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Authors: Contin, Manuela | Lopane, Giovanna | Cortelli, Pietro | Sambati, Luisa | Mohamed, Susan | Calandra-Buonaura, Giovanna

Article Type: Research Article

Abstract: Background: Differential diagnosis between Parkinson’s disease (PD) and atypical parkinsonisms (APs) may be difficult at disease onset. The response to levodopa (LD) is a key supportive feature but its definition is largely empirical. Studies evaluating this issue by quantitative tests are scanty. Objective: We aimed to assess the utility of a subacute low LD dose kinetic-dynamic test in the differential diagnosis between PD and APs. It was applied at the baseline of a prospective follow-up in patients with parkinsonian signs within three years of disease motor onset (“BoProPark” cohort) and eventually diagnosed as PD or APs according to consensus criteria. …Methods: Patients under at least 3-month LD therapy received a first morning fasting dose of LD/benserazide or carbidopa (100/25 mg) and underwent simultaneous serial assessments of plasma LD concentration and alternate finger tapping frequency up to 3 h. The main outcome was the extent of LD motor response, calculated by the area under the 3 h tapping effect–time curve (AUC_ETap). A receiver operating characteristic (ROC) curve analysis was performed to establish the optimal AUC_ETap cut-off to differentiate PD and APs. Results: The first 100 consecutive “BoProPark” patients were analyzed. Forty-seven patients were classified as possible, 37 as probable PD and 16 as APs. AUC_ETap medians were similar in the PD subgroups but reduced to a third in APs (p  < 0.001). The optimal AUC_ETap cut-off value was >2186 [(tap/min) x min], with a sensitivity of 92% and a specificity of 75%. Accuracy of the test was 0.85 (95% CI 0.74–0.95), p  < 0.0001. Conclusion: The estimation of 3 h AUC_ETap after a subacute low LD dose proved a reliable, objective tool to assess LD motor response in our cohort of patients. AUC_ETap value rounded to ≥2200 supports PD diagnosis, while lower values may alert to AP diagnoses. Show more

Keywords: Keywords: Levodopa, Parkinson’s disease, atypical parkinsonisms, alternate finger tapping test, kinetics-dynamics

DOI: 10.3233/JPD-202262

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 811-819, 2021

Authors: Contin, Manuela | Lopane, Giovanna | Belotti, Laura M.B. | Galletti, Margherita | Cortelli, Pietro | Calandra-Buonaura, Giovanna

Article Type: Research Article

Abstract: Background: Different studies, mostly with limited cohorts, have suggested the effects of patients’ characteristics on levodopa (LD) pharmacokinetics. Objective: We primarily aimed at investigating in a large population the relationship between patients’ features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics. Methods: The study was retrospective, based on data collected from subjects with parkinsonism on chronic LD undergoing LD therapeutic monitoring (TM). LD TM includes serial quantitative motor tests and blood samples to measure plasma drug concentrations after each subject’s chronically taken first-morning LD dose intake. Results: Five hundred patients, 308 males …(61.6%), mean (SD) age of 65 (10.1) years were included. Parkinsonian symptoms and LD therapy lasted 5.5 (4.5) and 3.4 (3.9) years, respectively. MDS-UPDRS part III “off” score was 28.8 (15.2). LD dose was 348.2 (187.1) mg/day. From multiple linear regression analysis, test dose, sex, type of LD decarboxylase inhibitor, weight and MDS-UPDRS part III score were linear predictors of both LD peak plasma concentration (Cmax ) (R2  = 0.52) and area under the 3-h plasma concentration-time curve (AUC) (R2  = 0.71), while age was a further predictor only for AUC. Besides test dose, sex was the strongest independent contributing variable to LD AUC, which resulted 27% higher in females compared to males. Conclusion: This is the largest collection of data on the relationship between demographic and clinical-therapeutic variables and LD kinetics in patients with parkinsonian symptoms. As a main clinically practical finding, women might require a 25% reduced weight-normalized LD dose compared with men to achieve the same LD bioavailability. Show more

Keywords: Levodopa, pharmacokinetics, sex, dopa decarboxylase inhibitors, levodopa therapeutic monitoring, levodopa-induced dyskinesias, pharmacodynamics

DOI: 10.3233/JPD-223374

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2519-2530, 2022

Authors: Baldin, Elisa | Zenesini, Corrado | Bauleo, Salvatore | Montanari, Federico | Santi, Sandra | Spampinato, Maurizio | Cortelli, Pietro | D’Alessandro, Roberto | Ascherio, Alberto

Article Type: Short Communication

Abstract: The aim of the study was to determine the feasibility of screening older adults attending general medical practice for features suggesting prodromal Parkinson’s disease (PD). Four general practitioners recruited 392 subjects aged ≥60 years, attending their primary clinics. A self-administered questionnaire collected information on history of probable rapid eye movements sleep behavior disorder (pRBD), constipation, risk markers for PD, and on subjective cognitive function. Olfactory function was tested. Constipation (27.8%), and hyposmia (19.9%), but not pRBD (4.3%), were more prevalent with age. Further supporting the feasibility of a longitudinal study, 299 subjects agreed to be followed.

Keywords: Parkinson’s disease, epidemiology, health policy and practice

DOI: 10.3233/JPD-191868

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 711-715, 2020

Authors: Abu-Rumeileh, Samir | Mometto, Nicola | Bartoletti-Stella, Anna | Polischi, Barbara | Oppi, Federico | Poda, Roberto | Stanzani-Maserati, Michelangelo | Cortelli, Pietro | Liguori, Rocco | Capellari, Sabina | Parchi, Piero

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer’s disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-β (Aβ)42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with definite and/or probable frontotemporal …lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, behavioral variant, corticobasal syndrome, frontotemporal dementia, neurofilament light, parkinsonism, primary progressive aphasia, progressive supranuclear palsy, tau, TDP-43

DOI: 10.3233/JAD-180409

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 551-563, 2018

Authors: Giannini, Giulia | Minardi, Raffaella | Barletta, Giorgio | Cani, Ilaria | Cecere, Annagrazia | Baldelli, Luca | Fiorentino, Alessia | Guaraldi, Pietro | Sambati, Luisa | Capellari, Sabina | Cortelli, Pietro | Carelli, Valerio | Calandra-Buonaura, Giovanna

Article Type: Research Article

Abstract: Background: Increased prevalence of cardiovascular autonomic failure might play a key role on Parkinson’s disease (PD) progression of glucocerebrosidase gene (GBA )-mutated patients, determining a malignant phenotype of disease in these patients. Objective: To objectively characterize, for the first time, the cardiovascular autonomic profile of GBA -mutated patients compared to idiopathic PD patients by means of cardiovascular reflex tests (CRTs). Methods: This is a case-control (1 : 2) study on PD patients belonging to well-characterized prospective cohorts. For each PD patient carrying GBA variants, two idiopathic PD patients, matched for sex and disease duration at CRTs, were selected. Patients recruited in these …cohorts underwent a complete clinical and instrumental evaluation including specific autonomic questionnaires, CRTs and extensive genetic analysis. Results: A total of 23 GBA -PD patients (19 males, disease duration 7.7 years) were included and matched with 46 non-mutated PD controls. GBA -mutated patients were younger than controls (59.9±8.1 vs. 64.3±7.2 years, p  = 0.0257) and showed a more severe phenotype. Despite GBA -mutated patients reported more frequently symptoms suggestive of orthostatic hypotension (OH) than non-mutated patients (39.1% vs 6.5%, p  = 0.001), the degree of cardiovascular autonomic dysfunction, when instrumentally assessed, did not differ between the two groups, showing the same prevalence of neurogenic OH, delayed OH and cardiovascular reflex impairment (pathological Valsalva maneuver). Conclusion: GBA -PD patients did not show different instrumental cardiovascular autonomic pattern than non-mutated PD. Our findings suggested that symptoms suggestive of OH should be promptly investigated by clinicians to confirm their nature and improve patient care and management. Show more

Keywords: Parkinson’s disease, cardiovascular autonomic failure, glucocerebrosidase (GBA) gene mutations, orthostatic hypotension, autonomic dysfunction, case-control study

DOI: 10.3233/JPD-230334

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 335-346, 2024

Authors: Abu-Rumeileh, Samir | Giannini, Giulia | Polischi, Barbara | Albini-Riccioli, Luca | Milletti, David | Oppi, Federico | Stanzani-Maserati, Michelangelo | Capellari, Sabina | Mantovani, Paolo | Palandri, Giorgio | Cortelli, Pietro | Cevoli, Sabina | Parchi, Piero

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-β (Aβ)42 and Aβ40 , total (t)-tau, phosphorylated (p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n  = 50) and subjects with iNPH (n  = 71), Alzheimer’s disease (AD) (n  = 60), and several other subtypes of dementia (n  = 145). Patients with iNPH showed significantly lower levels of Aβ42 …, Aβ40 , t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between “pure” iNPH cases and those with vascular or AD comorbidities. The Aβ42 /Aβ40 ratio showed higher diagnostic value than Aβ42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aβ- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aβ42 /Aβ40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables. Show more

Keywords: Aβ42/Aβ40 ratio, Alzheimer’s disease, amyloid, dementia with Lewy bodies, frontotemporal dementia, neurofilament light chain protein, prion protein, tau, vascular dementia

DOI: 10.3233/JAD-181012

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 723-733, 2019