Parkinson Disease: Papapetropoulos S

Post KK, Singer C, Papapetropoulos S. · Division of Movement Disorders, Department of Neurology, University of Miami, Miller School of Medicine, Clinical Research Building, 1120 N.W. 14th Street, 13th Floor, Room 1349, Miami, FL 33136, USA. · Parkinsonism Relat Disord. · Pubmed #18486523 No free full text.

Abstract: Parkinson's disease (PD) has classically been characterized by features of motor dysfunction, but these may manifest only after the nigrostriatal system has incurred significant damage. However, recent evidence suggests that cardiac sympathetic denervation occurs early on in PD. This may trigger a shift in physicians' attention to features of cardiovascular dysautonomia and allow for the evolution of earlier screening techniques. MIBG and PET (6F-DA) scans have demonstrated the functional loss of postganglionic sympathetic cardiac neurons, while immunohistochemical stains have revealed signs of morphological degeneration. Given this information, various screening techniques have been proposed, though most are particular to PD patients with orthostatic hypotension (OH). This is a considerable drawback given that the prevalence of OH in PD patients is estimated to be 41%. We present the argument that a shift in focus is needed; investigators should look for other manners by which to screen patients that are not reliant upon blood pressure. In our point of view, the problem with using blood pressure as a measurement is that it can be affected by many other factors unrelated to cardiac denervation. This may be why many patients with PD cannot be detected using these techniques. In order to make further progress on this front, we believe that investigators should start looking for variables that are more purely dependent upon cardiac denervation. We give one possible example of such a variable in this paper using heart transplant patients as a model.

Papapetropoulos S. · Department of Neurology, University of Miami, Miller School of Medicine, Rm. 4004, 1501 NW 9th Ave., FL 33136, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #16720791 links to  free full text

Abstract: Visual hallucinations in Parkinson's disease are usually treatment-related and occur in at least 30% of patients. Although their clinical and epidemiological features have been extensively reviewed, their etiopathogenesis remains a matter of debate. Based on the current evidence available, this review suggests that regional neurodegeneration of the ventral dopaminergic pathway, as evident in the aggregation of the protein alpha-synuclein, is the main event linked to the development of visual hallucinations in Parkinson's disease. Denervation supersensitivity of dopaminergic receptors in ventral striatal and mesocorticolimbic areas as well as defective synaptic buffering ability due to the loss of dopaminergic presynaptic terminals and dopamine transporter may be among the key factors leading to visual hallucinations in Parkinson's disease.

Papatsoris AG, Deliveliotis C, Singer C, Papapetropoulos S. · 2nd Department of Urology, University of Athens School of Medicine, Athens, Greece. · Urology. · Pubmed #16504269 No free full text.

This publication has no abstract.

Papapetropoulos S, Mash DC. · Department of Neurology, University of Miami, School of Medicine, Room 4004, 1501 NW 9th Avenue, Miami FL 33136, USA. · J Neurol. · Pubmed #15999234 No free full text.

Abstract: Psychotic symptoms are common in Parkinson's disease (PD) and occur in at least 20% of medication-treated patients. Benign visual hallucinations usually appear earlier, while malignant hallucinations, confusional states, delusions, paranoid beliefs, agitation, and delirium become more frequent with disease progression. Virtually all antiparkinsonian drugs may produce psychotic symptoms. Cognitive impairment, increased age, disease duration and severity, depression, and sleep disorders have been consistently identified as independent risk factors for their development. Although the precise pathoetiologic mechanisms remain unknown, we review evidence that links ventral dopaminergic pathway dysfunction (overactivity) together with the involvement of other neurotransmitter system imbalances as likely contributors. The clinical importance of the proposed mechanism is that successful management of psychotic symptoms in PD may rely on a multitarget approach to restore neurotransmitter imbalances rather than focusing exclusively on the dopaminergic dysfunction.

Singer C, Papapetropoulos S, Gonzalez MA, Roberts EL, Lieberman A. · Department of Neurology University of Miami, School of Medicine, Miami, Florida 33136, USA. · Mov Disord. · Pubmed #15809995 No free full text.

Abstract: We report our experience with 7 consecutive patients with Parkinson's disease (PD) who received rimantadine (the alpha-methyl derivative of amantadine) in substitution of amantadine due to peripheral side effects (lower limb edema, livedo reticularis). Mean age was 67.3 +/- 5.9 years, the mean disease duration was 13 +/- 6.3 years, and mean Hoehn and Yahr stage was 2.2 +/- 0.4. A total of 3 patients experienced marked improvement of edema, and 1 patient experienced marked improvement of livedo reticularis. Only 1 of the 7 patients reported significant loss of motor benefit when amantadine was replaced with rimantadine. Our results demonstrate that rimantadine may be considered as an alternative to amantadine in patients experiencing amantadine-induced peripheral side effects.

Shehadeh L, Mitsi G, Adi N, Bishopric N, Papapetropoulos S. · Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. · Mov Disord. · Pubmed #18951507 No free full text.

Abstract: In Parkinson's disease (PD) neuronal degeneration is associated with abnormal protein aggregation in various forms including Lewy bodies (LBs). A major component of LBs is alpha-synuclein; septin 4 (SEPT4), a polymerizing GTP-binding protein that serves as scaffold for diverse molecules has been found to colocalize with alpha-synuclein in LBs. The central role of SEPT4 in the etiopathogenesis of PD has been suggested since SEPT4 also shows a physiological association with alpha-synuclein and serves as a substrate for parkin. To this end, we studied the expression of septin 4 and alpha-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 alpha-synuclein in PD versus control subjects. We present for the first time similar signal expression patterns and parallel accumulation of SEPT4 and alpha-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.

Papapetropoulos S, Adi N, Shehadeh L, Bishopric N, Singer C, Argyriou AA, Chroni E. · Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA. · J Clin Neurosci. · Pubmed #18617409 No free full text.

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, especially the G2019S mutation, have been identified as a common cause of Parkinson's disease in southern European and other Mediterranean populations (Iberians, Ashkenazi Jews and North African Arabs). Owing to the geographic and historic vicinity of Greece with areas of high prevalence of LRRK2 mutations we studied the frequency of the G2019S mutation in a well characterized cohort of familial and sporadic Parkinson's disease patients of Greek origin from mainland Greece. The prevalence of the LRRK2 R1441C mutation and the G2385R Asian polymorphism was also determined. We identified no patients with any of the studied mutations/polymorphisms. Very low prevalence of the LRRK2 G2019S mutation has been reported in other southern European populations. LRRK2 mutations appear to be limited in certain populations and differing ancestry and founder effects may explain the reported variability. Accurate estimations of the frequency and penetrance of different LRRK2 mutations are essential for correct and cost-efficient use of genetic testing and proper genetic counseling of patients with Parkinson's disease.

Papapetropoulos S, Katzen H, Schrag A, Singer C, Scanlon BK, Nation D, Guevara A, Levin B. · Divisions of Movement Disorders Department of Neurology, University of Miami, Miller School of Medicine Miami, FL, USA. · BMC Neurol. · Pubmed #18570642 links to  free full text

Abstract: BACKGROUND: Hallucinations occur in 20-40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings. METHODS: The UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons. RESULTS AND DISCUSSION: Seventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles. CONCLUSION: Using the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations.

Papapetropoulos S, Jagid JR, Sengun C, Singer C, Gallo BV. · Division of Movement Disorders, Department of Neurology, University of Miami, Miller School of Medicine, 1120 NW 14th Street, Room 1349, Miami, FL 33136, USA. · Neurology. · Pubmed #18391156 No free full text.

Abstract: 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 x 12.5 in tremor intensity measurements in the stimulated/contralateral side (p = 0.002). An overall x 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.

Lesnick TG, Sorenson EJ, Ahlskog JE, Henley JR, Shehadeh L, Papapetropoulos S, Maraganore DM. · Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. · PLoS One. · Pubmed #18197259 links to  free full text

Abstract: BACKGROUND: We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD. METHODOLOGY/PRINCIPAL FINDINGS: Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60)), survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74)), and age at onset of ALS (R(2) = 0.86, p = 5.96x10(-66)). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively. CONCLUSIONS/SIGNIFICANCE: Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

Papapetropoulos S, Adi N, Ellul J, Argyriou AA, Chroni E. · Department of Neurology, Regional University Hospital of Patras, Patras, Greece. · Neurodegener Dis. · Pubmed #17934325 No free full text.

Abstract: BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Most cases are sporadic but about 10-15% of patients have a positive family history of PD. OBJECTIVE: To compare clinical phenotypes between familial (fPD) and sporadic (sPD) PD patients. METHODS: Fifty-nine consecutive patients with at least one first-degree relative with PD were prospectively studied. After exclusion of 9 PD patients with positive family carrying known disease causing mutations, the remaining 50 were compared with 50 age- and sex-matched sPD patients. RESULTS: Despite our methodological approach (strict diagnostic criteria, validated scales, structured interviews, multi- and two-member group formation and exclusion of patients with identifiable mutations) no major differences in the clinical phenotype between fPD and sPD were found. CONCLUSION: Similar phenotypic characteristics of motor signs and symptoms suggest that at least the topography of the neurodegenerative insult leading to the parkinsonian clinical syndrome in fPD and sPD is similar. Similar etiologies are also suggested.

Lesnick TG, Papapetropoulos S, Mash DC, Ffrench-Mullen J, Shehadeh L, de Andrade M, Henley JR, Rocca WA, Ahlskog JE, Maraganore DM. · Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America. · PLoS Genet. · Pubmed #17571925 links to  free full text

Abstract: While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 x 10(-38)), survival free of PD (hazards ratio = 19.0, p = 5.43 x 10(-48)), and PD age at onset (R(2) = 0.68, p = 1.68 x 10(-51)). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

Papapetropoulos S, Farrer MJ, Stone JT, Milkovic NM, Ross OA, Calvo L, McQuorquodale D, Mash DC. · Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL 33136, United States. · Neurosci Lett. · Pubmed #17204369 No free full text.

Abstract: Overlaps in clinical, pathological and molecular features of Parkinson's disease (PD), dementing and motor tauopathies have prompted association studies in search of common genetic risk factors that may predispose or modify this spectrum of disorders. To explore possible phenotypic implications, we studied common tau and ApoE gene polymorphisms, associated with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and PD, in a clinically and pathologically characterized cohort of PD patients and aged control subjects. Our results reveal a novel association between PD-related hallucinations and H1H1 genotype. We also report an association between PDD and the presence of the ApoE epsilon4 allele. Better determination of subsets of PD patients based upon the presence of specific phenotypic features may improve the accuracy of association studies.

Papapetropoulos S, Ffrench-Mullen J, McCorquodale D, Qin Y, Pablo J, Mash DC. · Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA. · Gene Expr. · Pubmed #17193926 No free full text.

Abstract: Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinson's disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.

Papapetropoulos S, Mash DC. · Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA. · J Neural Transm. · Pubmed #17146589 No free full text.

Abstract: Treatment-related motor fluctuations (MFs) and dyskinesias are considered one of the most important problems in the long-term management of Parkinson's disease (PD). However, only a few studies have focused on their characteristics during advanced and end stages of the disease. We therefore assessed MFs and dyskinesias in a cohort of 61 late/end stage patients with a clinical and pathological diagnosis of PD and investigated the influence of disease- and treatment-related variables on their occurrence. A total of 62.3% of our patients experienced "wearing-off" phenomena, 68.9% "on-off" motor fluctuations and 60.7% dyskinesias at advanced/end stage disease. Age at disease onset and disease duration were significantly associated with dyskinesias. A substantial number of patients experienced spontaneous resolution of their motor complications during the last two years of their disease without treatment modifications.The clinical heterogeneity of treatment-related motor complications in PD points towards a complex mechanism for their etiopathogenesis. Although advanced disease and L-dopa administration are closely tied to their development, other mechanisms involving synaptic aging, altered neuronal plasticity and post-synaptic degeneration may be involved.

Golbe LI, Di Iorio G, Markopoulou K, Athanassiadou A, Papapetropoulos S, Watts RL, Vance JM, Bonifati V, Williams TA, Spychala JR, Stenroos ES, Johnson WG. · Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17034008 No free full text.

Abstract: Monogenic forms of Parkinson's disease (PD) provide an opportunity to examine mechanisms underlying phenotypic variation. Glutathione S-transferase (GST) has detoxification and antioxidative functions. To screen genetic variations in GST for an effect on the onset age (OA) of PD, we typed seven common genetic polymorphisms in five GST isoenzymes, M1, M3, P1, T1, and Z1, in 36 affected individuals of Italian or Greek origin with the alpha-synuclein A53T (PARK1) mutation. Mean OA was 45.2 years with a wide SD of 11.03 years, similar to that of idiopathic PD. Our allelic analysis showed that the subjects homozygous for the GSTP1 G-for-A nucleotide substitution at position 313 had a mean OA acceleration of 15.2 years (31.3 +/- 7.09 years, n = 3 vs. 46.5 +/- 10.50 years, n = 33, P = 0.020). The GSTP1 C341T substitution was associated with a 9.7-year acceleration of OA, but the significance was borderline (36.4 +/- 8.35 years vs. 46.7 +/- 10.85 years, P = 0.0519). After correction for the five genes examined, both results lose statistical significance. Nevertheless, our results suggest that further investigation in GSTP1 variants and PD pathogenesis is warranted in sporadic PD and that a search for toxins that accelerate PD OA should pay particular attention to GST-P1 substrates.

Papapetropoulos S, Singer C, Ross OA, Toft M, Johnson JL, Farrer MJ, Mash DC. · Department of Neurology, University of Miami School of Medicine, Miami, FL, USA. · Arch Neurol. · Pubmed #16966501 links to  free full text

Abstract: BACKGROUND: Several pathogenic mutations have been reported in the leucine-rich repeat kinase 2 gene (LRRK2) that cause parkinsonism. The "common" LRRK2 G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease. OBJECTIVE: To observe the clinical heterogeneity presented by LRRK2 kinase mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: We screened 130 patients with pathologically confirmed Parkinson disease and 85 controls for 3 LRRK2 kinase domain pathogenic substitutions: I2012T, G2019S, and I2020T. MAIN OUTCOME MEASURES: Detailed clinical phenotypes for individuals who screened positive for LRRK2 mutations. RESULTS: Five LRRK2 G2019S carriers were identified, of whom 4 had Parkinson disease (clinically and pathologically confirmed), and the fifth was a control subject who died at age 68 years after an acute myocardial infarction with no evidence of neurodegenerative abnormalities. There was no evidence of the I2012T or I2020T mutation in these participants. CONCLUSIONS: The underlying disease mechanisms of LRRK2 G2019S-associated parkinsonism are similar to those of typical Parkinson disease. The identification of a control subject raises important questions concerning genetic diagnosis and counseling.

Papapetropoulos S, Mash DC. · Department of Neurology, University of Miami, Miller School of Medicine, Room 4004, 1501 NW 9th Avenue, Miami, FL 33136, USA. · Parkinsonism Relat Disord. · Pubmed #16962365 No free full text.

Abstract: Orthostatic hypotension (OH) in Parkinson's disease (PD) patients may be a significant source of morbidity and discomfort. Although peripheral ANS components have been associated with its development, central mechanisms are probably involved. The insular cortex is a central site of autonomic and limbic integration and neuropathologic studies have indicated its involvement in the neurodegenerative process of PD. To this end, we studied the neuropathology of the insular, temporal and parietal cortices in PD patients with and without OH. Our results suggest an association between the severity of PD-related neuropathology in the insular cortex and OH. Further research into the subject is warranted.

Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Krüger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C, Anonymous00088. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA. · JAMA. · Pubmed #16896109 links to  free full text

Abstract: CONTEXT: Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. OBJECTIVE: To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. DESIGN, SETTING, AND PARTICIPANTS: We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. MAIN OUTCOME MEASURES: Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. RESULTS: Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55). CONCLUSION: This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.

Papapetropoulos S, Lieberman A, Gonzalez J, Singer C, Laufer DZ, Mash DC. · Department of Neurology, University of Miami, Miller School of Medicine, Miami Fl, 33136, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #16525079 links to  free full text

Abstract: Parkinson's disease with dementia (PD-D) and dementia with Lewy bodies (DLB) may result from the same neurodegenerative process with different temporal and spatial courses. The authors report an association between DLB and family history of dementia in a comparison study between patients with a clinicopathological diagnosis of PD-D and DLB. Findings suggest that positive family history for dementia is associated with DLB with a yet unknown mechanism.

Papapetropoulos S, Gonzalez J, Mash DC. · No affiliation provided · Eur J Neurol. · Pubmed #16420403 No free full text.

This publication has no abstract.

Papapetropoulos S, McCorquodale DS, Gonzalez J, Jean-Gilles L, Mash DC. · Department of Neurology, Miller School of Medicine, University of Miami, 1501 NW 9th Avenue (NPF), Room 4004, Miami, FL 33136, USA. · Parkinsonism Relat Disord. · Pubmed #16368258 No free full text.

Abstract: Visual hallucinations (VH) are among the most common non-motor complications of Parkinson's disease (PD). A few studies on their etiopathogenesis have suggested involvement of cortical and amygdalar areas. In order to investigate the possible association between extranigral Lewy Body (LB) distribution across cortical and amygdalar regions and the presence of VH in PD brain donors, we conducted a clinico-pathological comparison of 10 PD patients with VH vs 10 closely matched PD patients without VH. The LB burden was significantly higher across the amygdala and the frontal, temporal and parietal cortical areas in patients with VH. Although our results suggest significant extranigral involvement, the precise etiopathologic mechanisms responsible for the development of VH need further clarification.

Singer C, Papapetropoulos S. · Department of Neurology, University of Miami, Miller School of Medicine, School of Medicine 1501 NW 9th Avenue Miami, FL 33136, USA. · J Neurol Sci. · Pubmed #16182312 No free full text.

Abstract: Fixed dystonic posturing of the hands and feet may complicate advanced Parkinson's disease (PD) and add considerably to the functional disability of patients. We report 3 PD patients who developed lower limb fixed dystonic posturing after a brief period of immobilization (<2 months). Two patients had been immobilized after hip and back injuries and one for transfusion therapy for anemia. This fixed dystonic posturing resulted in severe functional disability. Oral medications failed to control symptoms. Of two patients who received botulinum toxin injections only one experienced benefit. Orthopedic surgery resulted in clinical improvement with increased mobility and independence in one patient. Post-immobilization dystonia of lower limbs in PD is resistant to medical treatment and leads to significant functional disability. Botulinum toxin may provide partial relief in some cases and orthopedic surgery can also be considered.

Papapetropoulos S, Singer C, McCorquodale D, Gonzalez J, Mash DC. · Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA. · Parkinsonism Relat Disord. · Pubmed #16154793 No free full text.

Abstract: The aim of this study was to investigate the causes and seasonality of death and co-morbid conditions among progressive supranuclear palsy (PSP) patients. 22 consecutive clinicopathologically confirmed PSP patients were compared with 22 gender and age-matched Parkinson's disease (PD) patients and 26 non-neurological controls. All subjects consented during life to donate their brains to the University of Miami Brain Endowment Bank. Respiratory-related deaths were significantly more frequent in PSP when compared to PD patients. Recurrent respiratory infections were also very frequent in PSP patients and were commonly associated with respiratory-related deaths. Deaths that occurred during winter and spring months accounted for about 70% of deaths among PSP patients. The most common co-morbid condition in PSP was hypertension, present in 50% of cases.

Papapetropoulos S, Ellul J, Argyriou AA, Chroni E, Lekka NP. · Department of Neurology, Medical School of Patras, Greece; Department of Neurology, University of Miami, School of Medicine, Room 4004, 1501 NW 9th Avenue, Miami, FL 33136, USA. · Clin Neurol Neurosurg. · Pubmed #16150537 No free full text.

Abstract: OBJECTIVES: Approximately 40% of patients with Parkinson's disease (PD) experience symptoms of depression. Our aim was to evaluate the effect of depression on disease severity, motor function and other phenotypic characteristics of PD. PATIENTS AND METHODS: We studied 32 PD patients with major depression (PD-D) according to the DSM-IV criteria and 32 PD patients with no depression (PD-C) matched for gender, age of onset and duration. RESULTS: Major depression in PD patients was associated with increased disease severity, poorer motor function and worse performance in the activities of daily living as measured by UPDRS scores. Furthermore, there was an association of depression with the severity of bradykinesia and axial rigidity. CONCLUSIONS: Depression in PD can have a profound negative impact on a patient's sense of wellbeing and motor functioning. Therefore, PD patients should be routinely and carefully screened for the presence of depression and appropriate management should be considered. Larger studies on the subject are warranted.