Dissertation committee:
Λεωνίδας Στεφανής, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ελισσάβετ Καπάκη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Παναγιώτης Κοκότης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αναστάσιος Μπονάκης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Σωκράτης Παπαγεωργίου, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Πόταγας, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Κούτσης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Summary:
STUDY OBJECTIVES:
The objective of this study was to correlate the phenotype - whether it concerns the clinical characteristics or some biological or other markers - with the genotype in the most common monogenic forms of Parkinson's disease (PD) in Greece.
Specifically:
1) We wanted to determine whether in patients with PD carrying the GBA mutation (GBA-PD) in the Greek population there are distinct features in their motor and non-motor symptoms and whether these match with the findings of the previous reported literature.
2)To assess striatal dopaminergic denervation in a cohort of PD patients carrying the p.A53T SNCA mutation (A53T-PD).
3) To assess non-motor symptoms in a cohort of PD patients carrying the p.A53T SNCA mutation (A53T-PD).
4) Τo assess whether REM Sleep Behavior Disorder (RBD) and other sleep abnormalities occur in carriers of the p.A53T SNCA mutation, using both subjective and objective measures.
5) To evaluate whether there is a dysfunction of the autonomic nervous system (ANS), mainly concerning the cardiovascular system, in patients with genetic forms of PD in Greece.
6)To evaluate the non-motor characteristics of asymptomatic carriers of the p. A53T SNCA mutation (A53T-AC).
METHODS:
We conducted 6 parallel studies to test the spectrum of the disease as widely as possible and to avoid burdening each patient with too many tests:
1) To study the characteristics of GBA-PD in Greece, we compared with questionnaires and scales the phenotypic characteristics of 35 GBA-PD with those of 35 genetically unidentified PD patients (GU-PD) in the Greek population matched for age, sex and disease duration.
2) To assess dopaminergic striatal denervation in A53T-PD we compared findings from 11 A53T-PD who underwent 123I-FP-CIT SPECT imaging in basal ganglia with those of 33 age-, sex-, and disease duration–matched PD patients. Neuropsychological assessments were also performed in both groups.
3) The non-motor symptoms of A53T-PD (the presence of hyposmia, neuropsychiatric and dysautonomic symptoms as well as sleep disturbances) were assessed with questionnaires and scales in 18 A53T-PD and compared with those of 18 typical PD patients (t-PD) weighted for age, sex and disease duration.
4) To study sleep disturbances in A53T we have assessed 15 p.A53T carriers [10 manifesting Parkinson’s Disease (PD-A53T) and 5 asymptomatic carriers] with simultaneous Video-PSG (polysomnography) recording, the Epworth Sleepiness Scale (ESS) for daytime sleepiness, the Athens Insomnia Scale (AIS), the RBD Screening Questionnaire (RBDSQ) for clinical features of RBD, the Montreal Cognitive Assessment (MOCA) for cognition and the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction.
5) To study the possible autonomic dysfunction in genetic PD, we evaluated 9 A53T-PD, 9 GBA-PD and 10 i-PD (sporadic PD) with non-invasive tests of ANS function in the laboratory: standing, deep breathing, sustained hand grip and Valsalva maneuver. In addition, we evaluated the SCOPA-AUT for autonomic dysfunction, the MOCA scale for cognitive function, and the H&Y scale to assess motor function. We also calculated a subscore of the SCOPA-AUT with questions about cardiovascular function (SCOPA-C) and how many patients had abnormal ≥2 laboratory tests (AUT≥2).
6) To study the non-motor characteristics of asymptomatic p. A53T mutation carriers (A53T-AC), we assessed non-motor symptoms with questionnaires, scales and smell tests in 12 A53T-AC and compared them with those of 36 healthy controls (HC), matched for age and sex.
RESULTS:
1) We found a previously reported higher prevalence of cognitive impairment and a more frequent bilateral onset of the disease in GBA-PD vs GU-PD.
2) The p.A53T mutation carriers had significantly lower caudate nucleus binding ratio both contralaterally and ipsilaterally to the most affected side and a decreased contralateral caudate/putamen signal ratio as compared to PD. A similar degree of striatal asymmetry was observed in both subgroups. No correlation between scores in neuropsychological tests and caudate nucleus dopaminergic denervation could be demonstrated.
3) Regarding the non-motor symptoms of PD, in A53T PD the score on the olfactory test as well as some specific tests of cognitive function were lower than those in t-PD. In terms of the pattern of cognitive decline, frontal-executive and visuospatial functions are most affected, similar to the distinct profile of PD cognitive syndrome.
4) Regarding sleep disorders, 90% of A53T-PDs had at least one sleep disorder and 40% had two. No asymptomatic carrier had a confirmed sleep disorder. 6/7 A53T-PD with RBD had hyposmia and 4/7 had cognitive dysfunction. There was an association of both decreased olfaction and cognitive dysfunction with the presence of RBD.
5) The 3 groups were comparable for sex, age, disease duration, H&Y or MOCA performance. 87, 5% of A53T-PD had AUT≥2, significantly higher compared to 25% of GBA-PD and higher but not statistically significant compared to 40% of i-PD. SCOPA AUT was significantly higher only in GBA-PDs compared to i-PDs. SCOPA-C was significantly higher in both genetic PD forms compared to i-PDs. No differences were observed between the groups in terms of scores on the various non-invasive autonomic function tests in the laboratory.
6) Regarding non-motor symptoms in asymptomatic carriers, olfaction was more impaired and anxiety was marginally more severe in A53T-AC versus HC. A positive correlation was also found between the score on the olfaction test and the score on the cognitive function test in A53T-AC but not in HC.
CONCLUSIONS:
1) In the above study we confirm features of GBA-PD that demonstrate a more severe Parkinson's disease than GU-PD, especially in the domain of cognitive functions. The fact that the two groups were matched for age and disease duration did not allow us to determine in this study whether the presence of the GBA1 mutation in patients with Parkinson's disease is associated with earlier disease onset. Regarding the finding of more frequent symmetric onset of disease in GBA-PD should be taken with caution due to study limitations.
2) PD patients harboring the p.A53T SNCA mutation show evidence of a more severe nigrostriatal denervation, especially evident in the caudate nucleus. The lack of significant differences in the putaminal binding ratios may reflect a floor effect or a true preferential targeting of the caudate terminals in p.A53T SNCA associated PD.
3) The observed selective cognitive impairment reflecting frontal-parietal network dysfunction, together with impaired olfaction, define a set of nonmotor dysfunctions related to A53T PD. These results have implications for the prognosis of patients with A53T PD.
4) RBD occurs in the majority of PD-A53T, in contrast to most other genetic forms of PD, in which RBD is uncommon. The paucity of a sleep disorder in the asymptomatic carriers suggests that such carriers have not yet reached the prodromal phase when such sleep disorders manifest. Hyposmia in almost all subjects with RBD and cognitive decline in most of them are indicative of the general pattern of disease progression, which however is not uniform.
5) There is some indication that perhaps A53T-PDs have a greater burden on ANS function than GBA-PDs using laboratory ANS tests, and the discrepancy between questionnaire results and laboratory test results suggests that there is a need to use more objective methods to assess ANS.
6) The more affected olfaction in A53T-AC may indicate that olfactory function is affected quite early in A53T carriers. The strong positive correlation between UPSIT and MOCA in the A53T-AC group may indicate that cognitive dysfunction and olfactory impairment progress alongside, prior to nigrostriatal degeneration. Anxiety was also more prevalent in A53T-AC and may represent an additional prodromal feature in this group of subjects.
Keywords:
Parkinson's Disease, Monogenic forms of Parkinson's Disease, Phenotype, Genotype, Alpha-synuclein
