromal profile.
Conclusion: These studies contribute to our current understanding of the role of GBA mutations in the development and progression of PD. We confirm the biological effect of GBA mutations in determining clinical and biochemical distinctive profile of PD. We propose essays in PBMCs as an easily accessible and manageable model to provide a characteristic biochemical profile of GBA carriers, potentially useful for patient stratification or selection in clinical trials.Background: Parkinson’s disease (PD) is a common neurodegenerative disorder mainly characterized by dopaminergic neuronal loss in the substantia nigra and α-synuclein protein aggregation. Genetic factors are well known to contribute to PD susceptibility. Mutations in the glucocerebrosidase (GBA) gene are the commonest genetic risk factor for PD and also impact on disease development and progression. A better clinical and genetic classification of patients, as well as the identification of clinical and biochemical markers are therefore of utmost importance for multifold reasons:
- to improve the characterization of patient's clinical phenotype of different forms of PD;
- to identify reliable biomarkers for genetic subtypes of PD in order to obtain and early diagnosis and monitor disease progression;
- to include patients with specific mutations in ad hoc clinical trials aiming to tailor medical treatment.
Objective: The present project aims at exploring the bases of PD phenotype through the correlation of specific genetic and biochemical findings with the clinical picture, in subjects with GBA-related PD (GBA-PD) and subjects affected by idiopathic PD (non-mutated PD – NM-PD). We divided the investigation in three studies: i) definition of a clinical and biochemical profile which could distinguish GBA-PD from non-mutated PD (NM-PD) (study I); ii) longitudinal evaluation of the disease course of GBA-PD compared to NM-PD along 2-year follow-up, with a focus on clinical and biochemical parameters (study II); iii) definition of a biochemical prodomal profile in the asymptomatic GBA carriers that could differentiate subjects more at risk to develop PD.
Methods: a comprehensive clinical assessment of motor and non-motor symptoms alongside the analysis of α-synuclein levels, glucocerebrosidase (GCase) enzymatic activity and main GCase-related lysosomal proteins in peripheral blood mononuclear cells (PBMCs) were performed in all the three studies.
Results: At baseline, GBA-PD showed a worse clinical outcome both on motor and non-motor features compared to NM-PD, as well a distinctive biochemical profile in PBMCs showing significantly higher α –synuclein levels, lower GCase activity, higher LIMP-2 and lower Saposin C levels.
Over time, both the GBA-PD and the NM-PD groups separately displayed a significant deterioration in dysautonomic functions, motor performance, cognitive functions and mood disorder compared to baseline, while GBA-PD had a more severe motor progression with a higher disease severity compared to NM-PD. At 2-year follow-up, the level of α-synuclein in PBMCs was able to differentiate GBA-PD from NM-PD and HC.
Finally, a unique biochemical profile was observed also in the asymptomatic GBA mutation carriers, in which the combination of higher level of α-synuclein with lower Gcase activity was able to define a malignant prodromal profile.
Conclusion: These studies contribute to our current understanding of the role of GBA mutations in the development and progression of PD. We confirm the biological effect of GBA mutations in determining clinical and biochemical distinctive profile of PD. We propose essays in PBMCs as an easily accessible and manageable model to provide a characteristic biochemical profile of GBA carriers, potentially useful for patient stratification or selection in clinical trials
Who is at Risk of Parkinson Disease? Refining the Preclinical Phase of GBA1 and LRRK2 Variant Carriers: a Clinical, Biochemical, and Imaging Approach
No full textPurpose of Review: Genetic variants in GBA1 and LRRK2 genes are the commonest genetic risk factor for Parkinson disease (PD); however, the preclinical profile of GBA1 and LRRK2 variant carriers who will develop PD is unclear. This review aims to highlight the more sensitive markers that can stratify PD risk in non-manifesting GBA1 and LRRK2 variant carriers. Recent Findings: Several case–control and a few longitudinal studies evaluated clinical, biochemical, and neuroimaging markers within cohorts of non-manifesting carriers of GBA1 and LRRK2 variants. Summary: Despite similar levels of penetrance of PD in GBA1 and LRRK2 variant carriers (10–30%), these individuals have distinct preclinical profiles. GBA1 variant carriers at higher risk of PD can present with prodromal symptoms suggestive of PD (hyposmia), display increased α-synuclein levels in peripheral blood mononuclear cells, and show dopamine transporter abnormalities. LRRK2 variant carriers at higher risk of PD might show subtle motor abnormalities, but no prodromal symptoms, higher exposure to some environmental factors (non-steroid anti-inflammatory drugs), and peripheral inflammatory profile. This information will help clinicians tailor appropriate screening tests and counseling and facilitate researchers in the development of predictive markers, disease-modifying treatments, and selection of healthy individuals who might benefit from preventive interventions
Pain in focal dystonias - A focused review to address an important component of the disease
No full textFocal dystonia is characterized by involuntary muscle contractions that cause abnormal postures and/or twisting movements in a segment of the body. Motor symptoms have a major impact on disability in this condition, but the presence of pain represents an additional source of impairment and poor quality of life. Notwithstanding that pain occurs in up to 70% of patients with cervical dystonia and in a relevant proportion of subjects with focal dystonia of the limbs, it has received very little attention from researchers and controlled trials are scant. The aim of this review is to summarize the current knowledge on the clinical assessment and management of pain in focal dystonias. The search results will inform on the types of pain reported in focal dystonias, on the tools that are used to quantify pain and on the efficacy of pharmacological and non-pharmacological approaches. The collated data will hopefully improve the clinical management of focal dystonia and also stimulate future research on dystonia-associated pain. Optimization of the outcome indeed requires the identification and the management of all the factors that determine disability and hence relies on a multidisciplinary approach
Pain processing in atypical parkinsonisms and Parkinson disease. A comparative neurophysiological study
No full textOBJECTIVE:
Pain is a frequent non-motor feature in Parkinsonism but mechanistic data on the alteration of pain processing are insufficient to understand the possible causes and to define specifically-targeted treatments.
METHODS:
we investigated spinal nociception through the neurophysiological measure of the threshold (TR) of nociceptive withdrawal reflex (NWR) and its temporal summation threshold (TST) comparatively in 12 Progressive Supranuclear Palsy (PSP) subjects, 11 Multiple System Atrophy (MSA) patients, 15 Parkinson's disease (PD) subjects and 24 healthy controls (HC). We also investigated the modulatory effect of L-Dopa in these three parkinsonian groups.
RESULTS:
We found a significant reduction in the TR of NWR and in the TST of NWR in PSP, MSA and PD patients compared with HC. L-Dopa induced an increase in the TR of NWR in the PSP group while TST of NWR increased in both PSP and PD.
CONCLUSIONS:
Our neurophysiological findings identify a facilitation of nociceptive processing in PSP that is broadly similar to that observed in MSA and PD. Specific peculiarities have emerged for PSP.
SIGNIFICANCE:
Our data advance the knowledge of the neurophysiology of nociception in the advanced phases of parkinsonian syndromes and on the role of dopaminergic pathways in the control on pain processing
Body Weight Support Combined With Treadmill in the Rehabilitation of Parkinsonian Gait: A Review of Literature and New Data From a Controlled Study
No full textBackground: Gait disorders represent disabling symptoms in Parkinson's Disease (PD). The effectiveness of rehabilitation treatment with Body Weight Support Treadmill Training (BWSTT) has been demonstrated in patients with stroke and spinal cord injuries, but limited data is available in PD. Aims: The aim of the study is to investigate the efficacy of BWSTT in the rehabilitation of gait in PD patients. Methods: Thirty-six PD inpatients were enrolled and performed rehabilitation treatment for 4-weeks, with daily sessions. Subjects were randomly divided into two groups: both groups underwent daily 40-min sessions of traditional physiokinesitherapy followed by 20-min sessions of overground gait training (Control group) or BWSTT (BWSTT group). The efficacy of BWSTT was evaluated with clinical scales and Computerized Gait Analysis (CGA). Patients were tested at baseline (T0) and at the end of the 4-weeks rehabilitation period (T1). Results: Both BWSTT and Control groups experienced a significant improvement in clinical scales as FIM and UPDRS and in gait parameters for both interventions. Even if we failed to detect any statistically significant differences between groups in the different clinical and gait parameters, the intragroup analysis captured a specific pattern of qualitative improvement associated to cadence and stride duration for the BWSTT group and to the swing/stance ratio for the Control group. Four patients with chronic pain or anxious symptoms did not tolerate BWSTT. Conclusions: BWSTT and traditional rehabilitation treatment are both effective in improving clinical motor functions and kinematic gait parameters. BWSTT may represent an option in PD patients with specific symptoms that limit traditional overground gait training, e.g., severe postural instability, balance disorder, orthostatic hypotension. BWSTT is generally well-tolerated, though caution is needed in subjects with chronic pain or with anxious symptoms. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03815409
Parasympathetic Dysfunction Prevails in GBA1‐Associated Parkinson's Disease
No full textBackground: The role played by sympathetic and parasympathetic autonomic branches in patients with Parkinson's disease carrying variants in the GBA1 gene (GBA-PD) is still elusive. Objectives: To characterize cardiovascular autonomic function in GBA-PD and I-PD patients with early and mid-stage disease. Methods: These assessments were performed: cardiovascular autonomic tests, analysis of heart rate and blood pressure variability, cardiac noradrenergic imaging. The frequency and severity of autonomic symptoms were comparatively assessed with the SCOPA-AUT questionnaire. Results: Compared to the I-PD cohort, GBA-PD patients displayed an increased burden of autonomic symptoms. Autonomic tests revealed worse parasympathetic scores in GBA-PD while sympathetic indexes and the degree of cardiac sympathetic binding were comparable in the two groups. Heart rate variability indexes also revealed lower vagal modulation in the GBA-PD group. Conclusions: The cardiovascular autonomic profile in GBA PD is characterized by a prominent cardiovagal dysfunction compared to I-PD
A narrative review on the role and main findings of the Videofluoroscopic Study of Swallowing in Parkison's disease
No full textPurpose: Dysphagia is a common symptom in patients with Parkinson's disease (PD), though it may go undiagnosed until severe complications arise. Dysphagia can be suspected on a clinical basis, but an instrumental assessment is mandatory to confirm its presence and evaluate pathophysiological aspects and severity of the swallowing impairment. Aim of this review is to inform the clinician and the radiologist on the importance and the main radiological findings of the Video-Fluoroscopic-Swallow-Study (VFSS) in patients with PD starting from the most recent literature data on the topic. Materials and methods: Databases analysis identified 98 papers (January 2000/October 2022) of which 55 were excluded after reading title, abstract and full-text. After evaluation of the selected articles and their references 7 additional papers were added. Results: Fifty papers were reviewed to answer the following four main questions: Should VFSS be routinely used to screen dysphagia? Compared to other diagnostic tools, what is the role of VFSS in PD patients with suspected dysphagia? What are the main VFSS findings and technical expedients ? What is the role of VFSS in the choice of the best treatment strategy ? Conclusions: VFSS represents a gold standard technique in the diagnostic evaluation of dysphagia in PD, having a fundamental role in the identification of patients with high risk of aspiration pneumonia and also being extremely helpful to guide to the choice of treatment strategies for dysphagia
Apomorphine Subcutaneous Infusion Likely Induced Acute Thrombocytopenia in a Patient with Parkinson's Disease and Motor Fluctuations
No full textParkinson's disease following COVID-19: six cases report
No full textBackground: Core clinical manifestation of COVID-19 include flu-like and respiratory symptoms. However, it is now evident that neurological involvement may occur during SARS-CoV-2 infection, covering an extensive spectrum of phenotypical manifestations. A major challenge arising from this pandemic is represented by detecting emerging neurological complications following recovery from SARS-CoV-2 infection. To date, few post-COVID-19 infected subjects diagnosed with Parkinson's Disease (PD) were described, raising the possibility of a connection between the infection and neurodegenerative process. Here, we describe a cases series of six subjects, who developed PD after COVID-19. Methods: Patients were observed at IRCCS Mondino Foundation Hospital, Pavia (Italy), and San Paolo University Hospital of Milan (Italy) between March 2021 and June 2022. In all subjects, SARS-CoV-2 infection was confirmed by means of a RT-PCR from a nasopharyngeal swab. Subjects underwent an accurate neurological evaluation, and neuroimaging studies were performed. Results: We describe six subjects, who developed PD with an average time window after SARS-CoV-2 infection of 4-7 weeks. Apparently, no relationship with COVID-19 severity emerged, and no overt structural brain abnormalities were found. All subjects experienced unilateral resting tremor at onset and showed a satisfactory response to dopaminergic treatment. Conclusions: Immune responses to SARS-CoV-2 infection have been shown to shape the individual susceptibility to develop long-term consequences. We hypothesize that, in these subjects, COVID-19 has unmasked a latent neurodegenerative process. Characterization of the neuroinflammatory signatures in larger cohorts is warranted, which might provide novel insights in the pathogenesis of PD
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