Spyridon Papapetropoulos

SRRM2, a Potential Blood Biomarker Revealing High Alternative Splicing in Parkinson's Disease

Background Parkinsons disease (PD) is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms. Methodology/Principal Findings We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300), sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008) upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03) and amygdala (p = 0.003). To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls) and found a significant upregulation of the upstream (5′) exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04) of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression) in PD blood versus controls. Conclusions/Significance The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease.

The effect of vascular disease on late onset Parkinson's disease

The clinical severity of late onset Parkinsons disease (PD) varies from patient to patient and it is further complicated by the increasing prevalence of accompanying disorders in the elderly. We set out to study the impact of ischemic heart disease, minor stroke, hypertension and diabetes mellitus in a group of late onset PD patients (age ≥70 years). Consecutive late onset PD patients seen in the Department of Neurology, Medical School of Patras, Greece were included in this study. We used very strict criteria to eliminate the possibility of including patients with vascular parkinsonism. Comparisons were made between groups of patients suffering with idiopathic Parkinsons disease (IPD) and the above‐mentioned diseases. One hundred and sixty‐seven consecutive late onset PD patients were included in this study. The most common accompanying disorders in our group were hypertension in 31 (18%) of the patients and minor stroke in 20 (12%). The Hoen and Yahr score in late onset IPD patients who suffered from minor stroke, ischemic heart disease or diabetes mellitus was significantly higher when compared with patients without the above disorders. The results clearly suggest that the presence of vascular disease on an IPD patient may aggravate PD severity. In clinical grounds, these findings can be proved significant since early and aggressive prevention of vascular disease and treatment of vascular risk may contribute in controlling symptom severity in PD.

Patient Diaries As a Clinical Endpoint in Parkinson's Disease Clinical Trials

Parkinsons disease (PD) is the second most common neurodegenerative disorder with an estimated 4 million patients worldwide. L‐dopa is standard, and often initial, therapy for patients with this condition; however, with continued dopaminergic treatment and as the disease progresses, the majority of patients experience complications such as “wearing‐off” symptoms, dyskinesias, and other motor complications. These complications may become disabling and profoundly affect quality of life. Treatment modification and combination therapies with L‐dopa, dopamine agonists, monoamine oxidase type B inhibitors, and catechol‐O‐methyltransferase inhibitors are commonly used to manage complications. In recent years regulatory agencies, clinical researchers, and sponsors have widely accepted and utilized changes in “ON” and “OFF” time measured by Patient Hauser Diaries as endpoints for measuring efficacy of therapeutics seeking approval for symptomatic treatment of PD. Successful antiparkinsonian medications have been associated with treatment effects of more than 1 h in either reduction of “OFF” time of increase in “ON” time. Accurate “ON” and “OFF” time registration during clinical studies requires rigorous patient training. Reduced compliance, recall bias and diary fatigue are common problems seen with patient diary reported measures. Electronic diaries may help reducing some of these problems but may be associated with other challenges in large, multicenter studies.

Descriptive Epidemiology of Cervical Dystonia

Background Cervical dystonia (CD), the most common form of adult-onset focal dystonia, has a heterogeneous clinical presentation with variable clinical features, leading to difficulties and delays in diagnosis. Owing to the lack of reviews specifically focusing on the frequency of primary CD in the general population, we performed a systematic literature search to examine its prevalence/incidence and analyze methodological differences among studies. Methods We performed a systematic literature search to examine the prevalence data of primary focal CD. Sixteen articles met our methodological criteria. Because the reported prevalence estimates were found to vary widely across studies, we analyzed methodological differences and other factors to determine whether true differences exist in prevalence rates among geographic areas (and by gender and age distributions), as well as to facilitate recommendations for future studies. Results Prevalence estimates ranged from 20–4,100 cases/million. Generally, studies that relied on service-based and record-linkage system data likely underestimated the prevalence of CD, whereas population-based studies suffered from over-ascertainment. The more methodologically robust studies yielded a range of estimates of 28–183 cases/million. Despite the varying prevalence estimates, an approximate 2:1 female:male ratio was consistent among many studies. Three studies estimated incidence, ranging from 8–12 cases/million person-years. Discussion Although several studies have attempted to estimate the prevalence and incidence of CD, there is a need for additional well-designed epidemiological studies on primary CD that include large populations; use defined CD diagnostic criteria; and stratify for factors such as age, gender, and ethnicity.

Contemporary Encephalitis Lethargica: Phenotype, laboratory findings and treatment outcomes

BackgroundEncephalitis lethargica (EL) is a CNS disorder that manifests with lethargy sleep cycle disturbances, extrapyramidal symptomatology, neuropsychiatric manifestations, ocular features and cardio-respiratory abnormalities. Although there have been no reported outbreaks of EL recently, a number of reports show that cases of EL are still encountered regularly. Against this background we conducted a study aiming to elucidate the clinical characteristics, describe laboratory/ neuroimaging findings (MRI, PET) and present treatment options and outcomes in sporadic EL.MethodsPatients were diagnosed over a period of 3 years using proposed diagnostic criteria. Extensive laboratory and imaging tests were performed for exclusion of other causes. Anti-neuronal antibodies against human basal ganglia were detected with western immunoblotting and 18F-FDG PET imaging was performed. Selected cases were videotaped.ResultsOur patients (M/F: 5/3) ranged from 2–28 years (mean 9.3 ± 9.5). Encephalopathy, sleep disturbances and extrapyramidal symptoms were present in all cases. Laboratory investigations revealed CSF leukocytosis in 5/8 patients and anti-BG Ab in 4/7 patients. MRIs revealed structural abnormalities in 7/8 cases. 18F-FDG PET showed basal ganglionic hypermetabolism in 4/7 patients. Treatment approaches included immunomodulating and symptomatic therapies. We report no mortality from EL in our series.ConclusionsThere seems to be little doubt that cases of EL still occur. Diagnosis may be based on clinical suspicion and laboratory/imaging tests may lead to early initiation of immunomodulating and supporting therapies. We suggest that in addition to anti-BG Abs FDG PET should be considered as a diagnostic tool for EL.

Past tense formation and comprehension of passive sentences in Parkinson’s disease: Evidence from Greek

The present study investigates the production of regular and irregular verbs in the past tense and the comprehension of passive sentences by Greek-speaking PD patients, and compares their behavior to that of normal speakers. Although the two groups manifest large scale differences at all the above constructions, the behavior of PDs is not different at regular vs. irregular past tense formation neither did we obtain strong evidence that they do not comprehend passives, most importantly, they certainly do not perform at chance. On the basis of the above, we conclude that there are no indications for a clearly linguistic deficit of the PD group, hence, their difference with the control group should be attributed to other factors, such as the computational demands of the tasks.

Gastric stasis in migraineurs: Etiology, characteristics, and clinical and therapeutic implications

Background Migraine is a disabling neurological disorder often complicated by gastrointestinal conditions such as gastric stasis. The association between migraine and gastric stasis has received very little attention in the literature, but the existing evidence suggests that they may share a common etiology. Results Patients with migraine and those with gastric stasis exhibit abnormal autonomic nervous system function. Furthermore, empirical studies demonstrate that migraineurs experience significant delays in gastric emptying, both during and outside of attacks, when compared to non-migrainous controls. Conclusion More research is needed to establish the relationship between gastric stasis and migraine burden and to determine the impact of gastric stasis on migraine treatment.

Objective monitoring of tremor and bradykinesia during DBS surgery for Parkinson disease

Objective: High-frequency subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for patients with advanced Parkinson disease (PD). To date, intraoperative monitoring of parkinsonian symptoms, such as tremor and bradykinesia, is largely based on subjective strategies. We conducted a pilot study to evaluate short-term intraoperative outcomes of unilateral macrostimulation of the STN-DBS in PD patients using a neuromotor symptom registration device (CATSYS 2000 System). Methods: We studied 12 consecutive PD patients who received staged unilateral STN-DBS implants and 10 male control subjects free of neurologic deficits using a simple portable system with two sensors: a tremor pen and a touch recording plate. Results revealed excellent test–retest reliability for postural tremor in control subjects. PD patients were evaluated preoperatively during “off” state and intraoperatively for rest, postural tremor intensity, and frequency of finger tapping. Comparisons between premacrostimulation and postmacrostimulation were made using analysis of variance for repeated measures. Results: Electronic rest tremor registration revealed a mean improvement of ×12.5 in tremor intensity measurements in the stimulated/contralateral side (p = 0.002). An overall ×3.8 improvement was registered on the nonstimulated/ipsilateral side. Significant improvements after STN-DBS were also recorded for postural tremor and frequency of finger tapping. Conclusion: Using a noninvasive, simple, and sensitive electronic recording method of intraoperative motor symptom registration, we were able to supplement short-term clinical observation by objectively quantifying the characteristics of tremor and finger tapping in response to subthalamic nucleus deep brain macrostimulation.

Expression of Lewy body protein septin 4 in postmortem brain of Parkinson's disease and control subjects.

In Parkinsons disease (PD) neuronal degeneration is associated with abnormal protein aggregation in various forms including Lewy bodies (LBs). A major component of LBs is α‐synuclein; septin 4 (SEPT4), a polymerizing GTP‐binding protein that serves as scaffold for diverse molecules has been found to colocalize with α‐synuclein in LBs. The central role of SEPT4 in the etiopathogenesis of PD has been suggested since SEPT4 also shows a physiological association with α‐synuclein and serves as a substrate for parkin. To this end, we studied the expression of septin 4 and α‐synuclein in postmortem human substantia nigra (SN) and amygdala from patients with PD and healthy controls. Twenty patients (14 men : 6 women, onset 63.0 ± 11.4 years, age 77.3 ± 7.6 years, Hoehn and Yahr 4.05/5) and 9 neurologically healthy controls (4 men/5 women, age at death 80.1 ± 8.6 years) were studied. Sporadic PD cases showed a statistically significant decrease of the fold change (FC) of SNCA (FC = 0.31, P = 0.00001) and SEPT4 (FC = 0.67, P = 0.054) gene expressions in the SN and the amygdala (SNCA: FC = 0.49, P = 0.02; SEPT4: FC = 0.32, P = 0.007) versus healthy controls. However, an increase of both proteins in PD versus control subjects was observed with immunoblotting. The semi‐quantitative protein ratio calculations revealed more than 10‐fold increases for both SEPT4 and α‐synuclein in PD versus control subjects. We present for the first time similar signal expression patterns and parallel accumulation of SEPT4 and α‐synuclein in well‐characterized postmortem PD brain. Considering the heterogeneous etiology of sporadic PD and the variability of individual human samples, SEPT4 accumulation may be regarded as one of the common pathological changes in PD and should therefore be further explored.

Objective Quantification of Neuromotor Symptoms in Parkinson's Disease: Implementation of a Portable, Computerized Measurement Tool

Quantification of neuromotor symptoms with device-based measures provides a useful supplement to clinical evaluation. Research using the CATSYS has established its utility as a computerized measurement system to quantify neuromotor function. The primary objective of this study is to provide technical guidance on the use of the CATSYS in Parkinsons disease (PD). Forty-four patients with idiopathic PD and 28 healthy controls were prospectively recruited and evaluated with CATSYS, a portable, Windows-based system consisting of a data logger and four different sensors (tremor pen, touch recording plate, reaction time handle, and force plate for balance recording) for quantification of neuromotor functions. CATSYS discriminated between PD and controls on measurements of rest/postural tremor, pronation/supination, finger tapping, simple reaction time, and postural sway intensity and velocity. CATSYS measurements using the proposed test battery were associated with relevant clinician-rated Unified Parkinsons disease rating scale (UPDRS) items assessing tremor and bradykinesia. More work is warranted to establish CATSYS as a diagnostic/monitoring instrument in movement disorders using the proposed technical approaches.