Abstract Introduction The p.A53T point mutation in SNCA, the alpha-synuclein gene, has been linked to a rare dominant form of Parkinson's disease (PD). Methods Here, we describe two apparently ...unrelated cases of p.A53T (G209A) SNCA mutation carriers with an atypical initial manifestation and disease course. Moreover, cerebrospinal fluid (CSF) levels of tau, p-tau and amyloid Aβ42 were measured in these patients and in an additional cohort of 5 symptomatic and 2 asymptomatic p.A53T carriers without an initial manifestation of dementia. Results Both patients exhibited an early onset frontal-dysexecutive dysfunction with apathy and emotional blunting resembling frontotemporal dementia (FTD). Motor symptoms typical of Parkinson's disease appeared only later in the disease course and were less prominent than cognitive ones, which included language impairment. Autonomic dysfunction and myoclonus also emerged in a more advanced disease stage. In both patients, Brain Magnetic Resonance Imaging showed fronto-temporo-parietal atrophy, and CSF analysis showed elevated tau protein levels. In contrast, tau protein levels were normal in a cohort of 7 other p.A53T mutation carriers (5 symptomatic/2 asymptomatic). A screen of Greek patients presenting with frontotemporal dementia failed to identify any additional subjects with the p.A53T SNCA mutation. Conclusion Although cognitive decline has been recognized as a feature of the full-blown clinical picture of p.A53T related parkinsonism, a predominant frontotemporal dementia-like phenotype at presentation has not been previously described. This may represent a subtype of this disorder, with distinctive clinical, imaging and CSF biochemical characteristics, in which additional genetic or epigenetic factors may play a role.
Previous epidemiological evidence has established the co-occurrence of malignant melanoma (MM) and Parkinson's disease (PD). Shared molecular mechanisms have been proposed to be implicated in this ...relationship. The aim of the present study was to assess the prevalence of MM in patients with sporadic and genetic types of PD, as well as in asymptomatic carriers of PD-related genes.
Data regarding past medical history and concomitant disease of 1416 patients with PD (including 20 participants with prodromal disease who phenoconverted to PD), 275 healthy controls (HCs) and 670 asymptomatic carriers of PD-related genes were obtained from the database of the Parkinson's Progression Markers Initiative (PPMI). Focus was placed on information about a medical record of MM. We also retrieved data regarding the genetic status of selected PPMI participants with a positive MM history.
In total, 46 patients with PD reported a positive MM history. Concerning the genetic forms of PD, nine of these PD patients (2.47%) carried a Leucine Rich Repeat Kinase 2 (LRRK2) gene mutation (mainly the G2019S), while eight (4.49%) harbored a Glucocerebrosidase (GBA) gene mutation (mainly the N370S). No alpha-synuclein (SNCA) gene mutation was identified in patients with an MM history. The remaining 29 PD patients (3.5%) were genetically undetermined. In total, 18 asymptomatic carriers of PD-related genes had a positive medical history for MM: among them, 10 carried an LRRK2 gene mutation (2.69%) and 10 a GBA gene mutation (3.51%) (2 were dual carriers). MM history was identified for seven HCs (2.5%).
We replicated the previously reported association between genetically undetermined PD (GU-PD) and MM. A correlation of LRRK2 mutations with the development of MM could not be verified in either symptomatic PD patients or asymptomatic carriers, implicating distinct pathogenetic mechanisms as compared to GU-PD. Importantly, despite the limited literature evidence on Gaucher disease, this study highlights for the first time the relatively high prevalence of MM among asymptomatic and symptomatic PD GBA mutation carriers, with potential clinical implications.
Higher prevalence of motor and non-motor features has been observed in non-manifesting mutation carriers of Parkinson's Disease (PD) compared to Healthy Controls (HC). The aim was to detect the ...differences between GBA and LRRK2 mutation carriers without PD and HC on neuropsychiatric symptoms.
This is a cross-sectional retrospective study of non-manifesting GBA and LRRK2 mutation carriers and HC enrolled into Parkinson's Progression Markers Initiative (PPMI). Data extracted from the PPMI database contained: demographics and performance in MoCA scale and MDS-UPDRS scale part 1A (neuropsychiatric symptoms). All six features were treated as both continuous (MDS-UPDRS individual scores) and categorical variables (MDS-UPDRS individual score>0 and MDS-UPDRS individual score = 0). Logistic regression analyses were applied to evaluate the association between mutation carrying status and neuropsychiatric symptoms.
In this study, the neuropsychiatric evaluation was performed in 285 GBA non-manifesting carriers, 369 LRRK2 non-manifesting carriers and 195 HC. We found that GBA non-manifesting mutation carriers were 2.6 times more likely to present apathy compared to HC, even after adjustment for covariates (adjusted OR = 2.6, 95% CI = 1.1–6.3, p = 0.031). The higher percentage of apathy for LRRK2 carriers compared to HC was marginally non-significant. GBA carriers were 1.5 times more likely to develop features of anxiety compared to LRRK2 carriers (adjusted OR = 1.5, 95% CI = 1.1–2.2, p = 0.015). Other neuropsychiatric symptoms, such as psychotic or depressive manifestations, did not differ between groups.
Symptoms of apathy could be present in the prediagnostic period of non-manifesting mutation carriers, especially, GBA. Longitudinal data, including detailed neuropsychiatric evaluation and neuroimaging, would be essential to further investigate the pathophysiological basis of this finding.
•Apathy could be present in the premotor period of mutation carriers.•GBA non-manifesting carriers had a three-fold risk to develop apathy compared to controls.•Anxiety was more prevalent in GBA asymptomatic carriers, compared to LRRK2 carriers.•The prevalence of psychiatric features did not differ significantly between LRRK2 asymptomatic carriers and healthy controls.•Hallucinations, depression, anxiety and impulsivity did not differ between carriers and controls.
It has been reported that early onset Parkinson's Disease (PD) patients have a less profound dopaminergic degeneration. The aim of the current study was to determine whether there are longitudinal ...differences in dopaminergic denervation signal reduction in 123I-FP-CIT SPECT in early versus mid and late onset PD.
DaTSCAN (123I-FP-CIT SPECT) imaging was acquired at Parkinson's Progression Markers Initiative (PPMI) imaging centers and sent to the imaging core for calculation of striatal binding ratios. Data from the PPMI database of 58 early de novo PD patients (age ≤ 50 years) were compared to those of 362 mid and late onset PD patients (age > 50 years).
Although raw striatal binding ratios were higher in early onset versus mid/late onset PD, especially on the ipsilateral side, such differences were not observed, and were in fact reversed in the contralateral putamen, after age correction. The rate of signal decline was similar between the two groups. Interestingly, based on both raw and age-adjusted data, caudate nucleus and putamen asymmetry (contralateral/ipsilateral ratio) was more pronounced in early onset PD. Striatal asymmetry also significantly correlated with age at onset as a continuous variable.
Early onset PD patients exhibited similar rates of decline of dopaminergic denervation compared to mid/late onset PD. These results are not supportive of a more benign disease in this subgroup. The more pronounced asymmetry in early onset PD may however signify a qualitatively different pattern of neurodegeneration compared to mid/late onset PD.
•Early and mid/late onset PD groups exhibited similar rates of dopaminergic denervation.•A more benign disease in the early onset PD group could not be verified.•Striatal asymmetry was more pronounced in early onset PD.
Blood uric acid represents an important biomarker in sporadic Parkinson's disease (PD). Whether uric acid levels change in genetic forms of PD is beginning to be assessed. The aim of the present ...study was to evaluate differences in serum uric acid level among PD patients harboring mutations in the glucocerebrosidase (GBA1) gene, sporadic PD, and healthy controls followed longitudinally.
Longitudinal 2-year serum uric acid measurement data of 120 GBA-PD patients have been downloaded from the Parkinson's Progression Markers Initiative (PPMI) database. This cohort was compared with 369 de novo sporadic PD patients and 195 healthy controls enrolled in the same study.
Following adjustment for age, sex and BMI the GBA-PD cohort exhibited lower 2-year longitudinal uric acid level as compared to the controls (p = 0.016). Baseline uric acid measurements showed only a marginal difference (p = 0.119), but year 2 uric acid levels were lower in the GBA-PD cohort (p < 0.001). There was no difference in baseline, year 2 and 2-year longitudinal serum uric acid in the GBA-PD cohort as compared to sporadic PD (p = 0.664, p = 0.117 and p = 0.315).
This is the first study to assess serum uric acid in a GBA-PD cohort. Our findings suggest that low serum uric acid might be a progression biomarker in GBA-PD. However, more studies (ideally longitudinal) on the association between low serum uric acid and clinical data in GBA-PD are needed. These results are consistent with data from previous reports assessing uric acid as a biomarker in other genetic forms of PD.
•Serum uric acid levels were lower in PD patients carrying GBA1 mutations as compared to healthy controls.•Serum uric acid did not differ between GBA-PD vs sporadic PD.•There was a gradual decrease of uric acid levels in both PD cohorts.
PDF
